CHAPTER
90
Disorders of the Body Mass
90.1 OVERVIEW
There are numerous human conditions that produce
both elevated and reduced body mass, and extremes at
both ends of the body-size spectrum are associated with
increased relative risk of mortality (1). This chapter
will be devoted to increased body mass associated with
excess fat stores (obesity). Obesity-associated comorbidi-
ties include significantly increased risks for diabetes, car-
diovascular disease, the “metabolic syndrome,’’ cancer
(2), respiratory disease (asthma, sleep apnea), infertil-
ity, degenerative joint disease, depression, anxiety, and
discrimination both in social life and in the workplace.
It is likely that diabetes-related morbidities will contrib-
ute most to the disabilities related to obesity (3). The
metabolic syndrome, defined as the combined presence
of obesity, hyperinsulinemia, hypertension, and hyper-
lipidemia, is increasing in prevalence in parallel with
obesity in adults (4) and in youth (5,6). For the first
time in known history, the life expectancy in the United
States may potentially decline because of, in large part,
the obesity epidemic (7). The etiology of human obesity
is undoubtedly multifactorial, reflecting complex interac-
tions between genetic background, environmental condi-
tions, and developmental processes.
90.1.1 Definition
Centers for Disease Control and Prevention (CDC)
defines individuals as obese whose body mass index
(BMI) (weight in kilograms divided by the square of the
height in meters; kg/m2) exceeds the age- and sex-specific
95th percentile. Those who have a BMI between the 85th
and 95th percentiles are overweight and are at increased
risk for obesity-related comorbidities. High BMI corre-
lates well with excess body fat in all age groups and in
both genders, with the exception of persons with very
high muscle mass (e.g. “body builders”). A cutoff of
© 2013, Elsevier Ltd. All rights reserved.
Patricia A Donohoue and Omar Ali
Medical College of Wisconsin, Milwaukee, WI, USA
>30 kg/m2 is accepted as defining obesity in adult Ameri-
cans. For growing children, age- and sex-specific BMI
standards are used (Figure 90-1).
In the past, the CDC recommended that the term obe-
sity be avoided, and that the following terms be used:
At risk for overweight—BMI between the 85th and 95th
percentile for age and gender; overweight—BMI higher
than 95th percentile for age and sex. But in 2010, based
on the recommendations of an AMA expert panel, it
was decided that the terminology for children would be
the same as that used in adults, i.e. children whose BMI
ranges from the 85th to 95th percentile for age and sex
would be classified as overweight and those who exceed
the 95th percentile will be classified as obese (8).
The regulation of body fat stores is complex, and is
controlled by the interaction of environment and genetic
background. The great importance of environmental fac-
tors on body size is underscored by the marked increase
in obesity prevalence over the past 30 years, a time period
whose brevity most certainly did not allow for a signifi-
cant change in the gene pool. The prevalence of obesity
is increasing at a dramatic rate. This is illustrated in a
dramatic animation of US obesity prevalence by states
compiled by the CDC (http://www.cdc.gov/obesity/data/
trends.html). The prevalence is significantly higher, and
the trend is even more pronounced, in American minor-
ity groups, particularly in females. This is not only occur-
ring in adults (9) (Figure 90-2), but in youth as well (5)
(Table 90-1). There is some indication that the trend may
be flattening in some groups, but in others, the preva-
lence of overweight and obesity continues to rise. This
pattern has been observed throughout the United States
(10–12), has accelerated over the past 15  years, and is
mirrored by a rise in the prevalence of type 2 diabetes
mellitus in adults and youth. International trends paral-
lel those of the United States (13,14). The prevalence in
a given population, such as China, must be determined
1
2 CHAPTER 90  Disorders of the Body Mass
FIGURE 90-1  Childhood BMI curves, age 2–20 years. A. BMI for age, boys. http://www.cdc.gov/growthcharts/data/set1clinical/cj41c021.pdf.
using population-specific standards in order to avoid
underestimating the scale of the problem (15).
The impact of environment on the epidemic of obesity
includes unfavorable trends in food intake and physical
activity, as well as barriers to reversing these trends (16).
The impact of environment on body size is also under-
scored by the development of obesity in patients who
have survived leukemia (17,18), or who have suffered
hypothalamic damage (19), especially patients treated
for craniopharyngioma (20). In addition, a human virus
has been implicated in the etiology of animal obesity
(21,22) and human obesity (23).
While this pronounced secular trend is almost cer-
tainly environmental, it is also clear that there is a sig-
nificant heritable component in obesity risk, and that this
genetic component explains up to 80% of the variation
in BMI within a given environment. This genetic risk
of obesity may have been acquired during the stage of
human evolution when acquisition of food was achieved
through strenuous activity (hunting, digging, etc.), and
periods of prolonged fasting and famine were constant
threats, that genotypes were enriched to favor energy
storage. In the current environment of plentiful and eas-
ily accessible high-calorie food, these so-called “thrifty

FIGURE 90-1  cont’d. B. BMI for age, girls. http://www.cdc.gov/growthcharts/data/set1clinical/cj41c022.pdf.
genotypes” are highly prevalent and, unfortunately,
are now detrimental. This evolutionary pressure to pre-
vent weight loss has led to the “absence of protection”
(against weight gain) model of genetic control of obe-
sity. Another model, termed the “Central Resistance”
model, suggests that human genetic background would
provide equal defenses against weight gain or loss, but
that additional genetic or acquired defects impair the
homeostatic control (24). In addition to absolute differ-
ence in BMI, body composition and the distribution of
body fat also play an important role in the development
of obesity-related morbidities (25) and variation in body
CHAPTER 90  Disorders of the Body Mass 3
fat distribution also includes a genetic component (26).
Body fat may be preferentially located in the abdomen
(android or central obesity pattern) or surrounding the
hips and thighs (gynoid obesity pattern). The android
obesity pattern is more strongly associated with dyslip-
idemia, hypertension, and glucose intolerance (27), and
is associated with increased intra-abdominal or visceral
fat stores. This is the complex of features known as the
metabolic syndrome. Thus, even at the same level of
overweight, an individual with a greater amount of vis-
ceral fat is more likely to have or develop serious health
consequences associated with obesity.
4 CHAPTER 90  Disorders of the Body Mass

(A) 40

Overweight

30

Obese
Percentage

20

10

Extremely obese

0
1988–1994 1999–2000 2003–2004 2007–2008
2001–2002 2005–2006
Years

(B) 40

Overweight

30
Percentage

20

Obese

10

Extremely obese
0
1960–1962 1971–1974 1976–1980 1988–1994 1999–2000 2007–2008
2003–2004
Years
FIGURE 90-2  A. Trends in overweight, obesity, and extreme obesity among adults aged 20 years and over: United States, 1988–2008.
B. Trends in overweight, obesity, and extreme obesity among adults aged 20–74 years: United States, 1960–2008.

90.1.2 Heritability of BMI a significant correlation of BMI in biological sibs across

The important influence of heredity on human body size
has been demonstrated in multiple studies of dizygotic and
monozygotic twins, and of adopted individuals and their
biological siblings (28). Studies of twin pairs have con-
sistently demonstrated higher concordance for body size
among monozygotic than dizygotic twins. In a study of
1974 monozygotic and 2097 dizygotic pairs, concordance
for body size at six different degrees of overweight (15,
20, 25, 30, 35, and 40% overweight) at approximately
20 years of age were 1.9–3.6-fold higher for monozygotic
than dizygotic pairs (29). In a study of adult adoptees and
their biological siblings, both full and half sibs, there was
the entire distribution of body sizes. This correlation was
much stronger for the full sibs (30). In a study of pediat-
ric twins, there was a genetic contribution to percentage
body fat (PBF) measured by bioelectric impedance that
was distinct from the genetic contribution to BMI. This
contribution accounted for 75–80% of the variation in
PBF, and 62.5% of the total genetic variation in PBF was
due to genes that influenced PBF but not BMI (31).
In phenotypic analyses of large unrelated populations,
there is statistical evidence for recessive gene effects on
body size variables, though the specific genes were not
identified. Some examples include BMI in Muscatine,
 CHAPTER 90  Disorders of the Body Mass 5

(C) 50
1988–1994 2007–2008

40

30
Percentage

20

10

0
Non-Hispanic white Non-Hispanic black Mexican American
Race/ethnicity

(D) 50
1988–1994 2007–2008

40

30
Percentage

20

10

0
Non-Hispanic white Non-Hispanic black Mexican American
Race/ethnicity
FIGURE 90-2  cont’d. C. Prevalence of obesity among men aged 20 years and older, by race and ethnicity: United States, 1988–1994 and
2007–2008. D. Prevalence of obesity among women aged 20 years and over, by race/ethnicity: United States, 1988–1994 and 2007–2008.
All figures available in Reference (9).

Iowa (32), BMI in Caucasian and African-American
families (33), abdominal visceral fat in Québec (34),
relative fat pattern in Utah pedigrees (35), and obesity in
American Pima Indians (36).
Studies to identify factors contributing to the genetic
epidemiology of childhood obesity have been undertaken
using the population of Muscatine, Iowa. This population
has been studied extensively with longitudinal follow-up
of body size and relative fatness, cardiovascular risk fac-
tors, blood lipid levels, blood pressure, and other phe-
notypic features for over 40  years. The data obtained
from the children in this community established normal
ranges for tracking of height, weight, skin fold thickness,
blood pressure, cholesterol and triglyceride levels (37).
6 CHAPTER 90  Disorders of the Body Mass
TA B L E 9 0 - 1    Prevalence of Overweight (BMI
>95th percentile) for American
Children 6–19 years of Age
Years Age 6–11 years Age 12–19 years
1963–1970a 4.2 4.6
1971–1974 4.0 6.1
1976–1980 6.5 5.0
1988–1994 11.3 10.5
1999–2000 15.1 14.8
2001–2002 16.3 16.7
2003–2004 18.8 17.4
2005–2006 15.1 17.8
2007–2008 19.6 18.1
a1963–1965
data are for 6–11-year-old children, and 1966–1970 data are
for 12–17 (not 12–19)-year-old children.
Data obtained from References (412) and (5).
The relationship between ponderosity and increased cor-
onary risk factors was established for school children and
their family members (38). As an extension of this study,
it was demonstrated that there was increased familial car-
diovascular mortality among the obese school children
(39,40). A longitudinal study of trends in BMI in this
population indicated that both genetic and environmen-
tal factors were involved in the variability of BMI (32).
The data indicated strong support for a single autosomal-
recessive locus with a major effect that accounted for
almost 35% of the variation in adjusted BMI. Polygenic
loci accounted for an additional 42% of the variation.
Therefore, only 23% of the variation was not explained
by genetic factors and was presumed to represent the
environmental influence. The most recent report from the
Muscatine Studies show that childhood BMI is the most
predictive phenotype for adult obesity (41).
In other communities, longitudinal studies have also
demonstrated familial aggregation of obesity and cardio-
vascular risk. These include the Bogalusa Heart Study
(42,43), the San Antonio Family Heart Study (44), the
Heritage Study (45), the Québec Family Study (46), and
studies of American Pima Indians (47).
Human obesity in rare instances may be associated
with defects at a single genetic locus. These include the
Prader–Willi (48) and Bardet–Biedl/McKusick–Kaufman
Syndromes (49), Alström Syndrome (50), and intersti-
tial deletion of chromosome 18 (q12.2q21.1) (51). The
mechanisms by which these genetic defects produce the
obesity phenotype are not completely known. Several
rare single gene defects produce obesity through better
understood mechanisms (see Section 90.3).
An extremely important factor in maintenance of body
weight is the relationship between body weight and total
energy expenditure (52). The trend toward returning to a
specific set point for body weight is powerful, and results
from not only a reduction in total energy expenditure
in response to weight loss but also an increase in energy
expenditure with weight gain. There are no doubt genetic
factors controlling this set point (described in Section 90.2).
Sustained weight gain is also associated with an increase in
urinary norepinephrine excretion and in serum triiodothy-
ronine concentrations, with the reverse patterns seen with
sustained weight loss. The percentage of changes in these
parameters correlated with the percentage of changes in
energy expenditure (53). Changes in carbohydrate metab-
olism were also noted. In subjects with sustained weight
gain, trends toward insulin resistance were more apparent
in those who were obese than in never obese subjects, sug-
gesting to the investigators that there is a threshold effect
of total body fat on insulin sensitivity (53). Ethnic variabil-
ity in resting energy expenditure has been demonstrated,
being higher in white than in black prepubertal girls (54),
and higher in white than in black prepubertal children,
independent of PBF and sex (55). There is ethnic variabil-
ity in insulin sensitivity and atherogenic risk among ado-
lescents of comparable BMI. Black-obese adolescents have
a more diabetogenic insulin secretion and sensitivity pro-
file than white-obese adolescents. On the other hand, the
white-obese youth had more visceral adiposity and athero-
genic risk factors than their black peers with similar BMI
(56). Genetic factors are likely to have major influence on
the lower physical activity and resting energy expendi-
ture observed in infants who later become obese children
(57). A somewhat genetically isolated population, the Old
Order Amish, that is known to have high levels of physi-
cal activity has a lower rate of obesity despite high caloric
consumption (58).
90.2 GENETIC ARCHITECTURE
OF OBESITY
The detailed genetic architecture of obesity risk has not
yet been precisely defined. Even the true magnitude of
the heritability of obesity is not yet settled and estimates
range from as low as 20% to as much as 80% (59). A
relatively small percentage (5% or less) of obesity cases
is due to monogenic or syndromic obesity (60), but most
cases are due to complex interaction between multiple
genes and environmental factors. Whether the genetic
component of this risk is due to multiple common genetic
variants of small effect (common disease common vari-
ant hypothesis) or whether the effect is due to multiple
rare variants or even a few rare variants of large effect
has not yet been clarified. But whatever the nature of this
genetic influence, it does appear to become more promi-
nent as the prevalence and severity of obesity increases
in a given population, indicating that genes influencing
obesity may be more aggressively expressed in an obeso-
genic environment (61).
It is also becoming apparent that individual genomes
differ from each other much more than previously
assumed; for example, it has been estimated that as com-
pared to the reference haploid genome, each individual
human genome on average contains some three and a
half million single nucleotide variants (SNV) and about
 CHAPTER 90  Disorders of the Body Mass 7

1000 copy number variants (CNV) of >450 bp, many of
which are rare in the population from which the indi-
vidual was sampled and are unique to the individual’s
family or clan. Each individual genome is truly unique,
not just in terms of sequence variants in individual genes,
but in terms of the complex interaction between multiple
genes and gene networks. Our models of genetic risk,
therefore, need to be modified to take the interplay of
multiple variants within each unique individual genome
into consideration (62).
In the following pages, we will outline the known
monogenic and syndromic forms of obesity, their animal
models and human correlates, and the results of recent
genome-wide scans and linkage studies of common
(polygenic) obesity, keeping in mind that the boundaries
between these categories are not sharply defined. Genes
and chromosomal regions involved in monogenic forms
of obesity are also involved in polygenic common obesity
and all forms of obesity are ultimately the product of
complex interactions between multiple genes and envi-
ronmental factors. Thus, the same mutation that causes
morbid obesity in one individual may have a significantly
attenuated effect in another individual with a different
individual genetic background, environmental exposures
and family and clan genomic structure.
90.2.1 Animal Models and Human
Correlates (Spontaneous Mutations)
In rodents, multiple examples of spontaneous single
gene mutations producing obesity are known, and form
the basis for a candidate gene approach to identify the
genes responsible for human obesity (Table 90-2). Several
human counterparts of these rodent obesity syndromes
have been identified, and will be described in Section 90.3.
90.2.1.1 Leptin and Its Receptor.  The prototypic
obese mice with single gene defects are the obese (ob/ob,
Lepob) and diabetes (db/db, Leprdb) autosomal-recessive
mutations. If present on the same genetic background
strain, they cause the identical phenotypes of severe
hyperphagia, obesity, diabetes, defective thermogenesis,
and infertility due to hypogonadotropic hypogonad-
ism. Parabiosis experiments showed that ob/ob animals
were unable to produce a circulating factor regulating
food consumption, and that db/db mice were unable
to respond to this factor despite producing it in exces-
sive quantities (63). The phenotype of the ob/ob mouse
is partially obliterated by adrenalectomy (except for the
thermogenic defect) and these adrenalectomized obese
mice have significantly increased sensitivity to corticoste-
rone (64). Mice with electrolytic lesioning of the ventro-
medial hypothalamus (VMH) were found to be resistant
to the circulating factor thought to be absent in ob/ob
mice, but lacked the other phenotypic features of ob/ob
and db/db such as diabetes, defective thermoregulation,
and infertility (65). This led to the theory that the VMH
was only one of the several sites of action of this circulat-
ing “satiety” factor. The phenotypic expression of the
ob/ob and db/db genotypes is highly dependent upon the
background strain; for example, the BL/Ks background
is associated with more severe diabetes than the BL/6
background (65).
The mutant gene responsible for the phenotype in Lepob
mice encodes the protein leptin (66,67), which is deficient
in these animals. The main site of expression of ob (Lep)
mRNA is white adipose tissue (67). The Lep sequence
is highly conserved among vertebrates, and the human
gene maps to chromosome 7p31. Leptin is a cytokine-like
hormone secreted mainly by white (not brown) adipose
tissue (67,68), with myriad effects including modulation
of satiety and basal energy expenditure, and sexual matu-
ration. Treatment of ob/ob mice with recombinant leptin
or through leptin gene therapy (69,70) corrects the obe-
sity/diabetes phenotype.
Recombinant leptin treatment causes some weight
reduction in normal mice and rats, but has no effect in
db/db mice (71,72). Recombinant leptin also corrects
the infertility in ob/ob mice (73), and stimulates early

TA B L E 9 0 - 2    Rodent Obesity Mutations, Human Regions of Synteny, and Human Homologs

Mode of Inheritance Rodent Human Syntenic Human Mutation
Mutation Gene (Autosomal) Chromosome Region Described Mutant Protein
Mouse
Agouti Ay Dominant 2 20q11 Noa ASP
Diabetes db Recessive 4 1p31 Yes Lepr
Fat fat Recessive 8 4q21 Nob Carboxypeptidase E
Obese ob Recessive 6 7q31 Yes Leptin
Tubby tub Recessive 7 11p15 Noc Phosphodiesterase
Rat
Fatty fa Recessive 5 1p31 Yes Lepr
Corpulent faK Recessive 5 1p31 Yes Lepr
ASP, Agouti signaling protein; Lepr, leptin receptor; CPE, carboxypeptidase E.
aASP prevents binding of αMSH to its receptor MC4R. Several dominant MC4R mutations are associated with human obesity.
bCPE is required for normal prohormone processing by prohormone convertase 1 (PC1). PC1 mutations are associated with human obesity.
cPhenotype is similar to human Bardet–Biedl and Usher Syndromes.
8 CHAPTER 90  Disorders of the Body Mass
reproductive function despite slower growth in normal
mice (74). Leptin acts as a “metabolic gate” allowing
for pubertal maturation in the rat (75), similar to the
effect seen in normal mice. In normal rats, the effects of
recombinant leptin are enhanced by VMH injection rela-
tive to peripheral infusion (76), and leptin induces rapid
modulation of synaptic transmission in isolated arcuate
nucleus slices from rat hypothalami (77). In rats with
streptozocin-induced diabetes, the iatrogenic leptin defi-
ciency is reversed, and even overcompensated, by leptin
treatment. This effect is independent of the amount of
weight regained or the resulting blood glucose concen-
trations (78).
Leptin exists in protein-bound and free states in the
plasma, the latter being the predominant form in obese
subjects (79). The demonstration of high leptin levels in
the plasma of obese individuals correlating with BMI
and %BF, along with elevated leptin mRNA in adipose
tissue, lead to the hypothesis that obese humans are, to
some degree, leptin resistant (80). Leptin levels in plasma
are normally higher in women than in men (81–83), and
they correlate with %BF rather than genetic background
in identical twins discordant for obesity (84). Circulat-
ing leptin concentration, when normalized for total fat
mass, decreases in males as they progress to late puber-
tal stages, whereas the reverse trend is seen in females
(85). Plasma levels decrease significantly after 60  years
of age in both sexes (86). Fasting and sustained weight
loss result in a reduction in plasma leptin, however, high-
fat diet and energy expenditure per se have no effect
(83,87). As expected, leptin levels are low in women with
anorexia nervosa (88), high in patients with the Prader–
Willi Syndrome (PWS) (89), and relatively high in new-
borns (90), but correlate with %BF in all groups. There
is a normal oscillation and diurnal rhythm of leptin levels
(91), which shows a blunted pattern in women athletes
with amenorrhea relative to athletes with normal menses
(92). This perhaps provides a correlation to the defect
in sexual maturation seen in ob/ob mice. Exposure of
cultured human hepatocytes to high concentrations of
leptin results in attenuation of insulin-induced activities
including downregulation of gluconeogenesis (93), lead-
ing to the possibility that leptin is involved in the patho-
genesis of the diabetes associated with human obesity.
The gene encoding human leptin has been studied
extensively, but with the exception of leptin deficiency
caused by rare LEP gene mutations (94), its impor-
tance in altered human satiety and abnormal body
size determination has not been clearly demonstrated.
Studies of this gene in large panels of obese and/or dia-
betic individuals have failed to demonstrate mutations
(95–97). Linkage of obesity to this genetic region was
not demonstrated in Pima Indians (98), nor in Mexican-
Americans with NIDDM (99), and Mexican-American
obese sib pairs from Starr County, Texas (100). How-
ever, some investigators have shown a suggestion of link-
age of polymorphic markers near LEP to extreme obesity
(101,102), to obesity-related traits and insulin precur-
sors in Mexican-American families with a type II dia-
betic proband (103), and to lower leptin levels in obese
subjects (104). A leptin gene polymorphism is associated
with hypertension, independent of obesity, in a Japanese
population (105).
The cloning of the leptin receptor gene Lepr (106)
from mouse choroid plexus led to characterization of the
mutations causing the mouse db/db phenotype, and its
rat homologs, the Zucker fatty (fa/fa) and obese Koletsky
phenotypes (107–111). Thus, mutation of the same gene,
Lepr, occurred spontaneously in three different strains
and produced strikingly similar phenotypes. Multiple
splice variants of Lepr exist (112–114), and are expressed
in various tissues within and outside of the central ner-
vous system (CNS), including lung, liver, skeletal mus-
cle and kidney (106), the major site of leptin clearance
(115). One of these encodes a circulating (short) form
of the leptin receptor, which transports leptin across
the blood–brain barrier producing a saturable system of
transport into the CNS (79). If excess leptin is secreted,
such as in obese individuals with a large fat mass, plasma
levels of free leptin will increase significantly because of
the saturable transport of the system. The production of
this short or soluble form of the receptor is regulated
independently by many different physiological condi-
tions, and serves to modulate the amount of free leptin
available to the transmembrane signaling long form of
the receptor (116).
The cascade of effects downstream of leptin binding to
its receptors is not completely understood, but involves
activation of members of the STAT family of transcrip-
tional activators (117,118). Both insulin and leptin work
in parallel in many of these pathways. Treatment of fa/
fa (leptin receptor defective) rats with a thermogenic
mixture of sympathomimetic amines (ephedrine and
methylxanthines) can reverse or prevent their obesity
(119,120). Such findings suggest that the downstream
effects of leptin include actions on the sympathetic
nervous system. This has been confirmed in studies of
rodents as well as humans (121,122). Mice that are het-
erozygous for either the ob or the db mutation have body
composition and leptin homeostasis phenotypes that are
intermediate between homozygous wild-type and mutant
animals (123).
Other downstream effects of leptin include inhibition
of the neurons that produce neuropeptide Y (NPY), a
hypothalamic neurotransmitter that can cause obesity
through appetite stimulation (described in more detail
below), and which is found at high levels in the hypo-
thalami of ob/ob mice (124). Leptin also stimulates
neurons that increase production of POMC, which is
known to inhibit feeding. The NPY and POMC neurons
in the arcuate nuclei of mice are rapidly altered by leptin
administration. Genetically engineered wild-type and
leptin-deficient (ob/ob) mice, who express two differ-
ent green fluorescent proteins in the two neuronal types,

were administered systemic leptin treatment. In the
ob/ob mice, who normally had increased NPY excitatory
synapses and decreased inhibitory POMC synapses,
leptin treatment caused a rapid change in this pattern.
Within 6 h, before any effect on food intake or weight
was observed, the numbers of excitatory and inhibitory
synapses became indistinguishable from those of the
wild-type, untreated mice (Figure 90-3) (125).
In addition to the effects on feeding, leptin receptor-
mediated effects alter bone metabolism, the immune
system, angiogenesis, and the cardiovascular system
(126,127). Thus, it is clear that animals or humans with
defective leptin receptors would require therapeutic
intervention aimed at a number of organ systems in order
to correct the defect. Multiple factors exist that result
in leptin resistance at the tissue level in obese subjects,
including interactions with transcription factors that are
associated with obesity-induced endoplasmic reticulum
(ER) stress. These factors attenuate leptin signaling, and
may, in fact, promote more weight gain and adiposity in
obese individuals (128).
FIGURE 90-3  Changes in hypothalamic synapses of ob/ob mice
after leptin treatment. This diagram demonstrates the difference in
the number of excitatory (red) and inhibitory (blue) synaptic inputs
onto NPY (coexpressing AgRP) (yellow) and POMC (green) neurons
in wild-type and ob/ob mice. Leptin treatment to ob/ob mice rapidly
reversed the number of inputs onto NPY and POMC to wild-type
levels. NPY, neuropeptide Y; AgRP, Agouti-related protein; POMC,
proopiomelanocortin. Pinto et al. (125), Figure 94-4C, page 114.
CHAPTER 90  Disorders of the Body Mass 9
In population genetic studies, the LEPR region has
shown no relation to body size variables in the Pima
Indians (98), but a possible correlation was seen with
acute insulin response in the same group (129). In the
Québec Family Study, results of sib-pair linkage analy-
sis with 137 adult sibships suggested linkage of body
fat and insulin levels to polymorphic markers on chro-
mosome 1p32–p22, the cytogenetic location of LEPR
(130). These markers spanned the regions syntenic with
mouse db as well as one of the 10 mouse quantitative
trait loci (QTLs) related to susceptibility to diet-induced
obesity, termed Do1 (131). Polymorphisms within the
LEPR introns (130) and exons (132) have been tested
for their relationship to obesity in humans. Among these,
the sequence variations at coding exons 2 (Lys109Arg),
4 (Lys204Arg and Gln223Arg), and 12 (Lys656Asn)
are the most likely to have effects on receptor function.
These amino acid substitutions are at positions that are
conserved in rat, mouse, and humans. In addition, the
codon 223 and 656 variants cause changes in charge
(neutral to positive, and positive to neutral, respectively).
Of 20 nondiabetic American Pima Indians chosen for
extremes in body size, seven LEPR sequence variations
were identified, including Lys109Arg and Gln223Arg.
Three of these variants were within noncoding regions
of the gene and these were found exclusively in obese
Pima Indians (133). Lys109Arg and Gln223Arg were
associated with BMI and fat mass in Caucasians, but not
in African-Americans in the HERITAGE Family Study
(134). The Lys656Asn variant was significantly linked to
BMI in the Muscatine (135), and Gln223Arg was linked
to fat mass in the Québec Family Study (136). On the
other hand, in adult subjects from Baltimore, Gln223Arg
and Lys656Asn were not associated with obesity traits
(137), and the codon 109, 204, 223, and 656 changes
were not positively associated with juvenile-onset obesity
in 56 Danish men (138). However, a meta-analysis of
LEPR polymorphisms failed to confirm this as an impor-
tant population-wide locus (139).
Severe early-onset obesity caused by a mutant leptin
receptor was originally identified in three female sib-
lings (140). These homozygotes had failure of pubertal
development, and reduced growth hormone and thyroid
stimulating hormone secretion. Despite absence of leptin
signaling, and massively elevated plasma leptin concen-
trations, leptin mRNA levels in adipose tissue, assessed
by quantitative reverse transcription polymerase chain
reaction, were as expected for their BMI (141). This
argues against a direct negative feedback loop in regula-
tion of leptin gene expression in humans.
90.2.1.2 Tubby.  The tubby (tub) mutation in mice is an
autosomal-recessive trait, which is associated with less-
severe obesity and insulin resistance than ob or db, is not
associated with significant hyperphagia, causes variable
degrees of hyperlipidemia depending on background
strain, and is more severe in males than females. The pheno-
type also includes retinal degeneration and sensorineural
10 CHAPTER 90  Disorders of the Body Mass
hearing loss similar to the human Usher, Alström, and
Bardet–Biedl syndromes (BBS) (50,142,143). The map-
ping (144) and cloning (145,146) of tub has led to its
characterization as a gene which is expressed mainly
in the hypothalamus and encodes a protein with phos-
phodiesterase-like sequences, possibly affecting cellular
apoptosis. Further studies have identified and character-
ized several Tubby-like proteins (TULPs), mutations of
which in mammals can cause retinal degeneration, and/
or hearing loss (147), as well as alterations in neural tube
formation (148). The exact biological functions of these
proteins remain unknown, however, their roles in com-
plex cellular functions are being characterized. They are
membrane-bound transcriptional activators that translo-
cate to the nucleus, and interact in the G-protein system
of intracellular signaling (149). It appears that TUB is
the only member of this protein family that is implicated
in obesity. It is highly concentrated in the nuclei of the
hypothalamus that are involved in energy regulation
(148). Human tub maps to chromosome 11p15. Linkage
of human obesity to this cytogenetic region has not been
demonstrated, nor have tub mutations.
90.2.1.3 Fatty.  In the fatty (fat/fat) mouse, the reces-
sively inherited mutation causes hyperinsulinemia with-
out hyperglycemia, and postpubertal obesity that is
less severe than that seen in ob/ob or db/db mice. The
“hyperinsulinemia” is actually due to hyperproinsu-
linemia. The molecular defect is in the gene encoding
carboxypeptidase E (CPE), an endoprotease required for
normal processing of prohormones to active hormones,
including proinsulin to insulin (150), and for transport
and processing of propeptides in the granules of the regu-
lated secretory pathways of the CNS. The primary exam-
ple of such a peptide is proopiomelanocortin (POMC),
which is the precursor for adrenocorticotropic hormone
(ACTH), melanocyte-stimulating hormone (MSH), beta-
endorphin, and beta-lipoprotein. POMC has a “sorting
signal” consisting of two acidic N-terminal residues,
which bind to the two basic residues of CPE. Proinsulin
and proenkephalin also attach to this CPE-binding site
(151). POMC and proinsulin are then cleaved by prohor-
mone convertase 1 (PC1).
The role of CPE mutations (fa) in the expression of
the human obesity phenotype is unknown; however, a
correlate has been described in which there are muta-
tions of the PC1 gene (152). This patient has obesity
along with impaired processing of insulin leading to dia-
betes and hyperproinsulinemia, and ACTH deficiency
due to impaired processing of POMC. Polymorphic
genotypes of the PC1 gene and neighboring anonymous
DNA markers, however, do not confer susceptibility to
obesity, NIDDM, or gestational diabetes (153), but may
play a role as one of the important polygenes in these
syndromes.
90.2.1.4 POMC.  Since POMC processing defects lead to
obesity, it is not surprising that the POMC locus itself is
important in body size determination. Two siblings have
been identified with compound heterozygous POMC
gene mutations. They had early-onset severe obesity,
congenital ACTH deficiency, and red hair pigmenta-
tion (154). Both mutations alter the cleavage of POMC,
and blood levels of POMC cleavage products (ACTH,
αMSH) were subnormal. The heterozygous parents were
unaffected. In genome-wide searches, the region contain-
ing the POMC locus is linked to serum leptin levels and
fat mass in Mexican-Americans (155,156), and to serum
leptin levels in African-Americans (157) and French
Caucasians (158). However, POMC coding region and
promoter region sequence variants were not related to
obesity in Caucasians with juvenile-onset obesity (159).
A similar negative association with either extreme of
body size was seen when the POMC coding region was
screened in patients who were obese, underweight, or
with anorexia nervosa (160).
90.2.1.5 Agouti.  The yellow mutation of Agouti mice is
a dominant trait which causes yellow coat color (rather
than the wild-type hairs which are banded black and
yellow), obesity and diabetes. This was the first rodent
obesity gene to be cloned, and subsequently over 30
Agouti yellow alleles have been identified, which vary in
their phenotypic expression. The molecular defect in the
most dominant form Ay is a deletion in the 5′ regulatory
region, which brings a different promoter into contact
with the coding region. This results in excessive produc-
tion of Agouti signaling protein (ASP) through ectopic
overexpression of normal Agouti mRNA in many tissues,
rather than its normal site of expression which is limited
to the skin (161). Other Agouti alleles also result from
mutations that cause abnormal promoters to be utilized,
such as Aiapy which has an insertion of retroviral DNA
between exons C and D, directing use of an aberrant
promoter. This mutation is paternally imprinted. The
Aiy and Asy mutations have insertions upstream of the
first coding exon acting as ubiquitous promoters. When
transgenic mice overexpress ASP only in the hair follicles
of skin, obesity and diabetes are not observed, leading
to the hypothesis that these effects are due to a para-
crine rather than an endocrine effect of ASP (161). The
large number of these dominant Agouti alleles makes it
likely that this locus has a propensity toward spontane-
ous mutations, making it an interesting candidate gene
for studies of the genetics of obesity.
ASP and another similar peptide, Agouti-related pep-
tide (AgRP) act as antagonists of native ligand binding
to melanocortin receptors 1–4 (MC1R through MC4R),
each of which are expressed differentially in specific tis-
sues. AgRP binds specifically to the MC4R in the CNS,
and ASP binds to both CNS MC4R and to skin MC1R
(162). Transgenic mice with a knockout (KO) mutation
of the CNS-expressed MC4R (MC4R-KO) have features
of the yellow Agouti phenotype. Both Ay and MC4R-KO
mice have high levels of NPY expression in an abnormal
CNS site, the dorsal medial hypothalamus, which may
be an etiologic factor for the obesity phenotype in this

syndrome (163). Mice with MC4R haploinsufficiency
have an obese phenotype that is intermediate between
wild-type and null mice (164).
90.2.1.6 Melanocortin Receptors.  Although ASP
mutations have not yet been described in humans, sev-
eral MC4R mutations are now known to be associated
with obesity. Two frameshifts, a 4-bp deletion at codon
211 and a 4-bp insertion at nucleotide 732 of the cod-
ing sequence, are associated with dominantly inherited
obesity (165,166). A novel in-frame deletion of codons
88–92 has been described in one obese female (167). Sev-
eral other MC4R mutations have been identified among
obese cohorts (168,169). Up to 10% of obese subjects in
Germany have MC4R mutations (168). The prevalence
rate appears to be lower in the United States (170). Func-
tional analyses of several mutations have confirmed their
deleterious effects on receptor function (169–171). The
codon 88–92 deletion prevents ligand binding (167). The
dominant nature of these mutations is presumed to be
due to haploinsufficiency as it is in the transgenic mouse
model. In one child, homozygous for a 2-bp deletion
causing premature termination of MC4R, the obesity
phenotype was more severe and of earlier onset than
in his heterozygous siblings and parents (172). Interest-
ingly, this child did not have any significant differences
in insulin or glucose levels during an oral glucose toler-
ance test, when compared with 39 BMI/age/sex-matched
control children.
In the Québec Family Study, linkage and association
analyses showed that both MC4R and MC5R genotypes
were related to obesity phenotypes (173). The melano-
cortin receptor MC3R mutation I183N, identified in a
father and daughter with high PBF, alters agonist-induced
G-protein activation (174). It does not exert a dominant
negative effect on the wild-type receptor, thus is likely to
cause its phenotypic effect through haploinsufficiency. In
mice with MC3R KO, there is a decrease in food intake
and normal energy expenditure, but they have twice the
fat mass of their wild-type littermates (174).
90.2.2 Energy Expenditure
90.2.2.1 Hormonal and Genetic Control.  The genetic
control of energy expenditure and heat production is an
area of intense investigation as many of these metabolic
and neuronal pathways are involved in expression of the
genetic defects described above. Defects specific to this
system are also important as independent contributors
to obesity. In rodents, the generation of heat by brown
adipose tissue (BAT) is related to the pathways controlling
body fat content and distribution. BAT generates heat
through its capacity for uncoupling of mitochondrial
respiration from oxidative phosphorylation via several
mitochondrial uncoupling proteins (UCPs) (175–177).
BAT as well as white adipose tissue (WAT) contains the
beta adrenergic receptors (βARs). The βARs mediate
lipolysis in BAT and WAT, as well as mitochondrial
CHAPTER 90  Disorders of the Body Mass 11
UCP-mediated thermogenesis in BAT. The β3-AR is
thought to be adipose specific, is the predominant
subtype in rodent BAT, and can be chronically
stimulated by its specific agonists, as opposed to the
β1- and β2-ARs which become refractory to chronic
stimulation (178). In transgenic mice deficient in BAT
through targeted disruption of the UCP-1 gene, obesity
develops in the absence of hyperphagia (179). The
BAT-deficient mice have enhanced susceptibility to diet-
induced obesity and its comorbidities (insulin resistance,
hyperglycemia, and hyperlipidemia) (180), which are
not reversed by leptin treatment (181). Alternatively,
constitutive transgenic overexpression of UCP-1 in both
BAT and WAT of mice cause significant reduction in
subcutaneous fat, both in normal and genetically obese
(Avy) mice (182). Consumption of a high-fat diet can
alter UCP gene expression in some mouse strains but
not others, indicating variable polygenic control of body
composition and thermogenesis (183). In normal rats,
UCP protein and mRNA are regulated in a tissue-specific
and subtype-specific manner by fasting and by leptin
treatment. In some circumstances, the effects on specific
UCP subtype protein and mRNA are disparate (184).
In normal mice, there is strain-specific variation in the
prevention of high-fat-diet-induced obesity by β3-AR
agonists, which is related to the ability to recruit BAT
in WAT anatomic sites (185). Targeted disruption of
the β3-AR gene results in a much milder phenotype than
seen in the BAT-deficient mice. They have only modestly
increased fat stores (females greater than males), but also
have upregulated levels of β1 but not β2-AR mRNA in
adipose tissue (in BAT more so than in WAT) suggesting
crosstalk among the receptor subtypes (186). In WAT
of ob/ob mice, lipolysis and adenylyl cyclase activation
by the βARs is deficient. Whereas the β3-AR is the main
activator of cyclase activity in WAT of lean mice, it is
only partially responsible for adenylyl cyclase activity in
ob/ob mouse WAT (187,188). In normal rats, the inter-
action between the sympathetic nervous system, leptin,
UCPs, and regulation of fat cell energy utilization is com-
plex. The in vivo modulation of leptin and UCPs appears
to depend on sympathetic nerve activity, plasma insulin
and glucose, and hemodynamic factors (189).
Variation of the human β3-AR (ADRB3) gene sequence
has been studied extensively, again with disparate results.
The human gene has been cloned and its product exhibits
properties pharmacologically identical to rodent β3-ARs
(190). In omental fat tissue from obese individuals, there
is increased catecholamine-induced lipolysis relative to
cells from nonobese subjects, and this effect is mainly
due to increased β3-AR function (191). An ADRB3 mis-
sense mutation (Trp64Arg) has been associated with ear-
lier onset of NIDDM and lower resting metabolic rate
in Pima Indians (192), abdominal obesity, insulin resis-
tance, and BMR in Finns (193,194), and an increased
capacity to gain weight in a French cohort (195). There is
no association between this polymorphism and NIDDM
12 CHAPTER 90  Disorders of the Body Mass
susceptibility in at risk family members (196), obesity
phenotypes in the Québec Family Study or in the Swed-
ish Obese Subjects Cohorts (197), obesity and NIDDM
susceptibility in Nauruans (198), obesity in Japanese
men (199), BMI gained or response to a hypocaloric diet
in morbidly obese Finns (200), or obesity in a population
of healthy British men (201).
A polymorphism of UCP-1 (202) is reportedly associ-
ated with resistance to weight loss with a low-calorie diet
in the French (203), and this polymorphism may have an
additive effect with the ADRB3 polymorphism on rate of
weight gain in morbid obesity (204). From a physiologic
standpoint, there is no evidence quantifying the amount
of BAT in humans, and studies of brown adipocytes from
nonhuman primates indicate a lack of functional β3-ARs
(205). In addition, pharmacological characterization
of the Trp64Arg-mutant β3-AR shows no difference in
its response to agonists when compared with wild-type
receptors in CHO cells (206). In 204 Japanese subjects,
the Trp64Arg variant allele was not associated with
differences in BMI, plasma glucose or insulin, or fam-
ily history of obesity or diabetes. However, those with
the variant had lower resting autonomic nervous system
activity than those without it (207). This conflicting evi-
dence, combined with the mild phenotype in β3-AR KO
mice, would rule against this locus having a major gene
effect on obesity. However, a minor effect, when com-
bined with other defects affecting body fat deposition,
may contribute to the obesity phenotype.
UCP activity is stimulated by a number of physi-
ologic factors, including cold, βARs, and fatty acids
(208–211). When activated, the protein allows hydrogen
ions to “leak” through the respiratory chain of the inner
mitochondrial membrane, which abolishes the gradi-
ent of hydrogen ions required for ATP synthesis from
stored nutrients (209). Mammalian UCP-1 is expressed
mainly in BAT, which is present to a significant degree in
humans only in the newborn period. The human UCP-1
gene maps to chromosome 4q31 (210). Human UCP-2
and -3 are also expressed in WAT and skeletal muscle
(78,208,209), and the genes map to a duplicated locus as
adjacent genes on chromosome 11q13 (212,213). UCP-3
is preferentially expressed in skeletal muscle (212), and
has both long and short transcripts (214). In American
Pima Indians, BMI is negatively correlated with both the
UCP-3 long and short forms, but not with UCP-2. Meta-
bolic rate during sleep correlated positively with the long
form of UCP-3 (214). In the skeletal muscle of UCP-3
KO mice, there was reduced mitochondrial uncoupling
activity. However, there was no effect seen on body
weight regulation, exercise tolerance, fatty acid oxida-
tion, or cold-induced thermogenesis (215).
A UCP-1-associated Bcl-I RFLP may be associated
with increased body size (202). Seven sequence variants
of the UCP-1 gene were identified in Danish subjects, but
genetic variation in the coding region of the gene did not
contribute to obesity in this population (216). There is
no association between UCP-2 genotypes and obesity in
French Caucasians (217). Allele frequencies of a UCP-
2 gene polymorphism at codon 55 (A55V) were similar
in African-Americans and Caucasian Americans (218),
but its association with body size was not character-
ized. A 45-bp insertion polymorphism of the 3′ flanking
region of the UCP-2 gene is correlated with high BMI
and %BF in children (219). This insertion/deletion poly-
morphism results in mRNA species of different lengths,
and the insertion variant is less stable. The insertion vari-
ant is in linkage disequilibrium with a pair of linked pro-
moter region sequence variants (T/A at −2723 and G/A
at −866). The minor allele −866A is associated with a
decreased risk of obesity in middle-aged subjects from
Austria (220). Regarding UCP3, an exon 5 C–T sub-
stitution that does not change the codon 210 Tyrosine
residue was associated with significantly lower resting
energy expenditure in African-American but not White
women (221). There were no effects of genotypes of three
other UCP-3 variants, nor of two UCP-1 and two UCP-
2 variants. In a review of over 40 studies of UCP gene
variants in humans, UCP-1 was not felt to contribute
significantly to variability in BMI. However, UCP-2 and
UCP-3 effects on BMI are accepted. As they are adjacent
genes, it is likely that their genetic variants are in linkage
disequilibrium, and the effects of one gene on BMI may
reflect variants in the other (222).
90.2.3 Control of Feeding
Energy intake and expenditure is under the control of
complex interactions between peripheral signaling and
effector systems (e.g. βARs and UCPs discussed above)
and neuroendocrine systems (162,223). There is great
complexity in these interactions (224), and the details of
these pathways are under widespread investigation. Some
of the pathways are illustrated in Figure 90-4. The con-
tribution of signals from the gastrointestinal tract repre-
sents the more acute responses to feeding, rather than the
chronic responses to energy stores (225). Among these
are ghrelin from the stomach, insulin and glucagon from
the pancreas, and PYY and glucagon-like peptides from
the intestinal tract. The factors important in determin-
ing an individual’s set point for food intake may change
as individuals become obese because of attenuation of
leptin signaling induced by increasing adiposity (128).
90.2.3.1 Ghrelin.  Ghrelin was first discovered in the
1970s as a growth hormone secretagog. It’s major role,
however, is not modulation of growth hormone secretion
from the anterior pituitary, but rather its role in increasing
energy stores is felt to be more important, physiologically
(226). It is secreted mainly by the stomach, with minor
contributions from the brain, kidney, and placenta. These
other sources may compensate for gastric secretion as
patients having gastrectomies only have 65% reductions
in blood levels. Serum levels are inversely correlated with
BMI but are paradoxically elevated in children with the
 CHAPTER 90  Disorders of the Body Mass 13

FIGURE 90-4  Interactions that regulate food intake and body fat mass. Dashed lines: inhibitory effects. Solid lines: stimulatory effects. Y1R
and Y2R, neuropeptide Y (NPY) receptor subtypes; MC4R, melanocortin 4 receptor; GHsR, growth hormone secretagog receptor (ghrelin
receptor); AgRP, Agouti-related protein; POMC, proopiomelanocortin; α-MSH, α-melanocyte-stimulating hormone; LEPR, leptin receptor; INSR,
insulin receptor. (With permission from Kevin G. Murphy and Stephen R. Bloom. Gut Hormones and the Regulation of Energy Homeostasis.
Nature 444, 854–859.)

PWS (227). Ghrelin levels are high in anorexia nervosa,
and levels drop after food intake in lean subjects. How-
ever, in obese subjects, the levels do not drop after eating
(228). Ghrelin binds to specific receptors in the hypothal-
amus on NPY/AgRP neurons, and acts to some degree as
a stimulator of hunger (225). Despite evidence that sug-
gests a potentially strong influence of ghrelin on body size,
ghrelin-deficient mice created by gene KO are the same as
their wild-type littermates in terms of size, growth rate,
food intake, response to fasting, body composition, and
reproduction (229). In humans, variation in the ghrelin
gene was associated with higher BMI and lower insulin
response to glucose in a group of 70 tall obese children
(230). Other evidence points to a genetic contribution of
ghrelin to body size, including a study showing that ghre-
lin levels at baseline and in response to overfeeding, are
more similar in monozygotic than dizygotic twins (231).
90.2.3.2 Central Control of Feeding and Energy
Expenditure.  The hormone leptin is made almost
exclusively in peripheral (mainly adipose) tissues, and
acts centrally in the hypothalamus by modifying two
major effector systems. Low plasma concentrations of
leptin and insulin (e.g. during weight loss) increase food
intake and decrease energy expenditure by stimulating
NPY synthesis, and perhaps by inhibiting sympathetic
activity and other catabolic pathways. High leptin and
insulin concentrations (e.g. during feeding and weight
gain) decrease food intake and increase energy expendi-
ture through release of melanocortin and corticotropin
releasing hormone (CRH), among others (232). The
list of neuropeptides which are known to alter energy
balance is growing rapidly. Some of these are listed in
Table 90-3.
90.2.3.3 Neuropeptide Y.  NPY is a neurotransmit-
ter that is abundant in the hypothalamus, and may be
important in mediating obesity. Hypothalamic levels of
NPY and its message are elevated in ob/ob mice, db/db
mice, and fa/fa rats. Central administration of NPY to
lean rats causes hyperphagia, obesity, insulin resistance
and increased triglyceride deposition in WAT. These
effects are prevented by adrenalectomy before NPY
treatment (233). In a special strain of ob/ob mice that
are deficient in NPY, the obesity and hyperphagia are
less severe, infertility is less marked, and diabetes is seen
later and is milder than in ob/ob mice with intact NPY
(234). Otherwise, normal mice homozygous for NPY
KO mutations have normal fed and fasting plasma lev-
els of leptin, thyroxine, corticosterone, and sex steroids,
indicating NPY is not vital for normal pituitary func-
tion (235). They also have lower seizure thresholds and
higher ethanol consumption and tolerance. However,
after a fasted state, NPY KO mice have less food intake
than WT mice, have anxiogenic-like behavior, and hypo-
algesia (236). NPY receptor 1 KO mice have marked
obesity (159), but NPY receptor 5 KO mice have a less
severe obesity phenotype (237).
In human studies, iv NPY administration increases
sleep and decreases ACTH release in males (238).
14 CHAPTER 90  Disorders of the Body Mass

90.2.3.5 The Hypothalamic–Pituitary–Adrenal (HPA)

TA B L E 9 0 - 3    Central Nervous System Proteins
(Neuropeptides) Involved in
Axis in Feeding and Body Size Determination.  It
Energy Homeostasis has been demonstrated in multiple animal models that
adrenalectomy obliterates or attenuates the obesity syn-
Regulation by Leptin dromes expressed in genetically obese rats and mice,
Neuropeptide or Insulin
in diet-induced obesity, and in hypothalamic obesity
Orexigenic (stimulates feeding) (233). Replacement of only trace quantities of gluco-
Neuropeptide Ya Decreased corticoid to these adrenalectomized animals causes
Agouti-related peptidea Decreased prompt return of the phenotypes indicating heightened
Melanin concentrating hormone Decreased
sensitivity to the steroid. In humans and animals with
Orexin A and B (Hypocretin 1 and 2) Decreased
Galanin Decreased hypercortisolemia, obesity is prominent. However, in
Norepinephrine adrenalectomized animals, the effects seen could result
β-endorphinb from a combination of glucocorticoid deficiency alone
Ghrelinc or in combination with the secondary elevation of hypo-
Anorexigenic (inhibits feeding) thalamic CRH and pituitary ACTH production. Obese
Leptin Zucker (fa/fa) rats have no difference in hypothalamic
α-Melanocyte-stimulating hormonea Increased levels of CRH or in magnitude of CRH response to
Corticotropin releasing hormonea Increased
stressors when compared to lean littermates. However,
Thyrotropin releasing hormonea Increased
Cocaine- and amphetamine-regu- Increased
basal secretion of CRH is less in the obese rats, and
lated transcript (CART)a CRH response to adrenalectomy is more pronounced in
Interleukin-1βa Increased the obese rats. Corticosterone infusion is more effective
Urocortina in suppressing CRH levels in adrenalectomized obese
Glucagon-like peptide 1 rats than in adrenalectomized controls (247), leading to
Oxytocin the hypothesis that fa/fa rats have an abnormality of the
Neurotensin HPA axis at a site proximal to that which mediates glu-
Serotonin cocorticoid responsiveness. Central administration of
Somatostatin
CRH as well as a related hormone, urocortin (248,249),
aEffects
both energy intake and expenditure that change energy stores. mimics the events seen in the “stress response” includ-
bβ-endorphin treatment stimulates feeding in many animal models, but ing anorexia. This treatment prevents excessive weight
β-endorphin knockout male mice have hyperphagia and obesity. gain in fa/fa rats when compared with pair fed fa/fa
cMost ghrelin is secreted from the stomach, but some is produced in the

hypothalamus.
­controls (250,251).
Information obtained from Schwartz et al. (232), and Sahu (413).
Genetic studies of the human genes encoding NPY have
identified no deleterious mutations. Linkage analysis of
the NPY gene showed evidence of linkage to body size
in Mexican-American obese sib pairs (239), but not in
French Caucasian obese families (240).
The NPY Y1 and Y5 receptors are transcribed from
a common promoter region in opposite directions, sug-
gesting they evolved from a gene duplication event (241).
Linkage and association studies with these genes have
failed to identify an effect on body size in several popula-
tions (239,240,242).
90.2.3.4 Orexins.  Orexins A and B are stimulators
of feeding that are secreted as preprohormones by the
hypothalamus. They act through binding to orexin
receptors, which are of the classical G-protein-coupled
seven transmembrane domain class (243). Orexin KO
mice have narcolepsy (244), a finding that may correlate
with NPY-induced sleep in humans, described above.
Human orexin receptors are localized in the pituitary
gland (245) and in pheochromocytomas (246). Muta-
tional analyses and linkage studies of the genes encod-
ing these peptides have not yet been reported in humans
with altered body size.
Leptin treatment of normal mice and rats causes
a blunted HPA axis response to stress, perhaps via
decreased release of CRH (252). In Ay/a obese mice,
the effects of POMC and leptin pathway activation are
additive, yet independent (253). Full-length LEPR mes-
sage has been identified in human adrenal cortex, and to
a lesser degree in adrenal medulla. In cultured adrenal
cells, leptin inhibited ACTH-stimulated cortisol, aldo-
sterone, and dehydroepiandrosterone secretion (254). In
addition, some individuals may have heightened sensitiv-
ity to glucocorticoid because of a sequence variant of the
glucocorticoid receptor gene, which has been associated
with higher BMI and lower bone density in the Rotterdam
Study (255). These data suggest that therapeutic manipu-
lations of the HPA axis could alter the phenotype of cer-
tain genetically obese individuals.
One of the most interesting developments in this area
is the role of adipose tissue in the synthesis and degrada-
tion of cortisol through the action of 11β-hydroxysteroid
dehydrogenase (11β-HSD). 11β-HSD2 converts cortisol
to its inactive metabolite cortisone. In the kidney, this
prevents activation of the mineralocorticoid receptor by
cortisol, which is present in plasma in much higher con-
centrations than its native ligand, aldosterone. Cortisol
has equal affinity for the receptor, and aldosterone is
not a substrate for the enzyme. If 11β-HSD2 is deficient,

the syndrome of apparent mineralocorticoid excess
occurs (256). Glycyrrhetinic acid in licorice causes salt
retention and hypertension because it inhibits 11β-HSD2
activity (257). Topical administration of glycyrrhetinic
acid in females caused reduction in the underlying femo-
ral subcutaneous fat (258), presumably by causing a local
reduction in adipose tissue cortisol. Chronic ingestion of
licorice was associated with a reduction in fat mass in 15
normal-weight young adults, without a change in BMI or
in caloric intake (259).
11β-HSD1 (cortisone reductase) converts cortisone
back into cortisol in the liver. Defects in 11β-HSD1
activity have been implicated in several clinical settings
(260,261). There is mounting evidence that increased
11β-HSD1 activity in visceral adipose tissue contrib-
utes to obesity and the metabolic syndrome. Trans-
genic mice that overexpress 11β-HSD1 in adipose tissue
develop the typical metabolic syndrome, with visceral
obesity exaggerated by a high-fat diet, insulin-resistant
diabetes, hyperphagia, hyperleptinemia, and hyperlip-
idemia (262). Patients with hypothalamic obesity may
have increased 11β-HSD1 activity (263), and adipose
tissue of individuals with idiopathic obesity has been
shown to have higher than expected 11β-HSD1 activity
(264,265).
The human gene encoding 11β-HSD1 contains two
polymorphic intronic microsatellites, and one intronic
polymorphism useful for linkage and association stud-
ies. In a study of 439 normal adults from Glasgow, and
of 557 Danish military draftees (234 with ­juvenile-onset
obesity and the rest normal controls), there was no
significant association of 11β-HSD1 genotypes with
BMI in either group, but there were weak associations
between 11β-HSD1 activity and waist-to-hip ratio
(266). In American children, the intronic ins4436A
polymorphism was associated with BMI and insulin
resistance (267).
90.2.4 Adipose Tissue Development
and Function
Adipose tissue is a biologically active organ, involved not
only with energy storage and release but also with auto-
crine and paracrine effects that are widespread (268).
These effects are manifested in endocrine/hormonal
function, immune function including its role in cardio-
vascular risk, and the CNS communication through
leptin, tumor necrosis factor alpha (TNFα), interleukin 6
(IL6), adiponectin, resistin, and other adipokines. Leptin
and adiponectin are thought to be insulin sparing in their
effects, whereas TNFα, IL6, and resistin are thought to
contribute to the insulin resistance phenotype associated
with obesity (268,269).
Adipocytes play a pivotal role in the maintenance of
energy balance. The roles of BAT, WAT, sympathetic ner-
vous system signals, and UCPs were discussed in ­Section
90.2.2. The development of mature adipose tissue from
CHAPTER 90  Disorders of the Body Mass 15
preadipocytes is accompanied by a marked increase in the
expression of adipose-related transcripts such as leptin
and UCPs. The terminal differentiation of adipocytes is
controlled by several transcription factors, one of the
more important being peroxisome proliferator-activated
receptor-γ2 (PPAR-γ2). After differentiation, the fat cells
produce many products other than metabolic fuels that
are secreted into the circulation. Prominent examples
of these include the cytokines leptin (discussed in Sec-
tion 90.2.1) and TNFα. In addition, adipocyte macro-
phage colony-­stimulating factor has been shown to be
important in stimulating adipocyte hyperplasia (270).
Hormone-­sensitive lipase (HSL) stimulates breakdown
of triglycerides into fatty acids, which have been impli-
cated in the development of insulin resistance. The gene
encoding human HSL maps to chromosome 19q13, and
contains a dinucleotide repeat polymorphism within one
of its introns. This polymorphism was associated with
obesity and type 2 diabetes in a French population (271).
90.2.4.1 PPARs.  Members of the PPAR family of nuclear
receptors regulate adipocyte differentiation. PPARs are
divided into subtypes α, β, γ, and δ, each of which is
expressed in a tissue-specific manner. The PPAR-γ class
is expressed in adipose tissue, and has two isoforms, γ1
and γ2, which are differentially spliced products of the
same gene. The PPAR-γ2 isoform is the longer protein,
and is adipose specific (272). When PPAR-γ2 is binds its
ligands (prostaglandin derivatives, fatty acids, and thia-
zolidinediones), it forms a heterodimer with the retinoid
X receptor that activates a cascade of fatty acid metabo-
lism and preadipocyte differentiation (272–274). This
effect is adipose-depot specific (273), and can even occur
in fibroblasts (274). Homozygous PPARγ KO mice have
a prenatal lethal phenotype due to placental dysfunc-
tion. Heterozygous mice seem to be protected from the
development of insulin resistance, and have reduced fat
mass, smaller adipocyte size, and hypersecretion of leptin
(275). Mice that have a muscle-specific KO of PPARγ
had normal responsiveness to thiazoliadinediones, as
well as normal glucose and insulin levels, despite excess
adiposity with reduced caloric intake. However, they
have whole-body insulin resistance when tested with
a hyperinsulinemic euglycemic clamp, due to localized
insulin resistance in nonmuscle tissues (liver, and per-
haps, fat) (276).
The human gene encoding PPAR-γ2 has been cloned,
and maps to chromosome 3p25 (277). Several sequence
variants have been described, and as with other candi-
date genes for obesity, studies in human populations
have revealed differing results. A Pro115Gln variant was
shown to accelerate differentiation of murine fibroblasts
into adipocytes when it was over expressed (278). This
variant was identified more frequently in German obese
subjects than nonobese subjects (278). However, this
variant was not found in a different study of ­German
subjects (279), nor in Danish men (280). Another more
widely studied variant, Pro12Ala, has also shown both
16 CHAPTER 90  Disorders of the Body Mass
positive and negative correlations with obesity. It was
initially studied and ruled out as a candidate gene
for lipoatrophic diabetes (277). PPAR-γ2 Pro12Ala
occurred with the same gene frequency in obese and
lean German subjects (279). Association studies with
two different Caucasian populations revealed a positive
relationship between Pro12Ala and high BMI (281). In
French subjects, studies of this variant suggested a role
for it in weight control and lipid homeostasis, but not
in the etiology of type 2 diabetes (282). Among patients
with type 1 and type 2 diabetes, the variant had no effect
on lipids or BMI (283). In Mexican-Americans from
the San Antonio Heart Study, presence of the Pro12Ala
allele was positively associated with BMI and serum
leptin levels (284). A large study of Danish men under-
scores the conflicting nature of these study results. Obese
Danish men who were homozygous for Pro12Ala had
higher BMI and higher weight gain than wild-type carri-
ers. However, homozygotes for Pro12Ala in the control
group had a lower BMI and less weight gain than the
wild-type carriers (280).
90.2.4.2 TNFα.  TNFα is one of the several cytokines,
including leptin, interleukin 1 and 6, interferon, and
TNFβ, known to have profound effects on lipid metabo-
lism. It not only is secreted by adipose tissue but also
has direct effects on adipocyte metabolism (285). These
effects are mostly catabolic, including suppression of
many lipogenic enzymes, and development of insu-
lin resistance (285). TNFα inhibits human adipose cell
insulin signaling (286) and causes apoptosis in human
adipose cells (287), and in rat brown adipocytes (288).
TNFα stimulates leptin release from cultured human
adipocytes (289), and levels of the soluble TNFα recep-
tor (sTNFα-R55) are positively correlated with plasma
insulin and leptin levels in patients with type 2 diabetes
and in controls (290). TNFα infusion in humans induces
an increase in serum leptin levels in humans (291). KO
mice that are deficient in the adipocyte fatty-acid-binding
protein aP2 are equally susceptible to diet-induced obe-
sity as are control mice. However, the aP2 null mice fail
to express TNFα, and also failed to develop the insulin
resistance seen in the obese control mice (292).
TNFα KO mice did not have a significant change in
body size by 28 weeks of age, but there was an increase
in insulin levels, and a decrease in triglyceride, leptin,
and glucose levels (293). In mice with gold thioglucose-
induced obesity, TNFα deficient animals had lower lev-
els of glucose and insulin, and lower insulin and glucose
responses to a glucose tolerance test than the obese wild-
type animals (293). In KO mice simultaneously deficient
for both the p.55 and p.75 types of the TNFα receptor,
obesity and diabetes were present. However, KO of
either receptor alone did not produce this phenotype,
and db/db mice lacking p.55 were still diabetic and insu-
lin resistant (294).
The human TNFα gene maps to chromosome
6p21, within the region containing the class 3 major
histocompatibility locus and the steroid 21-hydroxylase
genes (295). Polymorphic dinucleotide repeat markers
that map near TNFα were genotyped in American Pima
Indian families. The marker closest to TNFα was linked
to %BF in a sib-pair analysis, and was associated with
BMI by analysis of variance (296). However, screening
of the TNFα coding region and promoter identified only
a single polymorphism, and this was not associated with
obesity in this population. A G–A substitution at position
−308 in the TNFα promoter, which causes a restriction
fragment length polymorphism (RFLP) with the enzyme
NcoI, was associated with a higher rate of transcription
of TNFα in vitro. In Spanish overweight individuals, this
RFLP was associated with %BF, insulin sensitivity, and
leptin levels, despite no differences in BMI and plasma
TNFα levels (297).
90.2.4.3 Adiponectin.  Adiponectin is a peptide secreted
by adipose tissue, and is preferentially secreted by mature
adipocytes over preadipocytes (298). It was originally
termed Acrp30 (adipocyte complement-related protein
of 30 kDa), because of its homology to complement fac-
tor C1q. It was also known as adipocyte most abundant
gene transcript 1 (apM1), having been isolated as the
most abundant mRNA in human adipose tissue (299).
Plasma levels are strongly positively correlated with
insulin sensitivity, and it has putative antiatherogenic
properties (298). Plasma levels are the reverse of those
of leptin—adiponectin concentrations are lower in obese
than lean subjects (300). Its gene expression in and secre-
tion from 3T3-L1 adipocytes is reversibly inhibited by
interleukin 6, an adipocytokine that is elevated in states
of insulin resistance (301). In mice, intravenous injection
of adiponectin was followed by a rise in CSF levels, con-
sistent with transport to the CNS. Intracerebroventricu-
lar administration of adiponectin in these animals caused
a decrease in body weight, due to an increase in energy
expenditure (302).
The adiponectin gene spans a 17-kb region on human
chromosome 3q27, and contains three exons and two
introns (303). Several polymorphisms of the gene have
been detected and analyzed in human subjects (303,304).
A conservative G/T substitution in exon 2 did not corre-
late with plasma adiponectin levels or with the presence
of obesity in Japanese subjects (304), but was associated
with serum cholesterol and waist circumference in obese
Swedish subjects (305). In the latter study, the frequen-
cies of the G or T allele did not differ between obese
and lean subjects. In obese subjects undergoing gastric
banding surgery, genotype haplotypes of two linked
polymorphisms 11,377 C/G and 11,391 G/A correlated
with adiponectin levels at baseline (306).
90.2.4.4 Visfatin.  Visfatin is one of the members of the
adipokine group. It was formerly known as pre-B-cell
colony-enhancing factor (PBEF), and also small-molecule
insulin mimetic compound 2 (307,308). This nonpep-
tidal activator of insulin receptor action is secreted by
visceral fat as well as lymphocytes. Plasma levels in
 CHAPTER 90  Disorders of the Body Mass 17

humans and in mice correlate positively with the quan-

TABLE 90-4     Transgenic Models for Altered
tity of visceral fat but not subcutaneous fat (309). Treat- Body Size or Body Fat
ment of mice with this compound reduces food intake
and prevents high-fat-diet-induced obesity (310). When Increased
mice with diabetes are treated with recombinant visfa- MC4R-KO (164)
tin, their diabetes improves whether they have type 2 or 5-HT2c Receptor KO (414)
streptozocin-induced diabetes. Homozygous visfatin KO CRH overexpression (415)
is a prenatal lethal mutation, and heterozygous mutants BAT ablation (416)
β3-AR KO (+/−) (186)
have a diabetic tendency but no change in body fat (309).
GLUT4 overexpressed in fat (417)
Studies of variation in the human gene for visfatin may NPY receptor 1 KO (159)
provide insight into the link between visceral adiposity Nhlh2 gene KO (418)
and type 2 diabetes. 11β-HSD1 KO (262)
MCH overexpression (413)
β-endorphin KO (413)
90.2.5 Gene Targeting and Effects MC3R KO (174)
on Body Fat/Feeding Muscle PPARγ-KO (276)
The widespread use of gene targeting to study a myriad Decreased
of genes has been applied extensively to the study of Dopamine D1Receptor KO (419)
obesity. Many examples of these animal models have UCP-1 overexpression (182)
been described above. These, along with other relevant Tyrosine phosphatase 1B KO (420)
GLUT4 KO (421)
animal models are summarized in Table 90-4, and they
MCH KO (422)
demonstrate both monogenic and polygenic effects on LPL overexpression in muscle (417)
body size variables. PKA RIIβ KO (423)
PPARγ KO heterozygotes (275)
MCH or MCH-R ablation (413)
90.2.6 Polygenic Models
No change on normal diet
The polygenic mouse models of obesity have allowed CRH KO (424)
identification of multiple autosomal and nonautosomal NPY KO (235)
QTLs within individual strains, which modify obesity, TNFα KO (293)
plasma cholesterol levels, specific deposition of body UCP-3 KO (215)
fat depots (311–314) and propensity toward develop- Ghrelin KO (229)
ment of high leptin levels and obesity on a high-fat diet Visfatin partial KO (309)
(315,316). To underscore the complexity of the contri- MC4R, melanocortin receptor 4; KO, knockout; 5-HT2c, 5-hyroxy-tryptophan
bution of genetic background to autosomal-recessive 2c; CRH, corticotropin releasing hormone; BAT, brown adipose tissue; β3-AR,
­obesity, obese Zucker (fa)/NKY13H intercross F2 rats beta 3-adrenergic receptor; GLUT4, glucose transporter 4; NPY, neuropeptide
have at least three QTLs unrelated to Lepr that control Y; Nhlh2, one of two helix–loop–helix transcription factors expressed in the
developing mouse nervous system; UCP, uncoupling protein; MCH, melanin
BMI and glucose homeostasis (317). In addition, het- concentrating hormone; LPL, lipoprotein lipase; PKA RIIβ, protein kinase A
erozygosity for Lepob and Leprdb in mice is known to regulatory subunit II beta; PPAR, peroxisome proliferator-activated receptor;
affect body composition and leptin homeostasis (123). TNF, tumor necrosis factor; 11β-HSD1, 11beta-hydroxysteroid dehydroge-
Polygenic models may more closely resemble the human nase type 1; MCH, melanin concentrating hormone; MCH-R, MCH receptor;
obesity phenotypes, however, the single gene defects pro- MC3R,melanocortin 3 receptor; PPARγ, peroxisome proliferator-activated
receptor gamma.
ducing recessive traits, dominant traits, promoter altera-
tions, and those subject to parental imprinting must
continue to be considered candidates for genetic effects
in human obesity (224). humans, physical activity may counteract the obesity
related to specific genotypes of the beta 2 adrenergic
receptor β2AR gene (318). The β3AR (319) and lipo-
90.2.7 Gene–Environment Interactions
protein lipase (LPL) genes (320) may be involved in
There are a number of examples of environmental fac- similar interactions. Both β2AR- and β3AR-mediated
tors influencing genotype expression. Consumption of effects involve interactions with UCPs in their produc-
a high-fat diet can alter UCP gene expression in some tion of thermogenesis and response to high-fat diets
mouse strains, indicating variable polygenic control of (321). Other loci that may impact individual responses
body composition and thermogenesis (183). In normal to increased energy intake include ApoE, ApoA-II, and
mice, there is strain-specific variation in the preven- the LDL receptor (322). These and other as-yet unchar-
tion of high-fat-diet-induced obesity by β3AR agonists, acterized interactions would be important in predicting
which is related to the ability to recruit brown adipose the responses to prevention strategies or treatments for
tissue in white adipose tissue anatomic sites (185). In obesity.
18 CHAPTER 90  Disorders of the Body Mass
90.2.8 Nonmammalian Models
While the above discussion has focused on rodent mod-
els, nonmammalian animal models are also playing an
increasing role in the investigation of obesity and related
traits. These nonmammalian animal models have sev-
eral advantages over rodents, including shorter genera-
tion times, ease of breeding, large population size and
the existence of tools for the creation and screening of
mutants and phenocopies on a large scale. Some high-
lights of genetic findings in nonmammalian models are
listed below.
90.2.8.1 Drosophila.  Mutations in the Laminin A
(LanA) gene, a fruit fly gene that is closely related with the
human LAMA5 gene, lead to a decrease in ­triacylglycerol
storage, body weight and total protein content (323).
The human LAMA5 gene maps to a well-replicated
­obesity-linkage region on chromosome 20q13.2–q13.3
and variants may play a role in body composition and
lipid phenotypes (324). Other studies indicate that mem-
bers of the syndecan gene family may play a role in energy
metabolism and regulation of body weight in Drosophila
and that variants in homologous human genes may influ-
ence the same phenotypes in humans (325). Further stud-
ies are needed to confirm if these genes play a role in
human obesity and to elucidate the mechanisms involved
in any such role.
90.2.8.2 Zebrafish.  Zebrafish are being used to study
the effects of KO or knockdown of various genes
involved in obesity and metabolic regulation (326) and
may provide a means of interrogating known obesity-
related genes as well as the discovery of novel genes in
the future.
90.2.8.3 Caenorhabditis elegans.  C. elegans provides
an excellent model for the study of the basic biology of
obesity and energy regulation (327). Genes identified in
human genetic studies can be knocked down or mutated
in C. elegans to study their physiology, and conversely,
targeted mutagenesis and screening of mutants can reveal
novel genes involved in energy metabolism and the regu-
lation of adiposity (328). For example, the Indy (I am
not dead yet) gene was shown to regulate lifespan and
adiposity phenotypes in Drosophila and C. elegans and
this finding was later replicated in rodents using a mouse
KO (329).
90.3 MENDELIAN DISORDERS
ASSOCIATED WITH INCREASED BMI
IN HUMANS
Increased risk of obesity can, in relatively rare cases,
be secondary to single gene disorders of large effect.
While these disorders are uncommon, they do shed
light on some of the complex hormonal and neural net-
works that regulate adiposity. Their murine models,
physiological role and known counterparts in humans
have been discussed in detail in Section 90.2.1. Here
we will briefly review known human genetic defects
and their clinical features.
90.3.1 Leptin Deficiency
Missense and nonsense mutations in the leptin gene are
an extremely rare cause of morbid obesity. Leptin defi-
ciency is inherited in an autosomal-recessive manner
and leads to early-onset extreme obesity characterized
by intense hyperphagia. Resting and free-living energy
expenditure is normal. Patients also have hypogonado-
tropic hypogonadism with delayed spontaneous puberty,
immune deficiency and may have other neuroendocrine
defects (e.g. hypothyroidism) (330). They respond dra-
matically to treatment with recombinant human leptin,
with resolution of hyperphagia and associated pheno-
types (331,332). Recently, a patient with a leptin muta-
tion and relatively mild obesity and hypogonadotropic
hypogonadism has been described, raising the possibility
that milder clinical forms of leptin deficiency may also
exist (333).
90.3.1.1 Leptin Receptor Mutations.  Human leptin
receptor deficiency was initially reported in a single
family with very severe early-onset obesity and growth
retardation secondary to impaired growth hormone
secretion. Since then, it has been found that mutations
in the leptin receptor may be present in up to 3% of the
cases of morbid obesity (334). These subjects presented
with early-onset hyperphagia and morbid obesity with-
out significant elevation of leptin levels or developmental
abnormalities or dysmorphism.
90.3.1.2 MC4R.  Defects in the melanocortin 4 receptor
may be the most common form of monogenic obesity
in humans. These mutations appear to be codominant,
with more severe obesity seen in homozygotes. Preva-
lence of MC4R mutations ranges from 1% to 6% in
morbidly obese patients (335), but has not been con-
firmed in all populations (336,337). Functional studies
of these mutants have confirmed the deleterious effects
in many cases (167,171). Nonpathogenic mutations and
mutations that exert only a mild effect on BMI are more
common than mutations associated with morbid obesity,
making genetic diagnosis relatively complicated in these
cases (335).
90.3.1.3 POMC Mutation.  POMC is processed to
produce the hormones ACTH, MSH alpha, beta and
gamma, and beta-endorphin. Defects in POMC are an
extremely rare cause of obesity, ACTH deficiency and
red hair (154) though mutations that were not associated
with red hair have also been reported (338,339).
90.3.1.4 PC1 Mutation.  PC1 cleaves prohormones
before processing by carboxypeptidase. A mutation in
PC1 has been described a patient with obesity, elevated
proinsulin, hypocortisolism, hypoglycemia, hypogonad-
otropic hypogonadism and elevated POMC (152). In at
least one case, a mutation in PC1 was also associated
with neonatal diarrhea and malabsorption (340).

90.3.1.5 Cohen Syndrome.  Mutations in the VPS13B
gene (vacoular protein sorting 13, yeast, homolog B),
located on chromosome 8q22, are associated with
Cohen syndrome. Cohen syndrome is characterized by
truncal obesity, thin extremities and short stature and is
inherited in an autosomal-recessive manner (341).
90.3.1.6 Alstrom Syndrome.  Alstrom syndrome
(ALMS) is an autosomal-recessive ciliopathy that is
characterized by truncal obesity, short stature, reti-
nal cone dystrophy, progressive hearing loss, dilated
­cardiomyopathy, type 2 diabetes and progressive
­pulmonary, hepatic, and renal dysfunction. The involved
gene, ALMS1, is located on chromosome 2p13 and
encodes a large protein that is involved in ciliary func-
tion (342). How and why a ciliopathy causes ­obesity is
the focus of intense research and may shed new light on
the regulation of adiposity and energy metabolism in
humans (343).
90.3.1.7 Others.  Individual cases of mutations in sev-
eral other genes involved in the CNS appetite regula-
tion and the development of neuronal circuits have been
described in patients with morbid obesity, e.g. in SIM1
(single-minded, Drosophila, homolog of, 1) gene (344)
and NTRK2 (neurotropic tyrosine kinase receptor 2)
gene (345).
90.3.2 Syndromic Obesity
Syndromic obesity describes obesity that is associated
with well-defined combinations of other phenotypes
such as mental retardation, dysmorphic features and
other developmental abnormalities. Examples of such
syndromes with their known genetic cognates include
the following.
90.3.2.1 Prader–Willi Syndrome.  PWS is the most
common obesity syndrome with an incidence of
1/15,000–1/25,000 live births. It is caused by loss of
expression of paternally expressed genes in the imprinted
(differentially methylated) 15q11–13 region. This loss
may be secondary to deletions of the paternal 15q11–
13 region (70–75% of cases), maternal uniparental
disomy of chromosome 15 (20–25%), microdeletions
in the imprinting center at the SNURF–SNRPN gene
locus (<3%) and paternal translocations (<1%) (346).
Diagnostic testing is best performed by analyzing the
methylation status of the PWS region using methylation-
specific PCR. The clinical features of PWS include low
birth weight, severe hypotonia and feeding difficulties
in early infancy, followed by hyperphagia and obesity
starting in early childhood. Other characteristic features
include hypogonadism, short stature, small hands and
feet, facial dysmorphology (narrow bifrontal diameter,
almond-shaped eyes, triangular mouth) and a distinctive
behavioral phenotype (347). The 15q11–13 region in
an imprinted region in which at least 10 genes are only
expressed from the paternal chromosome and these were
therefore considered candidate genes for PWS (348).
CHAPTER 90  Disorders of the Body Mass 19
Some of the variations in clinical phenotypes between
different PWS patients are due to variation in the num-
ber of deleted or silenced genes in this region. But while
several genes contribute to the phenotype, deletion of
genes involved in the production and processing of small
nucleolar RNAs, particularly snoRNA SNORD116 clus-
ter (HBII-85) appear to be sufficient to cause the core
phenotypes of PWS (349).
90.3.2.2 Bardet–Biedl Syndrome.  BBS is a rare syn-
drome characterized by early-onset obesity, rod–cone
dystrophy, dyslexia, learning disabilities, postaxial poly-
dactyly, hypogonadism and progressive renal disease.
The McKusick–Kaufman syndrome is an allelic form of
BBS. It was initially thought to be a classic autosomal-
recessive disorder, but the genetics of BBS turn out to
be much more complex, with at least 15 different genes
now identified as being associated with this syndrome
(350,351). Some behave in an autosomal-recessive man-
ner, but others are “triallelic,” requiring a homozygous
recessive mutation in one gene and an additional muta-
tion at a second locus. Most of these genes are involved
in ciliary function and the syndrome is now considered
ciliopathy that overlaps clinically with ALMS (352). Its
recurrence risk depends on the specific locus containing
genetic mutation of each pedigree (353).
90.3.2.3 WAGR Syndrome.  Wilms' Tumor, aniridia,
genitourinary abnormalities and mental retardation
(WAGR) syndrome is associated with heterozygous
interstitial deletions of chromosome 11p-13. This syn-
drome included obesity in some but not all patients and
comparison of the deleted regions between obese and
nonobese patients indicated that obesity is associated
with deletion of the brain-derived neurotrophic factor
(BNDF) gene (354). Polymorphisms in the same gene
have since been found to be associated with obesity in
GWAS cohorts. This gene is expressed in the CNS and
appears to be involved in the regulation of appetite.
90.3.2.4 16p11.2 Deletions.  Deletions in this region are
associated with obesity and in some cases with autism.
This region includes the gene SH2B1, which codes for
an adapter protein involved in tyrosine kinase signaling
including leptin and insulin signaling (355).
90.3.3 Polygenic Obesity
In most cases, the inherited risk of obesity appears to be
complex and is very likely polygenic in origin. It remains
a matter of dispute if this risk is due to rare variants of
large effect or common variants of small effect. At the
dawn of the genomic era, it was generally assumed that
common variants, each of small effect, are responsible
for the main genetic contribution to risk of obesity. But
very large genome-wide association studies (GWAS) have
explained a relatively small proportion of the genetic risk
of obesity and some researchers have proposed that his
may be due to the fact that rare variants of large effect
that arise relatively recently in extended families or clans
20 CHAPTER 90  Disorders of the Body Mass
are responsible for a large proportion of the hereditary
risk of obesity (62).
90.3.3.1 Linkage and Candidate Gene Studies of
the Genetics of Human Obesity.  Starting in the 90s,
several research groups attempted to identify genes asso-
ciated with obesity using candidate gene and linkage
studies. Genes thought to be involved in appetite regu-
lation, partitioning of body fat, energy storage, energy
expenditure and other physiologic processes that could
play a role in obesity were investigated to see if variants
in their sequences were linked to risk of obesity. Link-
age studies using minisatellites and other markers were
used to identify genomic regions that appeared linked to
BMI variation. Among the regions and genes found to be
possibly linked to obesity were a region on chromosome
3 that included the adiponectin gene as well as other
genes that were previously not known to be involved in
the control of body composition or energy metabolism
(e.g. PSARL and VPS8) (356). Overall, the results of
these studies were somewhat disappointing and did not
explain most of the genetic risk of obesity.
90.3.3.1.1 GWAS in Humans.  With advancements
in technology, it has become feasible to genotype hun-
dreds of thousands to several million SNPs in individual
microarrays and to test their association with obesity
and related traits. The first large GWAS in humans
led to the identification of FTO (Fat Mass and Obe-
sity associated gene) as a gene that is associated with
variation in BMI in almost every population studied to
date (357). Since then, large GWAS and meta-analyses
have identified dozens of new genes and intergenic loci
associated with BMI, while also replicating many of the
genes identified earlier by candidate and linkage studies
(Table 90-5) shows many of the genes found to be asso-
ciated with obesity in GWAS. We will discuss a few of
these in greater detail:
90.3.3.1.2 FTO.  FTO (Fat mass and obesity asso-
ciated) is a large gene, over 400 kb in size, and several
different SNPs in the first intron have been robustly asso-
ciated with obesity in at least 22 different population
groups (358). The effect size is modest (3 kg increase in
weight in individuals homozygous for the risk allele) but
the risk allele is prevalent at a level of almost 50% in the
Caucasian population, so the gene may still contribute
to obesity in a very large number of individuals. When
it was initially discovered, nothing was known about its
function, let alone its role in the regulation of BMI. Since
then, it has been discovered that the FTO gene product
is an oxoglutarate-dependent demethylase that is able to
bind and demethylate single-stranded DNA and RNA.
How this relates to regulation of body weight remains
unknown at this time.
The first complete Fto null mouse (Fto−/−) was reported
in 2009. The homozygote displayed a phenotype that
includes growth retardation, decreased fat mass and
lean mass, increased metabolic rate and increased food
intake after correction for lean body mass. Heterozy-
gotes, interestingly, are resistant to high-fat-diet-induced
obesity (359). A different mutation that causes partial
loss-of-function of the FTO gene is associated with
decreased fat mass and increased energy expenditure,
but no hyperphagia or growth retardation is seen (360).
The FTO gene is widely expressed in the body, with high
levels of expression in the CNS and particularly in the
hypothalamus. Overexpression of FTO in the arcuate
nucleus in mice leads to a reduction in daily food intake,
while knocking down its expression leads to increased
food intake (361).
The effects of an FTO mutation in humans have been
studied in one extended family and all affected homozy-
gotes suffered from a polymalformation syndrome that
includes postnatal growth retardation, microcephaly,
severe brain deficits, dysmorphic facies, cardiac abnor-
malities and cleft palate and all affected members died
within the first 30 months of life. Heterozygotes in the
extended family have not been studied in detail, but no
overt body weight phenotype has been reported. Thus,
FTO appears to be essential for the normal development
of a number of major organs and a complete lack of FTO
activity is incompatible with life beyond early childhood.
The physiological role of FTO in body-weight regula-
tion remains unknown at this time. The FTO protein may
play a role in appetite regulation as well as resting energy
expenditure. As it is capable of demethylating both DNA
and RNA (362), it may be involved in epigenetic modula-
tion of DNA as well as in the regulation of various RNAs.
90.3.3.1.3 Peroxisome Proliferator-Activated
Receptor Gamma Gene (PPARγ).  A polymorphism
(Pro115Gln) in this gene was found to be associated
with adipocyte differentiation and greater cellular accu-
mulation of triglyceride (278). Another polymorphism
(Ala allele of Pro12Ala polymorphism) was associated
with lower BMI, increased insulin sensitivity and higher
plasma HDL levels (363). Associations of these and
other (PPARγ) polymorphisms with obesity and other
metabolic syndrome phenotypes were replicated in sev-
eral populations (364,365), but explained only a tiny
fraction of the inherited risk of obesity.
90.3.3.1.4 Beta 2- and Beta 3-Adrenergic Recep-
tor Genes (ADRB2, ADRB3).  As described in Section
90.2.2.1, polymorphisms in this adrenergic receptor gene
were associated with BMI and fasting fatty acid levels
in some populations in linkage and candidate gene stud-
ies (366,367). The beta 2- and beta3-adrenergic receptor
genes were also implicated in onset of obesity as well as
blood pressure elevation in other studies (368) but these
associations have not replicated in all studies (369,370).
Some evidence suggests an additive effect of the Beta 3
adrenergic gene and UCP-1 gene variants on body-size
phenotypes (371,372).
90.3.3.1.5 MC4R.  The melanocortin 4 receptor
is an integral component of the leptin–melanocortin
 CHAPTER 90  Disorders of the Body Mass 21

TA B L E 9 0 - 5    
Chromosomal Location Suspected Gene(s) Function Reference
1p31 NEGR1(Neuronal growth regulator 1) Axonal growth promoter (425)
1q25 SEC16B, RASAL2 Endoplasmic reticulum/protein export, GTPase (425)
activator
1q41 LYPLAL1, ZC3H11B Lipase, zinc finger pseudogene (26)
1q43-44 SDCCAG8 Centrosomal protein (426)
2p25 TMEM18 Cell migration modulator (427)
3q27 Near ETV5 Transcription factor (425)
4p13 GNPDA2 Glucosamine-6-phosphate isomerase (427)
6p12 TFAP2B Transcription factor (26)
6p22.2–p21.3 PRL Prolactin (428)
8p23.1 MSRA Reduction of methionine sulfoxide/repair (26,426)
oxidative damage
10p12 PTER Phosphodiesterase related (428)
11p11.2 MTCH2 Mitochondrial carrier protein (427)
12q13 FAIM2, BCDIN3D Neuronal membrane protein/apoptosis (425)
­inhibition. Methyltransferase
14q31 NRXN3 Neurexin; CNS cell adhesion (428,429)
16p11.2 SH2B1 Kinase signaling pathways (425,427)
16q22–q23 MAF Transcription factor; pancreas development (428)
and insulin gene transcription
16q22.2 FTO Nucleic acid demethylase; other functions? (357) Multiple others
18q11.2 NPC1 Niemann–Pick disease gene; intracellular (428)
cholesterol trafficking
18q22 MC4R Melanocortin 4 receptor, appetite regulation. (430) Multiple others
Associated with monogenic obesity
19q13.11 KCTD15 Potassium channel (425,427)
Human genetic loci associated with GWAS or epigenetics studies. Based on Reference (375), Figure 90-1.

regulatory pathway and disruptions in this receptor are
the most common monogenic cause of severe obesity.
GWAS scans reveal that polymorphisms in and around
this gene are also associated with BMI in diverse pop-
ulations (373,374). It is likely that variations in the
functionality of this receptor lead to alterations in sati-
ety and a change in body weight because of increased
appetite.
90.3.3.1.6 UCP Genes.  UCPs are mitochondrial
proteins that help to dissipate the proton gradient at the
inner mitochondrial membrane, decreasing the genera-
tion of ATP. It has been postulated that polymorphisms
in the various uncoupling proteins (UCP1, 2 and 3) can
lead to alteration in energy expenditure and thus in the
accumulation of fat. Members of this gene family were
initially implicated in obesity using candidate gene
approaches (177) and these associations have been repli-
cated in several populations.
90.3.3.1.7 Others.  Other genes including TNFα
gene (TNFA), angiotensin-converting enzyme gene
(ACE), G-protein beta3 subunit gene (GNB3), leptin
gene (LEP), leptin receptor (LEPR), SLC6A14,GAD2,
TMEM18, INSIG2 and ENPP1 have been linked to the
risk of obesity in different studies (375,376). Their exact
role remains unclear in many cases and their combined
contribution to the obesity epidemic is relatively small.
Many examples of human loci identified in GWAS and
imprinting or epigenetics studies as correlated with body
size variables are listed in Table 90-5.
90.3.3.2 Addressing the Human Obesity Problem:
Predictive Factors, Prevention Strategies, and
Treatments.
90.3.3.2.1 Prediction of Adult Obesity during
Childhood.  It is well known that blood pressure, blood
lipid levels, and obesity in childhood tracks into adulthood
(377). Thus childhood obesity itself is a predictor of adult
obesity (378), and of higher-than-expected adult morbid-
ity and mortality (379). These late effects may be unre-
lated to the presence of overweight in adulthood (380).
The presence of a specific growth pattern termed early
adiposity rebound may predict adult obesity in young
children (381). Early adiposity rebound is associated with
parental obesity but not with socioeconomic status or
dietary variables (382). Whereas most of the comorbidi-
ties of obesity occur in adults, they are definitely present
in youth in their presymptomatic or early symptomatic
forms (38,42,383,384), and when present in children,
they are associated with increased cardiovascular mor-
bidity and mortality in their relatives (38–40). The preva-
lence of clinically significant obesity-related morbidities
in youth is definitely on the rise (385), and predicts earlier
onset of more severe problems in adolescents, especially
among African-Americans (386), and in young adults
(387). The alarming increase in type 2 ­diabetes among
22 CHAPTER 90  Disorders of the Body Mass
children and adolescents is directly related to the obesity
epidemic (388).
Many investigators have established the importance
of parental obesity as a predictive factor for childhood
obesity. In a study of the influence of different aspects
of the home environment on obesity in nearly 3000 chil-
dren <8 years of age, maternal obesity was the most sig-
nificant predictor of childhood obesity (389). High birth
weight is a significant predictor of later obesity, and the
most important factor contributing to high birth weight
is maternal diabetes and, to a lesser degree, maternal
obesity (390). The relative risk of developing obesity
in young adulthood is higher for young children if they
have obese parents, and higher for older children if they
themselves are obese (391) (Table 90-6).
The influence of lack of physical activity on the devel-
opment of obesity is reflected in the NHANES data,
especially from the most recent survey. Lack of physi-
cal activity is directly related to television viewing, and
hours of television are significantly correlated to weight
gain during the growing years (392). Reduction in tele-
vision viewing significantly reduced the rate of weight
gain in a study of third-grade children, when compared
to third graders with no intervention (393).
90.3.3.2.2 Prevention Strategies.  Obviously,
community-wide efforts need to be directed toward
increasing physical activity, and changing dietary hab-
its. Reduction of dietary calories and fat, and increas-
ing dietary fiber are recommended (394). The CDC has
developed a resource guide for prevention of obesity and
other chronic diseases that cover many aspects of nutri-
tion, physical activity, and other lifestyle interventions
(395). Counseling obese parents about the risk of child-
hood obesity in their children must be practiced by health
care providers. Enhancement of physical education pro-
grams must be instituted by the school systems. It has
been established that breast-fed infants are less likely to
develop adult obesity than bottle-fed infants (396), add-
ing obesity prevention to the list of benefits of breast
feeding, which health care providers should convey.
90.3.3.2.3 Treatments.  Despite the identification of
specific single gene defects and metabolic abnormalities
TA B L E 9 0 - 6    Odds Ratios for Obesity in Young
Adulthood According to Obesity
Status in Childhood and Parents’
Obesity Status
Obese as Child Number of Obese Parents
Age (yr) Yes versus No 1 versus 0 2 versus 0
1–2 1.3 3.2 13.6
3–5 4.7 3.0 15.3
6–9 8.8 2.6 5.0
10–14 22.3 2.2 2.0
15–17 17.5 2.2 5.6
Data were obtained with permission from Reference (391).
resulting in obesity, novel efficacious therapeutic inter-
ventions have not been forthcoming.
90.3.3.2.4 Medications.  Current medical therapeu-
tic options for treatment of obesity are not very promis-
ing, and the principals of therapy are flawed. Therapy
must be long-term and ongoing, as is the case with treat-
ment of hypertension and diabetes. Current obesity drugs
are not approved for prolonged use, or for use in youth,
have not been extensively tested for safety over long
periods of time, may only benefit a minority of patients
(12,397), and are associated with serious cardiovascu-
lar side effects (398). The latter has resulted in two such
agents being taken off the market. The major classes of
drugs are those that reduce food intake (monoamine
oxidase inhibitors, sympathomimetic drugs), those that
increase energy expenditure (ephedrine, caffeine), and
those that inhibit fat absorption. The use of agents to
induce dietary fat malabsorption has been only mini-
mally successful, and is associated with significant intes-
tinal discomfort if not accompanied by a low-fat diet. Of
course, the diet itself may be nearly equally effective over
the long-term.
The use of recombinant leptin in humans resulted in
a modest and highly variable loss of weight (loss of fat
mass), which was dose related, and occurred in both lean
and obese subjects (399). Leptin treatment in the rare
leptin-deficient patients produced a rapid reduction in
weight and increase in energy expenditure, and antibod-
ies to leptin developed after 2 months (400).
In an animal study, mice that were treated with fatty
acid synthase inhibitors had a reduction in food intake
and in body weight (401). This treatment was effective
when given either systemically or intracerebroventricu-
larly. It inhibited NPY expression in the hypothalamus,
as well as leptin expression in WAT.
90.3.3.2.5 Surgery.  Bariatric surgery perhaps
provides the best weight loss results (402), but both
short- and long-term risks are present. Bariatric surgi-
cal procedures fall into two categories—those reducing
gastric volume, such as vertical banded gastroplasty or
adjustable gastric band, and those that also result in
moderate selective malabsorption such as gastric bypass.
Bypass results in more rapid and more significant weight
loss. As a result, there is a recent trend toward gastric
bypass as the preferred procedure. However, there is an
altered gut hormone response to feeding, potential for
deficiencies of vitamin B12, folate, and iron leading to
anemia, as well as secondary hyperparathyroidism, pre-
sumably due to reduction of calcium absorption due
to loss of gastric acidity. Vertical banded gastroplasty
has been associated with loss of bone density without
hyperparathyroidism (403). Several studies confirmed
that gastric bypass results in reduction in diabetes and
hypertension (404,405), but the risk for metabolic bone
disease, vitamin deficiencies, and intestinal complications
is high (406–409). Surgery to remove fat (liposuction), if
used alone, is not a long-term solution. However, it may

be a useful cosmetic adjunct in patients who are success-
ful with diet and exercise, or surgical gastroplasty.
90.3.3.2.6 Future Directions in Treatment.  Diabetes, and Obesity-related Health Risk Factors, 2001. J.
Of course, the most significant impact on the obesity
epidemic will have to be achieved through patient edu-
cation and prevention strategies. Many resources offer-
ing guidance in these areas are available (410) (see also
www.cdc.gov and www.surgeongeneral.gov). New
medical treatments, including potent agonists for the
β3-AR and the MC4R, are under development. Pres-
ymptomatic genotyping using microarray technologies
may be able to identify those individuals genetically pre-
disposed to obesity, allowing prevention strategies to be
initiated early. Gene or hormone replacement therapy
may become available for those rare patients with single
gene defects. Direct electrostimulation of specific hypo-
thalamic nuclei has been successful in increasing met-
abolic rate and fat utilization, and decreasing feeding
in rats (411). Similar techniques are used in humans to
treat tremors, and perhaps could be applied to obesity
treatment.
REFERENCES
1. Strawbridge, W. J.; Wallhagen, M. I.; Shema, S. J. New
NHLBI Clinical Guidelines for Obesity and Overweight:
Will They Promote Health? Am. J. Public. Health. 2000, 90
(3), 340–343.
2. Calle, E. E.; Rodriguez, C.; Walker-Thurmond, K.; Thun, M. J.
Overweight, Obesity, and Mortality from Cancer in a Prospec-
tively Studies Cohort of U.S. Adults. N. Engl. J. Med. 2003,
348, 1625–1638.
3. Visscher, T. L.S.; Seidell, J. C. The Public Health Impact of
Obesity. Annu. Rev. Public. Health. 2001, 22, 355–375.
4. Ford, E. S.; Giles, W. H.; Mokdad, A. H. Increasing Preva-
lence of the Metabolic Syndrome among U.S. Adults. Diabe-
tes Care 2004, 27 (10), 2444–2449.
5. Hedley, A. A.; Ogden, C. L.; Johnson, C. L.; Carroll, M. D.;
Curtin, L. R.; Flegal, K. M. Prevalence of Overweight and
Obesity among US Children, Adolescents, and Adults, 1999-
2002. J. Am. Med. Assoc. 2004, 291, 2847–2850.
6. Weiss, R.; Dziura, J.; Burgert, T. S.; Tamborlane, W. V.;
Taksali, S. E.; Yeckel, C. W.; Allen, K.; Lopes, M.; Savoye,
M.; Morrison, J., et al. Obesity and the Metabolic Syndrome
in Children and Adolscents. N. Engl. J. Med. 2004, 350,
2362–2374.
7. Olshansky, S. J.; Passaro, D. J.; Hershow, R. C.; Layden, J.;
Carnes, B. A.; Brody, J.; Hayflick, L.; Butler, R. N.; Allison,
D. B.; Ludwig, D. S. A Potential Decline in Life Expectancy
in the United States in the 21st Century. N. Engl. J. Med.
2005, 352 (11), 1138–1145.
8. Ogden, C. L.; Flegal, K. M. Changes in Terminology for
Childhood Overweight and Obesity. Natl. Health Stat. Rep.
2010, 25 (25), 1–5.
9. Ogden, C. L.; Carroll, M. D. Prevalence of Overweight,
Obesity, and Extreme Obesity among Adults: United States,
Trends 1960–1962 through 2007–2008; National Center for
Health Statistics, Centers for Disease Control and Preven-
tion, 2010.
10. Mokdad, A. H.; Serdula, M. K.; Dietz, W. H.; Bowman, B. A.;
Marks, J. S.; Koplan, J. P. The Spread of the Obesity Epidemic
in the United States, 1991–1998. J. Am. Med. Assoc. 1999,
282 (16), 1519–1522.
CHAPTER 90  Disorders of the Body Mass 23
11. Mokdad, A. H.; Ford, E. S.; Bowman, B. A.; Dietz, W. H.;
Vinicor, F.; Bales, V. S.; Marks, J. S. Prevalence of Obesity,
Am. Med. Assoc. 2003, 289 (1), 76–79.
12. National Task Force on the Treatment of Obesity ­Long-Term
Pharmacotherapy in the Management of Obesity. J. Am.
Med. Assoc. 1996, 276, 1907–1915.
13. Wang, M. Trends of Obesity and Underweight in Older
Children and Adolescents in the United States, Brazil, China,
and Russia. Am. J. Clin. Nutr. 2002, 75 (6), 971–977.
14. Friedrich, M. J. Epidemic of Obesity Expands its Spread to
Developing Countries. J. Am. Med. Assoc. 2002, 287 (11),
1382–1386.
15. Fu, W. P.C.; Lee, H. C.; Ng, C. J.; Tay, Y. -K.D.; Kau, C.
Y.; Seow, C. J.; Siak, J.; Hong, C. Y. Screening for Child-
hood Obesity: International vs Population-Specific Defini-
tions. Which Is More Appropriate? Int. J. Obes. 2003, 27 (9),
1121–1126.
16. Hill, J.; Peters, J. Environmental Contributions to the Obe-
sity Epidemic. Science 1998, 280, 1371–1374.
17. Didi, M.; Didcock, E.; Davies, H. A.; Oglivy-Stuart, A. L.;
Wales, J. K. H.; Shalet, S. M. High Incidence of Obesity in
Young Adults After Treatment of Acute Lymphoblastic Leu-
kemia in Childhood. J. Pediatr. 1995, 127, 63–67.
18. Van Dongen-Melman, J. E.W.M.; Hokken-Koelega, A.
C. S.; Hählen, K.; De Groot, A.; Tromp, C. G.; Egeler, R.
M. Obesity After Successful Treatment of Acute Lympho-
blastic Leukemia in Childhood. Pediatr. Res. 1995, 38,
86–90.
19. Choi, S.; Dallman, M. F. Hypothalamic Obesity: Multiple
Routes Mediated by Loss of Function in Medial Cell Groups.
Endocrinology 1999, 140, 4081–4088.
20. De Vile, C. J.; Grant, D. B.; Hayward, R. D.; Kendall, B. E.;
Neville, B. G.R.; Stanhope, R. Obesity in Childhood Cra-
niopharyngioma: Relation to Post-Operative Hypothalamic
Damage Shown by Magnetic Resonance Imaging. J. Clin.
Endocrinol. Metab. 1996, 81, 2734–2737.
21. Dhurandhar, N.; Israel, B.; Kolesar, J.; Mayhew, G.; Cook, M.;
Atkinson, R. Increased Adiposity in Animals Due to a Human
Virus. Int. J. Obes. 2000, 24, 989–996.
22. Dhurandhar, N.; Kulkarni, P.; Ajinkya, S. M.; Sherikar, A.;
Atkinson, R. Association of Adenovirus Infection with Human
Obesity. Obes. Res. 1997, 5, 464–469.
23. Dhurandhar, N. V.; Atkinson, R.; Ahmed, A. Obesity of
Infectious Origin—A Review. Growth Genet. Horm. 2004,
20, 33–39.
24. Schwartz, M. W.; Niswender, K. D. Adiposity Signaling and
Biological Defense Against Weight Gain: Absence of Protec-
tion or Central Hormone Resistance? J. Clin. Endocrinol.
Metab. 2004, 89 (12), 5889–5897.
25. Dulloo, A. G.; Jacquet, J.; Solinas, G.; Montani, J. P.;
Schultz, Y. Body Composition Phenotypes in Pathways to
Obesity and the Metabolic Syndrome. Int. J. Obes. 2010, 34
(Suppl 2), S4–S17.
26. Lindgren, C. M.; Heid, I. M.; Randall, J. C., et  al. Giant
Consortium Genome-Wide Association Scan Meta-Analysis
Identifies Three Loci Influencing Adiposity and Fat Distribu-
tion. PLoS 2009, 5 (6), e1000508.
27. Kissebah, A. H.; Krakower, G. R. Regional Adiposity and
Morbidity. Physiol. Rev. 1994, 74, 761–811.
28. Maes, H. H.; Neale, M. C.; Eaves, L. J. Genetic and Environ-
mental Factors in Relative Body Weight and Human Obe-
sity. Behav. Genet. 1997, 27 (4), 325–351.
29. Stunkard, A. J.; Foch, T. T.; Hrubec, Z. A Twin Study of
Human Obesity. J. Am. Med. Assoc. 1986, 256, 51–54.
30. Sorensen, T.; Price, R. A.; Stunkard, A. J.; Schulsinger, F.
Genetics of Obesity in Adult Adoptees and their Biological
Siblings. Br. Med. J. 1989, 298, 87–90, (January 14).
24 CHAPTER 90  Disorders of the Body Mass
31. Faith, M. S.; Pietrobelli, A.; Nunez, C.; Heo, M.;
Heymsfield, S. B.; Allison, D. B. Evidence for Independent
Genetic Influences on Fat Mass and Body Mass Index in a
Pediatric Twin Sample. Pediatrics 1999, 104, 61–67.
32. Moll, P. P.; Burns, T. L.; Lauer, R. M. The Genetic and
Environmental Sources of Body Mass Index Variability: The
Muscatine Ponderosity Family Study. Am. J. Hum. Genet.
1991, 49, 1243–1255.
33. Price, R. A. Within Birth Cohort Segregation Analyses
­Support Recessive Inheritance of Body Mass Index in White
and African-American Families. Int. J. Obes. 1996, 20,
1044–1047.
34. Bouchard, C.; Rice, T.; Lemieux, S.; Després, J.-P.; Pérusse, L.;
Rao, D. C. Major Gene for Abdominal Visceral Fat Area in the
Québec Family Study. Int. J. Obes. 1996, 20, 420–427.
35. Hasstedt, S. J.; Ramirez, M. E.; Kuida, H.; Williams, R. R.
Recessive Inheritance of a Relative Fat Pattern. Am. J. Hum.
Genet. 1988, 45, 917–925.
36. Knowler, W. C.; Pettitt, D. J.; Saad, M. F.; Charles, M. A.;
Nelson, R. G.; Howard, B. V.; Bogardus, C.; Bennett, P. H.
Obesity in the Pima Indians: Its Magnitude and Relationship
with Diabetes. Am. J. Clin. Nutr. 1991, 53, 1543s–1551s.
37. Coleman, D. L.; Hummel, K. P. The Influence of Genetic
Background in the Expression of the Obese (ob) Gene in the
Mouse. Diabetologia 1973, 9, 287–293.
38. Burns, T. L.; Moll, P. P.; Lauer, R. M. The Relation Between
Ponderosity and Coronary Risk Factors in Children and
Their Relatives. Am. J. Epidemiol. 1989, 129, 973–987.
39. Burns, T. L.; Moll, P. P.; Lauer, R. M. Increased Familial
Cardiovascular Mortality in Obese School Children: The
Muscatine Ponderosity Family Study. Pediatrics 1992, 89
(2), 262–268.
40. Schrott, H. G.; Clarke, W. R.; Wiebe, D. A.; Connor, W. E.;
Lauer, R. M. Increased Coronary Mortality in Relatives of
Hypercholesterolemic School Children: The Muscatine Study.
Circulation 1979, 59 (2), 320–326.
41. Burns, T. L.; Letuchy, E. M.; Paulos, R.; Witt, J. Child-
hood Predictors of the Metabolic Syndrome in Middle-Aged
Adults: The Muscatine Study. J. Pediatr. 2009, 155 (3), S5.
42. Freedman, D. S.; Dietz, W. H.; Srinivasan, S. R.; Berenson,
G. S. The Relation of Overweight to Cardiovascular Risk
Factors among Children and Adolescents: The Bogalusa
Heart Study. Pediatrics 1999, 103, 1175–1182.
43. Srinivasan, S. R.; Myers, L.; Berenson, G. S. Temporal Asso-
ciation Between Obesity and Hyperinsulinemia in Children,
Adolescents, and Young Adults: The Bogalusa Heart Study.
Metab. Clin. Exp. 1999, 48, 928–934.
44. Mahaney, M. C.; Blangero, J.; Comuzzie, A. G.; VandeBerg,
J. L.; Stern, M. P.; MacCluer, J. W. Plasma HDL Choles-
terol, Triglycerides, and Adiposity: A Quantitative Genetic
Test of the Conjoint Trait Hypothesis in the San Antonio
Family Heart Study. Circulation 1995, 92 (11), 3240–3248.
45. Hong, Y.; Rice, T.; Gagnon, J.; Despres, J.-P.; Nadeau,
A.; Perusse, L.; Bouchard, C.; Leon, A. S.; Skinner, J. S.;
Wilmore, J. H., et  al. Familial Clustering of Insulin and
Abdominal Visceral Fat: The Heritage Family Study. J. Clin.
Endocrinol. Metab. 1998, 83, 4239–4245.
46. Rice, T.; Nadeau, A.; Perusse, L.; Bouchard, C.; Rao, D. C.
Familial Correlations in the Québec Family Study: Cross-
trait Familial Resemblance for Body Fat with Plasma Glu-
cose and Insulin. Diabetologia 1996, 39, 1357–1364.
47. Norman, R. A.; Thompsom, D. B.; Foroud, T.; Garvey, W.
T.; Bennett, P. H.; Bogardus, C.; Ravussin, E. Genome Wide
Search for Genes Influencing Percent Body Fat in Pima Indi-
ans: Suggestive Linkage at Chromosome 11q21-q22. Am. J.
Hum. Genet. 1997, 60, 166–173.
48. Knoll, J. H.; Sinnett, D.; Wagstaff, J.; Glatt, K.; Schanz
Wilcox, A.; Whiting, P. M.; Wingrove, P.; Sikela, J. M.;
Lalande, M. FISH Ordering of References Markers and of
the Gene for the α5 Subunit of the Gamma-Aminobutyric
Acid Receptor (GABRA5) within the Angelman and
Prader–Willi Syndrome Chromosomal Regions. Hum.
Mol. Genet. 1993, 2, 183–189.
49. Sheffield, V. C. Use of Isolated Populations in the Study of
a Human Obesity Syndrome, the Bardet–Biedl Syndrome.
Pediatr. Res. 2004, 55 (6), 908–911.
50. Michaud, J. L.; Heon, E.; Guilbert, F.; Weill, J.; Puech, B.;
Benson, L.; Smallhorn, J. F.; Shuman, C. T.; Buncic, J. R.;
Levin, A. V., et  al. Natural History of Alstrom Syndrome
in Early Childhood: Onset with Dilated Cardiomyopathy. J.
Pediatr. 1996, 128, 225–229.
51. Wilson, G. N.; Al Saadi, A. A. Obesity and Abnormal Behav-
iour Associated with Interstitial Deletion of Chromosome 18
(q12.2q21.1). J. Med. Genet. 1988, 26, 62–63.
52. Leibel, R. L.; Rosenbaum, M.; Hirsch, J. Changes in Energy
Expenditure Resulting from Altered Body Weight. N. Engl.
J. Med. 1995, 332, 621–628.
53. Rosenbaum, H. Effects of Changes in Body Weight on
Carbohydrate Metabolism, Catecholamine Excretion,
and Thyroid Function. Am. J. Clin. Nutr. 2000, 71 (6),
1421–1432.
54. Morrison, J. A.; Alfaro, M. P.; Khoury, P.; Thornton, B. B.;
Daniels, S. R. Determinants of Resting Energy Expenditure
in Young Black Girls and Young White Girls. J. Pediatr.
1996, 129, 637–642.
55. Kaplan, A. S.; Zemel, B. S.; Stallings, V. A. Differences in
Resting Energy Expenditure in Prepubertal Black Children
and White Children. J. Pediatr. 1996, 129, 643–647.
56. Bacha, F.; Saad, R.; Gungor, N.; Janosky, J.; Arslanian, S. A.
Obesity, Regional Fat Distribution, and Syndrome X in Obese
Black Versus White Adolescents: Race Differential in Diabe-
togenic and Atherogenic Risk Factors. J. Clin. Endocrinol.
Metab. 2003, 88 (6), 2534–2540.
57. Roberts, S. B. Energy Expenditure and the Development of
Early Obesity. Ann. NY Acad. Sci. 1993, 699, 18–25.
58. Bassett, D. R., Jr.; Schneider, P. L.; Huntington, G. E. Physi-
cal Activity in an Old Order Amish Community. Med. Sci.
Sports Excerc. 2004, 36, 79–85.
59. Bouchard, C. Defining the Genetic Architecture of the Pre-
disposition to Obesity: A Challenging but not Insurmount-
able Task. Am. J. Clin. Nutr. 2010, 91 (1), 5–6.
60. Chung, W. K. An Overview of Monogenic and Syndromic
Obesities in Humans. Pediatr. Blood Cancer 201110.1002/
pbc.23372.
61. Rokholm, B.; Silventoinen, K.; Skytthe, A.; Kyvik, K. O.;
Sørensen, T. I. Increased Genetic Variance of BMI with
a Higher Prevalence of Obesity. PLoS One 2011, 6 (6),
e20816.
62. Lupski, J. R.; Belmont, J. W.; Boerwinkle, E.; Gibbs, R. A.
Clan Genomics and the Complex Architecture of Human
Disease. Cell 2011, 147 (1), 32–43.
63. Coleman, D. L. Effects of Parabiosis of Obese with Diabetes
and Normal Mice. Diabetologia 1973, 9, 294–298.
64. Tokuyama, K.; Himms-Hagen, J. Increased Sensitivity of the
Genetically Obese Mouse to Corticosterone. Am. J. Phys.
1987, 252, E202–E208.
65. Coleman, D. L. Obese and Diabetes: Two Mutant Genes
Causing Diabetes-Obesity Syndromes in Mice. Diabetologia
1978, 14, 141–148.
66. Friedman, J. M.; Leibel, R. L.; Siegel, D. S.; Walsh, J.;
Bahary, N. Molecular Mapping of the Mouse ob Mutation.
Genomics 1991, 11, 1054–1062.
67. Zhang, Y.; Proenca, R.; Maffel, M.; Barone, M.; Leopold, L.;
Friedman, J. M. Positional Cloning of the Mouse Obese Gene
and its Human Homologue. Nature 1994, 372, 425–432,
(December 1).

68. Cinti, S.; Frederich, R. C.; Zingaretti, M. C.; De Matteis, R.;
Flier, J. S.; Lowell, B. B. Immunohistochemical Localization
of Leptin and Uncoupling Protein in White and Brown Adi-
pose Tissue. Endocrinology 1997, 138, 797–804.
69. Pelleymounter, M. A.; Cullen, M. J.; Baker, M. B.; Hecht, R.;
Winters, D.; Boone, T.; Collins, F. Effects of the Obese Gene
Product on Body Weight Regulation in ob/ob Mice. Science
1995, 269, 540–543, (July 28).
70. Muzzin, P.; Eisensmith, R. C.; Copeland, K. C.; Woo, S. L.C.
Correction of Obesity and Diabetes in Genetically Obese
Mice by Leptin Gene Therapy. Proc. Natl. Acad. Sci. 1996,
93, 14804–14808.
71. Halaas, J. L.; Gajiwala, K. S.; Maffei, M.; Cohen, S. L.;
Chait, B. T.; Rabinowitz, D.; Lallone, R. L.; Burley, S. K.;
Friedman, J. M. Weight-Reducing Effects of the Plasma
Protein Encoded by the Obese Gene. Science 1995, 269,
543–546, (July 28).
72. Chen, G.; Koyama, K.; Yuan, X.; Lee, Y.; Zhou, Y. T.;
O’Doherty, R.; Newgard, C. B.; Unger, R. H. Disappear-
ance of Body Fat in Normal Rats Induced by Adenovirus-­
mediated Leptin Gene Therapy. Proc. Natl. Acad. Sci. 1996,
93, 14795–14799, (December).
73. Chehab, F. F.; Lim, M. E.; Lu, R. Correction of the Steril-
ity Defect in Homozygous Obese Female Mice by Treatment
with the Human Recombinant Leptin. Nat. Genet. 1996, 12,
318–320, (March).
74. Chehab, F. F.; Mounzih, K.; Lu, R.; Lim, M. E. Early Onset
of Reproductive Function in Normal Female Mice Treated
with Leptin. Science 1997, 275, 88–90, (3 January).
75. Cheung, C. C.; Thornton, J. E.; Kuijper, J.; Weigle, D. S.;
Clifton, D. K.; Steiner, R. A. Leptin Is a Metabolic Gate for
the Onset of Puberty in The Female Rat. Endocrinology
1997, 138 (2), 855–858.
76. Jacob, R. J.; Dziura, J.; Medwick, M. B.; Leone, P.; Caprio, S.;
During, M.; Shulman, G. I.; Sherwin, R. S. The Effect of Leptin
is Enhanced by Microinjection into the Ventromedial Hypo-
thalamus. Diabetes 1997, 46, 150–152.
77. Glaum, S. R.; Hara, M.; Bindokas, V. P.; Lee, C. C.;
­Polonsky, K. S.; Bell, G. I.; Miller, R. J. Leptin, the Obese
Gene Product, Rapidly Modulates Synaptic Transmission in
the Hypothalamus. Mol. Pharmacol. 1996, 50, 230–235.
78. Sivitz, W. I.; Walsh, S.; Morgan, D.; Donohoue, P.;
Haynes, W.; Leibel, R. L. Plasma Leptin in Diabetic and
Insulin-Treated Diabetic and Normal Rats. Metabolism
1998, 8, 584–591.
79. Sinha, M. K.; Opentanova, I.; Ohannesian, J. P.; Kolaczynski,
J. W.; Heiman, M. L.; Hale, J.; Becker, G. W.; Bowsher, R.
R.; Stephens, T. W.; Caro, J. F. Evidence of Free and Bound
Leptin in Human Circulation. J. Clin. Invest. 1996, 98,
1277–1282.
80. Considine, R. V.; Sinha, M. K.; Heiman, M. L.;
Kriauciunas, A.; Stephens, T. W.; Nyce, M. R.; Ohan-
nesian, J. P.; Marco, C. C.; McKee, L. J.; Bauer, T. L.,
et  al. Serum Immunoreactive-leptin Concentrations in
Normal-Weight and Obese Humans. N. Engl. J. Med.
1996, 334, 292–295.
81. Kichey, M. S.; Israel, R. G.; Gardiner, S. N.;
Considine, R. V.; McCammon, M. R.; Tyndall, G. L.;
Houmard, J. A.; Marks, R. H. L.; Caro, J. F. Gender Dif-
ferences in Serum Leptin Levels in Humans. Biochem. Soc.
Trans. 1996, 59, 1–6.
82. Rosenbaum, M.; Nicolson, M.; Hirsch, J.; Heymsfield, S.
B.; Gallagher, D.; Chu, F.; Leibel, R. L. Effects of Gender,
Body Composition, and Menopause on Plasma Concen-
trations of Leptin. J. Clin. Endocrinol. Metab. 1996, 81,
3424–3427.
83. Kennedy, A.; Gettys, T. W.; Watson, P.; Wallace, P.; Gan-
away, E.; Pan, Q.; Garvey, T. The Metabolic Significance
CHAPTER 90  Disorders of the Body Mass 25
of Leptin in Humans: Gender-based Differences in Rela-
tionship to Adiposity, Insulin Sensitivity, and Energy
Expenditure. J. Clin. Endocrinol. Metab. 1997, 82,
1293–1300.
84. Ronnemaa, R.; Karonen, S. L.; Rissanen, A.; Koskenvuo, M.;
Koivisto, V. A. Relation Between Plasma Leptin Levels and
Measures of Body Fat in Identical Twins Discordant for Obe-
sity. Ann. Intern. Med. 1997, 126, 26–31.
85. Horlick, M. B.; Rosenbaum, M.; Nicolson, M.; Levine, L. S.;
Fedun, B.; Wang, J.; Pierson, R. N., Jr.; Leibel, R. L. Effect of
Puberty on the Relationship Between Circulating Leptin and
Body Composition. J. Clin. Endocrinol. Metab. 2000, 85 (7),
2509–2518.
86. Ostlund, R. E.; Yang, J. W.; Klein, S.; Gingerich, R. Rela-
tion Between Plasma Leptin Concentration and Body Fat,
Gender, Diet, Age, and Metabolic Covariates. J. Clin. Endo-
crinol. Metab. 1996, 81, 3909–3913.
87. Havel, P. J.; Kasim-Karakas, S.; Mueller, W.; Johnson, P. R.;
Gingerich, R. L.; Stern, J. S. Relationship of Plasma Leptin
to Plasma Insulin and Adiposity in Normal Weight and
­Overweight Women: Effects of Dietary Fat Content and Sus-
tained Weight Loss. J. Clin. Endocrinol. Metab. 1996, 81,
4406–4413.
88. Grinspoon, S.; Gulick, T.; Askari, H.; Landt, M.; Lee,
K.; Anderson, E.; Ma, Z.; Vignati, L.; Bowsher, R.;
Herzog, D., et  al. Serum Leptin Levels in Women with
Anorexia ­Nervosa. J. Clin. Endocrinol. Metab. 1996, 81,
3861–3863.
89. Weigle, D. S.; Ganter, S. L.; Kuijper, J. L.; Leonetti, D. L.;
Boyko, E. J.; Fujimoto, W. Y. Effect of Regional Fat Distri-
bution and Prader–Willi Syndrome on Plasma Leptin Levels.
J. Clin. Endocrinol. Metab. 1997, 82, 566–570.
90. Hassink, S. G.; Delancey, E.; Sheslow, D. V.; Smithkirwin,
S. M.; O’Connor, D. M.; Considine, R. V.; Opentanova, I.;
Dostal, K.; Spear, M. L.; Leef, K., et al. Placental Leptin—An
Important New Growth Factor in Intrauterine and Neonatal
Development. Pediatrics 1997, 100, E11–E16.
91. Sinha, M. K.; Sturis, J.; Ohannesian, J.; Magosin, S.;
­Stephens, T.; Heiman, M. L.; Polonsky, K. S.; Caro, J. F.
Ultradian Oscillations of Leptin Secretion in Humans. Bio-
chem. Biophys. Res. Commun. 1996, 228 (1724), 733–738.
92. Laughlin, G. A.; Yen, S. S. C. Hypoleptinemia in Women
Athletes: Absence of a Diurnal Rhythm with Amenorrhea. J.
Clin. Endocrinol. Metab. 1997, 82 (1), 318–321.
93. Cohen, B.; Novick, D.; Rubinstein, M. Modulation of
­Insulin Activities by Leptin. Science 1996, 274, 1185–1188,
(15 November).
94. Montague, C. T.; Farooqi, S.; Whitehead, J. P.; Soos, M.
A.; Rau, H.; Wareham, N. J.; Sewter, C. P.; Digby, J. E.;
­Mohammed, S. N.; Hurst, J. A., et  al. Congenital Leptin
Deficiency Is Associated with Severe Early-Onset Obesity in
Humans. Nature 1997, 387, 903–908.
95. Considine, R. V.; Considine, E. L.; Williams, C. J.;
Nyce, M. R.; Magosin, S. A.; Bauer, T.; Rosato, E. L.;
­Colberg, J.; Caro, J. F. Evidence Against Either a Premature
Stop Codon or the Absence of Obese Gene mRNA in Human
Obesity. J. Clin. Invest. 1995, 95, 2986–2988.
96. Maffei, M.; Stoffel, M.; Barone, M.; Moon, B.;
Dammerman, M.; Ravussin, E.; Bogardus, C.; Ludwig, D.
S.; Flier, J.; Talley, M., et  al. Absence of Mutations in the
Human ob Gene in Obese/Diabetic Subjects. Diabetes 1996,
45, 679–682.
97. Considine, R. V.; Concsidine, E. L.; Williams, C. J.;
Nyce, M. R.; Zhang, P.; Opentanova, I.; Ohannesian, J. P.;
Kolaczynski, J. W.; Bauer, T. L.; Moore, J. H., et al. Muta-
tion Screening and Identification of a Sequence Variation
in the Human ob Coding Region. Biochem. Biophys. Res.
Commun. 1996, 220, 735–739.
26 CHAPTER 90  Disorders of the Body Mass
98. Norman, R. A.; Leibel, R. L.; Chung, W. K.; Power-Kehoe, L.;
Chua, S. C., Jr.; Knowler, W. C.; Thompson, D. B.; Bogardus,
C.; Ravussin, E. Absence of Linkage of Obesity and Energy
Metabolism to Markers Flanking Homologues of Rodent Obe-
sity Genes in Pima Indians. Diabetes 1996, 45, 1229–1232.
99. Stirling, B.; Cox, N. J.; Bell, G. I.; Hanis, C. L.; Speilman, R. S.;
Concannon, P. Identification of Microsatellite Markers near
the Human ob Gene and Linkage Studies in NIDDM-Affected
Sib Pairs. Diabetes 1995, 44, 999–1001.
100. Bray, M.; Boerwinkle, E.; Hanis, C. L. OB Gene not
Linked to Human Obesity in Mexican American Affected
Sib Pairs from Starr County, Texas. Hum. Genet. 1996,
98, 590–595.
101. Clement, K.; Garner, C.; Hager, J.; Philippi, A.; LeDuc, C.;
Carey, A.; Harris, T. J. R.; Jury, C.; Cardon, L. R.; Bas-
devant, A., et  al. Indication for Linkage of the Human ob
Gene Region with Extreme Obesity. Diabetes 1996, 45,
687–690.
102. Reed, D. R.; Ding, Y.; Xu, W.; Cather, C.; Green, E. D.;
Price, R. A. Extreme Obesity May Be Linked to Markers
Flanking the Human ob Gene. Diabetes 1996, 45, 691–694.
103. Duggirala, R.; Stern, M. P.; Mitchell, B. D.; Reinhart, L. J.;
Shipman, P. A.; Uresandi, O. C.; Chung, W. K.; Leibel, R. L.;
Hales, C. N.; O’Connell, P., et al. Quantitative Variation in
Obesity-Related Traits and Insulin Presursors Linked to the
ob Gene Region on Human Chromosome 7. Am. J. Hum.
Genet. 1996, 59, 694–703.
104. Hager, J.; Clement, K.; Francke, S.; Dina, C.; Raison, J.;
Lahlou, N.; Rich, N.; Pelloux, V.; Basdevant, A.; Guy-Grand,
B., et al. A Polymorphism in the 5’ Untranslated Region of
Human ob Gene Is Associated with Low Leptin Levels. Int.
J. Obes. 1998, 22, 200–205.
105. Shintani, M.; Ikegami, H.; Fujisawa, T.; Kawaguchi, Y.;
Ohishi, M.; Katsuya, T.; Higaki, J.; Shimamoto, K.; Ogi-
hara, T. Leptin Gene Polymorphism Is Associated with
Hypertension Independent of Obesity. J. Clin. Endocrinol.
Metab. 2002, 87 (6), 2909–2912.
106. Tartaglia, L. A.; Dembski, M.; Weng, X.; Deng, N.;
­Culpepper, J.; Devos, R.; Richards, G. J.; Campfield, L.
A.; Clark, F. T.; Deeds, J., et al. Identification and Expres-
sion Cloning of a Leptin Receptor, OB-R. Cell 1996, 83,
1263–1271.
107. Truett, G. E.; Bahary, N.; Friedman, J. M.; Leibel, R. L. Rat
Obesity Gene Fatty (fa) Maps to Chromosome 5: Evidence
for Homology with the Mouse Gene Diabetes (db). Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 7806–7809.
108. Chua, S. C.; White, D. W.; Wu-Peng, X. S.; Liu, S. M.;
Okada, N.; Kershaw, E. E.; Chung, W. K.; Power-Kehoe, L.;
Chua, M.; Tartaglia, L. A., et al. Phenotype of Fatty due to
Gln269Pro Mutation in the Leptin Receptor (lepr). Diabetes
1996, 45, 1141–1143.
109. Iida, M.; Murakami, T.; Ishida, K.; Mizuno, A.; Kuwajima, M.;
Shima, K. Phenotype-Linked Amino Acid Alteration in Leptin
Receptor cDNA from Zucker Fatty (fa/fa) Rat. Biochem. Bio-
phys. Res. Commun. 1996, 222, 19–26.
110. Chua, S. C.; Chung, W. K.; Wu-Peng, S.; Zhang, Y.;
Liu, S. -M.; Tartaglia, L.; Leibel, R. L. Phenotypes of Mouse
Diabetes and Rat Fatty Due to Mutations in the OB (Leptin)
Receptor. Science 1996, 271, 994–996.
111. Wupeng, X. S.; Chua, S. C.; Okada, N.; Liu, S. M.;
Nicolson, M.; Leibel, R. L. Phenotype of the Obese Koletsky
(F) Rat Due to Tyr763Stop Mutation in the Extracellular
Domain of the Leptin Receptor (Lepr)- Evidence for Defi-
cient Plasma-to-CSF Transport of Leptin in both Zucker and
Koletsky Obese Rat. Diabetes 1997, 46, 513–518.
112. Lee, G. -H.; Proenca, R.; Montez, J. M.; Carroll, K. M.;
­Darvishzadeh, J. G.; Lee, J. I.; Friedman, J. M. Abnormal
Splicing of the Leptin Receptor in Diabetic Mice. Nature
1996, 379, 632–635.
113. Chen, H.; Charlat, O.; Tartaglia, L. A.; Woolf, E. A.; Weng, X.;
Ellis, S. J.; Lakey, N. D.; Culpepper, J.; Moore, K. J.; Breitbart,
R. E., et al. Evidence that the Diabetes Gene Encodes the Leptin
Receptor: Identification of a Mutation in the Leptin Receptor
in db/db Mice. Cell 1996, 84, 491–495.
114. Cioffi, J. A.; Shafer, A. W.; Zupancic, T. J.; Smith-Gbur, J.;
Mikhail, A.; Platika, D.; Snodgrass, H. R. Novel B219/OB
Receptor Isoforms: Possible Role of Leptin in Hematopoi-
esis and Reproduction. Nat. Med. 1996, 2 (5), 585–589,
(May).
115. Cumin, F.; Baum, H. P.; Levens, N. Leptin Is Cleared from
the Circulation Primarily by the Kidney. Int. J. Obes. 1996,
20, 1120–1126.
116. Yang, G.; Ge, H.; Boucher, A.; Yu, X.; Li, C. Modulation
of Direct Leptin Signaling by Soluble Leptin Receptor. Mol.
Endocrinol. 2004, 18 (6), 1354–1362.
117. Ghilardi, N.; Ziegler, S.; Wiestner, A.; Stoffel, R.; Heim, M.
H.; Skoda, R. C. Defective STAT Signaling by the Leptin
Receptor in Diabetic Mice. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 6231–6235.
118. Vaisse, C.; Halaas, J. L.; Horvath, C. M.; Darnell, J. E.;
­Stoffel, M.; Friedman, J. M. Leptin Activation of STAT3 in
the Hypothalamus of Wildtype and ob/ob Mice but not in
db/db Mice. Nat. Genet. 1996, 14, 95–97.
119. Dulloo, A. G.; Miller, D. S. Prevention of Genetic fa/fa Obe-
sity with an Ephedrine-Methylxanthines Thermogenic Mix-
ture. Am. J. Phys. 1987, 252, R507–R513.
120. Dulloo, A. G.; Miller, D. S. Reversal of Obesity in the Genet-
ically Obese fa/fa Zucker Rat with an Ephedrine/Methylxan-
thines Thermogenic Mixture. J. Nutr. 1987, 117, 383–389.
121. Eikelis, S. A.K.E. Interactions Between Leptin and the
Human Sympathetic Nervous System. Hypertension 2003,
41 (5), 1072–1079.
122. Hausberg, M.; Morgan, D. A.; Chapleau, M. A.; Sivitz, W.
I.; Mark, A. L.; Haynes, W. G. Differential Modulation of
Leptin-induced Sympathoexcitation by Baroreflex Activa-
tion. J. Hypertens. 2002, 20 (8), 1633–1641.
123. Chung, W. K.; Belfi, K.; Chua, M.; Wiley, J.; Mackintosh, R.;
Nicolson, M.; Boozer, C.; Leibel, R. L. Heterozygosity for Lepob
and Leprdb Affects Body Composition and Leptin Homeostasis
in Adult Mice. Am. J. Phys. 1998, 274, R985–R990.
124. Stephens, T. W.; Basinski, M.; Bristow, P. K.; Bue-Valleskey,
J. M.; Burgett, S. G.; Craft, L.; Hale, J.; Hoffmann, J.; Hsi-
ung, H. M.; Kriauciunas, A. The Role of Neuropeptide Y in
the Antiobesity Action of the Obese Gene Product. Nature
1995, 377 (6549), 530–532, (October 12).
125. Pinto, S.; Roseberry, A. G.; Liu, H.; Diano, S.; Shanabrough,
M.; Cai, X.; Friedman, J. M.; Horvath, T. L. Rapid Rewir-
ing of Arcuate Nucleus Feeding Circuits by Leptin. Science
2004, 304, 110–115.
126. Huang, L. Leptin: A Multifunctional Hormone. Cell
Research 2000, 10 (2), 81–92.
127. Shirasaka, T.; Takasaki, M.; Kannan, H. Cardiovascular
effects of Leptin and Orexins. Am. J. Physiol. Regul. Integr.
Comp. Physiol. 2003, 284 (3), R639–R651.
128. Myers, M. G.; Leibel, R. L.; Seeley, R. J.; Schwartz, M. W.
Obesity and Leptin Resistance: Distiguishing Cause from
Effect. Trends. Endocrinol. Metab. 2010, 21 (11), 643–651.
129. Thompson, D. B.; Janssen, R. C.; Ossowski, V. M. P. M.;
Knowler, W. C.; Bogardus, C. Evidence for Linkage Between
a Region on Chromosome 1 p and the Acute Insulin Response
in Pima Indians. Diabetes 1995, 44, 478–481.
130. Chung, W. K.; Power-Kehoe, L.; Chua, M.; Lee, R.;
Leibel, R. L. Genomic Structure of the Human OB Recep-
tor and Identification of Two Novel Intronic Microsatellites.
Genome. Res. 1996, 6, 1192–1199.
131. Chagnon, Y. C.; Perusse, L.; Lamothe, M.; Chagnon, M.;
Nadeau, A.; Dionne, F. T.; Gagnon, J.; Chung, W. K.; Leibel,
R. L.; Bouchard, C. Suggestive Linkages Between Markers

on Human 1p.32-p22 and Body Fat and Insulin Levels in
the Québec Family Study. Obes. Res. 1997, 5 (2), 115–121.
132. Chung, W. K.; Power-Kehoe, L.; Chua, M.; Chu, F.;
Aronne, L.; Huma, Z.; Sothern, M.; Udall, J. N.; Kahle, B.;
Leibel, R. L. Exonic and Intronic Sequence Variation in the
Human Leptin Receptor Gene (LEPR). Diabetes 1997, 46,
1509–1511.
133. Thompson, D. B.; Ravussin, E.; Bennett, P. H.; Bogardus, C.
Structure and Sequence Variation at the Leptin Receptor Gene
in Lean and Obese Pima Indians. Hum. Mol. Genet. 1997, 6,
675–679.
134. Chagnon, Y. C.; Wilmore, J. H.; Borecki, I. B.; Gagnon, J.;
Perusse, L.; Chagnon, M.; Collier, G. R.; Leon, A. S.; Skin-
ner, J. S.; Rao, D. C., et al. Associations Between the Leptin
Receptor Gene and Adiposity in Middle-Age Caucasian
Males from the HERITAGE Family Study. J. Clin. Endocri-
nol. Metab. 2000, 85, 29–34.
135. Donohoue, P. A.; Burns, T. L.; Mendoza, M. C.B.;
Chung, W. K.; Leibel, R. L. Lys656Asn Variant of the Leptin
Receptor Gene (LEPR) and the β-3 Adrenergic Receptor
(B3AR) Gene Linked to Body Mass Index in Humans: The
Muscatine Study. Pediatr. Res. 2000, 47, 127A.
136. Chagnon, Y. C.; Chung, W. K.; Perusse, L.; Chagnon, M.;
­Leibel, R. L.; Bouchard, C. Linkages and Associations
Between the Leptin Receptor (LEPR) Gene and Human Body
Composition in the Québec Family Study. Int. J. Obes. 1999,
23, 278–286, Ref Type: Abstract.
137. Silver, K.; Walston, J.; Chung, W. K.; Yao, F.; Parikh, V. V.;
Andersen, R.; Cheskin, L. J.; Elahi, D.; Muller, D.; Leibel,
R. L., et al. The Gln223Arg and Lys656Asn Polymorphisms in
the Human Leptin Receptor Do Not Associate with Traits
Related to Obesity. Diabetes 1997, 46, 1898–1900.
138. Echwald, S. M.; Sorenson, T. D.; Sorenson, T. I. A.;
­Tybjaerg-Hansen, A.; Andersen, T.; Chung, W. K.; Leibel,
R. L.; Pedersen, O. Amino Acid Variants on the Human
Leptin Receptor: Lack of Association to Juvenile Onset
Obesity. Biochem. Biophys. Res. Commun. 1997, 233,
248–252.
139. Heo, M.; Leibel, R. L.; Fintaine, K. R.; Boyer, B. B.; Chung,
W. K.; Koulu, M.; Karvonene, M. K.; Pesonen, U.; Rissanen,
A.; Laasko, M., et al. A Meta-Analytic Investigation of Link-
age and Association of Common Leptin Receptor (Lepr)
Polymorphisms with Body Mass Index and Waist Circum-
ference. Int J Obesity 2002, 26, 640–646.
140. Clement, K.; Vaisse, C.; Lahlous, N.; Cabrol, S.; Pelloux, V.;
Cassuto, D.; Gourmelen, M.; Dina, C.; Chambaz, J.; Lacortw,
J. -M., et al. A Mutation in the Human Leptin Receptor Gene
Causes Obesity and Pituitary Dysfunction. Nature 1998,
392, 398–401.
141. Clement, K.; Vega, N.; Laville, M.; Pelloux, V.; Guy-Grand,
B.; Basdevant, A.; Vidal, H. Adipose Tissue Gene Expression
in Patients with a Loss of Function Mutation in the Leptin
Receptor. Int. J. Obes. 2002, 26 (12), 1533–1538.
142. Smith, R. J.; Berlin, C. I.; Hejtmancil, J. F.; Keats, B. J.;
­Kimberling, W. J.; Lewis, R. A.; Moller, C. G.; Pelias, M. Z.;
Tranebjaerg, L. Clinical Diagnosis of the Usher Syndromes.
Usher Syndrome Consortium. Am. J. Med. Genet. 1994, 50,
32–38.
143. Carmi, R.; Rokhlina, T.; Kwitek-Black, A. E.; Elbedour, K.;
Nishimura, D.; Stone, E. M.; Sheffield, V. C. Use of a DNA
Pooling Strategy to Identify a Human Obesity Syndrome
Locus on Chromosome 15. Hum. Mol. Genet. 1995, 4, 9–13.
144. Chung, W. K.; Goldberg-Berman, J.; Power-Kehoe, L.;
Leibel, R. L. Molecular Mapping of the Tubby (tub)
­Mutation on Mouse Chromosome 7. Genomics 1996, 32,
210–217.
145. Noben-Trauth, K.; Naggert, J. K.; North, M. A.; Nishina,
P. M. A Candidate Gene for the Mouse Mutation Tubby.
Nature 1996, 380, 534–538.
CHAPTER 90  Disorders of the Body Mass 27
146. Kleyn, P. W.; Fan, W.; Kovats, S. G.; Lee, J. J.; Pulido, J. C.;
Wu, Y.; Berkemeier, L. R.; Misumi, D. J.; Holmgren, L.; Char-
lat, O., et al. Identification and Characterization of the Mouse
Obesity Gene Tubby: A Member of a Novel Gene Family. Cell
1996, 85, 281–290.
147. Boggon, T. J.; Shan, W.-S.; Santagata, S.; Myers, S. C.;
­Shapiro, L. Implication of Tubby Proteins as Transcription
Factors by Structure-Based Functional Analysis. Science
1999, 286, 2119–2125.
148. Carroll, G. Tubby Proteins: The Plot Thickens. Nature
Reviews. Molecular Cell Biology 2004, 5 (1), 55–63.
149. Santagata, S.; Boggon, T. J.; Baird, C. L.; Gomez, C. L.; Zhao,
J.; Shan, W. S.; Myszka, D. G.; Shapiro, L. G-Protein Signal-
ing through Tubby Proteins. Science 2001, 292, 2041–2050.
150. Naggert, J. K.; Fricker, L. D.; Varlamov, O.; Nishina, P. M.;
Rouille, Y.; Steiner, D. F.; Carroll, R. J.; Paigen, B. J.; Leiter,
E. H. Hyperproinsulinaemia in Obese Fat/Fat Mice Associ-
ated with a Carboxypeptidase E Mutation which Reduces
Enzyme Activity. Nat. Genet. 1995, 10, 135–142.
151. Zhang, C. -F.; Snell, C. R.; Loh, Y. P. Identification of a
Novel Prohormone Sorting Signal-Binding Site on Carboxy-
peptidase E, a Regulated Secretory Pathway-Sorting Recep-
tor. Mol. Endocrinol. 1999, 13, 527–536.
152. Jackson, R. S.; Creemers, J. W.M.; Ohagi, S.; Raffin-Sansom,
M. -L.; Sanders, L.; Montague, C. T.; Hutton, J. C.; O’Rahilly,
S. Obesity and Impaired Prohormone Processing Associated
with Mutations in the Prohormone Convertase 1 Gene. Nat.
Genet. 1997, 16, 303–306.
153. Kalidas, K.; Dow, E.; Saker, P. J.; Wareham, N.; Halsall, D.;
Jackson, R. S.; Chan, S.-P.; Gelding, S.; Walker, M.;
Kousta, E., et al. Prohormone Convertase 1 in Obesity, Ges-
tational Diabetes Mellitus, and NIDDM. Diabetes 1998, 47,
287–289.
154. Krude, H.; Beibermann, H.; Luck, W.; Horn, R.; Brabant, G.;
Grüters, A. Severe Early-Onset Obesity, Adrenal Insufficiency
and Red Hair Pigmentation Caused by POMC Mutations in
Humans. Nat. Genet. 1998, 19 (2), 155–157.
155. Hixson, J. E.; Almasy, L.; Cole, S.; Birnbaum, S.;
Mitchell, B. D.; Mahaney, M. C.; MacCluer, J. W.; Blangero,
J.; Comuzzie, A. G. Normal Variation in Leptin Levels Is
Associated with Polymorphisms in the Proopiomelanocor-
tin Gene. POMC. J. Clin. Endocrinol. Metab. 1999, 84,
3187–3191.
156. Comuzzie, A. G.; Hixson, J. E.; Almasy, L.; Mitchell, B. D.;
Mahaney, M. C.; Dyer, T. D.; Stern, M. P.; MacCluer, J. W.;
Blangero, J. A Major Quantitative Trait Locus Determining
Serum Leptin Levels and Fat Mass Is Located on Human
Chromosome 2. Nat. Genet. 1997, 15, 273–276.
157. Rotimi, C.; Comuzzie, A. G.; Lowe, W.; Luke, A.; Blangero,
J.; Cooper, R. The Quantitative Trait Locus on Chromo-
some 2 for Serum Leptin Levels Is Confirmed in African-
Americans. Diabetes 1999, 48, 643–644.
158. Hager, J.; Dina, C.; Francke, S.; Dubois, S.; Houari, M.;
Vatin, V.; Vaillant, E.; Lorentz, N.; Basdevant, A.; Clement,
K., et  al. A Genome-Wide Scan for Human Obesity Genes
Reveals a Major Susceptibility Locus on Chromosome 10.
Nat. Genet. 1998, 20, 304–308.
159. Kushi, A.; Sasai, H.; Koizumi, H.; Takeda, N.; Yokoyama, M.;
Nakamura, M. Obesity and Mild Hyperinsulinemia Found
in Neuropeptide Y-Y1 Receptor-Deficient Mice. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 15659–15664.
160. Hinney, A.; Becker, I.; Heibült, O.; Nottebom, K.;
Schmidt, A.; Ziegler, A.; Mayer, H.; Siegfried, W.; Blum,
W. F.; ­Remschmidt, H., et  al. Systematic Screening of the
­Pro-opiomelanocortin Gene: Identification of Several Genetic
Variants Including Three Different Insertions, One Nonsense
and Two Missense Point Mutations in Probands of Differ-
ent Weight Extremes. J. Clin. Endocrinol. Metab. 1998, 83,
3737–3741.
28 CHAPTER 90  Disorders of the Body Mass
161. Kucera, G. T.; Bortner, D. M.; Rosenberg, M. P. Overex-
pression of an Agouti cDNA in the Skin of Transgenic Mice
Recapitulates Dominant Coat Color Phenotypes of Sponta-
neous Mutants. Dev. Biol. 1996, 173, 162–173.
162. Seeley, R. J.; Schwartz, M. W. Neuroendocrine Regulation
of Food Intake. Acta. Paediatr. Suppl. 1999, 88 (Suppl 428),
58–61.
163. Kesterson, R. A.; Huszar, D.; Lynch, C. A.; Simerly, R. B.;
Cone, R. D. Induction of Neuropeptide Y Gene Expression
in the Dorsal Medial Hypothalamic Nucleus in Two Models
of the Agouti Obesity Syndrome. Mol. Endocrinol. 1997, 11,
630–637.
164. Huszar, D.; Lynch, C. A.; Fairchild-Huntress, V.; Dunmore, J.;
Fang, Q.; Berkemeier, L. R.; Gu, W.; Kesterson, R. A.; Boston, B.
A.; Cone, R. D., et al. Targeted Disruption of the Melanocortin-4
Receptor Results in Obesity in Mice. Cell 1997, 88, 131–141.
165. Yeo, G. S.H.; Farooqi, S.; Aminian, S.; Halsall, D.;
Stanhope, R.; O’Rahilly, S. A Frameshift Mutation in MC4R
Associated with Dominantly Inherited Human Obesity. Nat.
Genet. 1998, 20, 111–112.
166. Vaisse, C.; Clement, K.; Guy-Grand, B.; Froguel, P. A
Frameshift Mutation in Human MC4R Is Associated with a
Dominant Form of Obesity. Nat. Genet. 1998, 20, 113–114.
167. Donohoue, P. A.; Tao, Y. X.; Collins, M.; Yeo, G. S.H.;
O’Rahilly, S.; Segaloff, D. L. Deletion of Codons 88-92 of
the Melanocortin-4 Receptor Gene: A Novel Deleterious
Mutation in an Obese Female. J. Clin. Endocrinol. Metab.
2003, 88 (12), 5841–5845.
168. Hinney, A.; Schmidt, A.; Nottebaum, K.; Heibült, O.;
Becker, I.; Ziegler, A.; Gerber, G.; Sina, M.; Görg, T.; Mayer,
H., et  al. Several Mutations in the Melanocortin-4 Recep-
tor Gene Including a Nonsense and a Frameshift Mutation
Associated with Dominantly Inherited Obestiy in Humans. J.
Clin. Endocrinol. Metab. 1999, 84, 1483–1486.
169. Donohoue, P. A.; Tao, Y.-X.; Collins, M.; Yeo, G. S. H.;
O'Rahilly, S.; Segaloff, D. L. Deletion of Codons 88–92 of
the Melanocortin-4 Receptor Gene: A Novel Deleterious
Mutation in an Obese Female. J. Clin. Endocrin. Metab.
2003, 88, 5841–5845.
170. Gu, W.; Tu, Z.; Kleyn, P. W.; Kissebah, A.; Duprat, L.; Lee,
J.; Chin, W.; Maruti, S.; Deng, N.; Fisher, S. L., et al. Iden-
tification and Functional Analysis of Novel Human Mela-
nocortin-4 Receptor Variants. Diabetes 1999, 48, 635–639.
171. Tao, Y. X.; Segaloff, D. L. Functional Characterization of
Melanocortin-4 Receptor Mutations Associated with Child-
hood Obesity. Endocrinology 2003, 144 (10), 4544–4551.
172. Lubrano-Berthelier, C.; Le Stunff, C.; Bougneres, P.; Vaisse,
C. A Homozygous Null Mutation Delineates the Role of the
Melanocortin-4 Receptor in Humans. J. Clin. Endocrinol.
Metab. 2004, 89 (5), 2028–2032.
173. Chagnon, Y. C.; Chen, W.; Perusse, L.; Chagnon, M.;
Nadeau, A.; Wilkison, W.; Bouchard, C. Linkage and Asso-
ciation Studies Between the Melanocortin Receptors 4 and 5
Genes and Obesity-Related Phenotypes in the Québec Fam-
ily Study. Mol. Med. 1997, 3, 663–673.
174. Tao, Y. X.; Segaloff, D. L. Functional Characterization
of Melanocortin-3 Receptor Variants Identify a Loss-of-
Function Mutation Involving an Amino Acid Critical for G
Protein-Coupled Receptor Activation. J. Clin. Endocrinol.
Metab. 2004, 89 (8), 3936–3942.
175. Vidal-Puig, A.; Solanes, G.; Grujic, D.; Flier, J. S.; Lowell, B. B.
UCP3: An Uncoupling Protein Homologue Expressed Preferen-
tially and Abundantly in Skeletal Muscle and Brown Adipose
Tissue. Biochem. Biophys. Res. Commun. 1997, 235, 79–82.
176. Gimeno, R. E.; Dembski, M.; Weng, X.; Deng, N.; Shyjan,
A. W.; Gimeno, C. J.; Iris, F.; Ellis, S. J.; Woolf, E. A.; Tar-
taglia, L. A. Cloning and Characterization of an Uncoupling
Protein Homolog. Diabetes 1997, 46, 900–906.
177. Fleury, C.; Neverova, M.; Collins, S.; Raimbault, S.;
­Champigny, O.; Levi-Meyrueis, C.; Bouillaud, F.; Seldin, M.
F.; Surwit, R. S.; Ricquier, D., et al. Uncoupling Protein-2: A
Novel Gene Linked to Obesity and Hyperinsulinemia. Nat.
Genet. 1997, 15, 269–272, (March).
178. Giacobino, J. P. β3-Adrenoceptor: An Update. Eur. J. Endo-
crinol. 1995, 132, 377–385.
179. Lowell, B. B.; S-susulic, V.; Hamann, A.; Lawitts, J. A.;
Himms-Hagen, J.; Boyers, B. B.; Kozak, L. P.; Flier, J. S.
Development of Obesity in Transgenic Mice After Genetic
Ablation of Brown Adipose Tissue. Nature 1993, 366 (23),
740–742.
180. Hamann, A.; Flier, J. S.; Lowell, B. B. Decreased Brown Fat
Markedly Enhances Susceptibility to Diet-Induced Obesity,
Diabetes, and Hyperlipidemia. Endocrinology 1996, 137
(1), 21–29, (January).
181. Hamann, A.; Busing, B.; Kausch, C.; Ertl, J.; Preibisch, G.;
Greten, H.; Matthei, S. Chronic Leptin Treatment Does Not
Prevent the Development of Obesity in Transgenic Mice with
Brown Fat Deficiency. Diabetologia 1997, 40, 810–815.
182. Kopecky, J.; Clarke, G.; Enerback, S.; Spiegelman, B.;
Kozak, L. P. Expression of the Mitochondrial Uncoupling
Protein Gene from the aP2 Gene Promoter Prevents Genetic
Obesity. J. Clin. Invest. 1995, 96, 2914–2923.
183. Surwit, R. S.; Wang, S.; Petro, A. E.; Sanchis, D.;
Raimbault, S.; Ricquier, D.; Collins, S. Diet-Induced
Changes in Uncoupling Proteins in Obesity-Prone and
­Obesity-Resistant Strains of Mice. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4061–4065.
184. Sivitz, W. I.; Fink, B. D.; Donohoue, P. A. Fasting and Leptin
Modulate Adipose and Muscle Uncoupling Protien: Diver-
gent Effects Between mRNA and Protein Expression. Endo-
crinology 1998, 140, 1511–1519.
185. Collins, S.; Daniel, K. W.; Petro, A. E.; Surwit, R. S. Strain-
Specific Response to β3-Adrenergic Receptor Agonist Treat-
ment of Diet-Induced Obesity in Mice. Endocrinology 1997,
138 (1), 405–413.
186. Susulic, V. S.; Frederich, R. C.; Lawitts, J.; Tozzo, E.;
Kahn, B. B.; Harper, M. E.; Himms-Hagen, J.; Flier, J. S.;
Lowell, B. B. Targeted Disruption of the β3-Adrenergic
Receptor Gene. J. Biol. Chem. 1995, 270 (49), 29483–
29492, (December).
187. Begin-Heick, N. β3-Adrenergic Activation of ­Adenylyl
Cyclase in Mouse White Adipocytes: Modulation by
Gtp and Effect of Obesity. J. Cell. Biochem. 1995, 58,
­464–473.
188. Trayhurn, P.; Duncan, J. S.; Rayner, D. V.; Hardie, L. Rapid
Inhibition of ob Gene Expression and Circulating Leptin
Levels in Lean Mice by the β3-Adrenoceptor Agonists BRL
35135A and ZD2079. Biochem. Biophys. Res. Commun.
1996, 228 (1704), 605–610.
189. Sivitz, W. I.; Fink, B. D.; Morgan, D.; Fox, J.; Donohoue, P.;
Haynes, W. Sympathetic Inhibition, Leptin, and Uncoupling
Protein Subtype Expression in Normal Fasting Rats. Am. J.
Phys. 1999, 277, E668–E677, (Endocrinol Metab 40).
190. Emorine, L. J.; Marullo, S.; Briend-Sutren, M. M.; Patey, G.;
Tate, K.; Delavier-Klutchko, C.; Strosberg, A. D. Molecular
Characterization of the Human β3-Adrenergic Receptor. Sci-
ence 1989, 245, 1118–1121, (September).
191. Lonnqvist, F.; Thorne, A.; Nilsell, K.; Hoffstedt, J.; Arner, P.
A Pathogenic Role of Visceral Fat β3-Adrenoceptors in Obe-
sity. J. Clin. Invest. 1995, 95, 1109–1116, March.
192. Walston, J.; Silver, K.; Bogardus, C.; Knowler, W. C.;
Celi, F. S.; Austin, S.; Manning, B.; Strosberg, A. D.; Stern,
M. P.; Raben, N., et  al. Time of Onset of Non-Insulin-
Dependent Diabetes Mellitus and Genetic Variation in the
β3-Adrenergic-Receptor Gene. N. Engl. J. Med. 1995, 333,
343–347.

193. Widen, E.; Lehto, M.; Kanninen, T.; Walston, J.; Shuldiner,
A. R.; Groop, L. C. Association of a Polymorphism in the
β3-Adrenergic-receptor Gene with Features of the Insulin
Resistance Syndrome in Finns. N. Engl. J. Med. 1995, 333,
348–351.
194. Sipilainen, R.; Uusitupa, M.; Heikkinen, S.; Rissanen, A.;
Laakso, M. Polymorphism of the β3-Adrenergic Receptor
Gene Affects Basal Metabolic Rate in Obese Finns. Diabetes
1997, 46, 77–80.
195. Clement, K.; Vaisse, C.; Manning, B. S.J.; Basdevant, A.;
Guy-Grand, B.; Ruiz, J.; Silver, K. D.; Shuldiner, A. R.;
Froguel, P.; Strosberg, A. D. Genetic Variation in the β3-
Adrenergic Receptor and Increased Capacity to Gain Weight
in Patients with Morbid Obesity. N. Engl. J. Med. 1995,
333, 352–354.
196. Elbein, S. C.; Hoffman, M.; Barrett, K.; Wegner, K.; Miles, C.;
Bachman, K.; Berkowitz, D.; Shuldiner, A. R.; Leppert, M. F.;
Hasstedt, S. Role of the β3-Adrenergic Receptor Locus in Obe-
sity and Noninsulin-Dependent Diabetes among Members of
Caucasian Families with a Diabetic Sibling Pair. J. Clin. Endo-
crinol. Metab. 1996, 81, 4422–4427.
197. Gagnon, J.; Mauriege, P.; Roy, S.; Sjostrom, D.; Chagnon,
Y. C.; Dionne, F. T.; Oppert, J. M.; Perusse, L.; Sjostrom, L.;
Bouchard, C. The Trp64Arg Mutation of the β3 Adrenergic
Receptor Gene has no Effect on Obesity Phenotypes in the
Québec Family Study and Swedish Obese Subjects Cohorts.
J. Clin. Invest. 1996, 98 (9), 2086–2093.
198. Silver, K.; Walston, J.; Wang, Y.; Dowse, G.; Zimmet, P.;
Shuldiner, A. R. Molecular Scanning for Mutations in the
β3-Adrenergic Receptor Gene in Nauruans with Obesity and
Noninsulin-Dependent Diabetes Mellitus. J. Clin. Endocri-
nol. Metab. 1996, 81, 4155–4158.
199. Nagase, T.; Aoki, A.; Yamamoto, M.; Yasuda, H.; Kado, S.;
Nishikawa, M.; Kugai, N.; Akatsu, T.; Nagata, N. Lack of Asso-
ciation Between the Trp64Arg Mutation in the β3-Adrenergic
Receptor Gene and Obesity in Japanese Men: A Longitudinal
Analysis. J. Clin. Endocrinol. Metab. 1997, 82, 1284–1287.
200. Oksanen, L.; Mustajoki, P.; Kaprio, J.; Kainulainen, K.;
Janne, O.; Peoltonen, L.; Kontula, K. Polymorphism of the
β3-Adrenergic Receptor Gene in Morbid Obesity. Int. J.
Obes. 1996, 20, 1055–1061.
201. O’Dell, S. D.; Bolla, M. K.; Miller, G. J.; Cooper, J. A.;
Humphries, S. E.; Day, I. N.M. W64R Mutation in β-3-
Adrenergic Receptor Gene and Weight in a Large Population
Sample. Int. J. Obes. 1997, 22, 377–379.
202. Cassard-Doulcier, A. M.; Bouillaud, F.; Chagnon, M.;
Gelly, C.; Dionne, F. T.; Oppert, J. M.; Bouchard, C.;
Chagnon, Y.; Ricquier, D. The Bcl I Polymorphism of the
Human Uncoupling Protein (UCP) Gene Is Due to a Point
Mutation in the 5′-Flanking Region. Int. J. Obes. 1994, 18,
526–531.
203. Fumeron, F.; Durack-Brown, I.; Betoulle, D.; Cassard-
Doulcier, A. M.; Tuzet, S.; Bouillaud, F.; Melchior, J. C.;
Ricquier, D.; Apfelbaum, M. Polymorphisms of Uncoupling
Protein (UCP) and β3 Adrenoreceptor Genes in Obese People
Submitted to a Low Calorie Diet. Int. J. Obes. 1996, 20,
1051–1054.
204. Clement, K.; Ruiz, J.; Cassard-Doulcier, A. M.; Bouillaud, F.;
Ricquier, D.; Basdevant, A.; Guy-Grand, B.; Froguel, P. Addi-
tive Effect of A to G (-3826) Variant of the Uncoupling Pro-
tein Gene and the Trp64Arg Mutation of the β3-Adrenergic
Receptor Gene on Weight Gain in Morbid Obesity. Int. J.
Obes. 1996, 20, 1062–1066.
205. Viguerie-Bascands, N.; Bousquet-Melou, A.; Galitzky, J.;
Larrouy, D.; Ricquier, D.; Berlan, M.; Casteilla, L. Evi-
dence for Numerous Brown Adipocytes Lacking Functional
β3-Adrenoceptors in Fat Pads from Nonhuman Primates. J.
Clin. Endocrinol. Metab. 1996, 81, 368–375.
CHAPTER 90  Disorders of the Body Mass 29
206. Candelore, M. R.; Deng, L.; Tota, L. J.; Cascieri, M. A.;
Strader, C. D. Pharmacological Characterization of a
Recently Described Human β3-Adrenergic Receptor Mutant.
Endocrinology 1996, 137, 2638–2641.
207. Shihara, N.; Yasuda, K.; Moritani, Y.; Ue, H.; Adachi, T.;
Tanaka, K.; Seino, Y. The Association Between Trp64Arg
Polymorphism of the β3-Adrenergic Receptor and Auto-
nomic Nervous System Activity. J. Clin. Endocrinol. Metab.
1999, 84, 1623–1627.
208. Boivin, M.; Camirand, A.; Carli, F.; Hoffer, L.; Silva, J.
Uncoupling Protein-2 and -3 Messenger Ribonucleic Acids in
Adipose Tissue and Skeletal Muscle of Healthy Males: Vari-
ability, Factors Affecting Expression, and Relation to Mea-
sures of Metabolic Rate. J. Clin. Endocrinol. Metab. 2000,
85, 1975–1983.
209. Boss, O.; Hagen, T.; Lowell, B. B. Uncoupling Proteins 2 and
3: Potential Regulators of Mitochondrial Energy Metabo-
lism. Diabetes 2000, 49, 143–156.
210. Palou, A.; Picó, C.; Bonet, M.; Oliver, P. The Uncoupling Pro-
tein, Thermogenin. Int. J. Biochem. Cell. Biol. 1998, 30, 7–11.
211. Samec, S.; Seydoux, J.; Dulloo, A. G. Interorgan Signalling
Between Adipose Tissue Metabolism and Skeletal Muscle
Uncoupling Protein Homologs: Is There a Role for Circulat-
ing Free Fatty Acids? Diabetes 1998, 47, 1693–1698.
212. Solanes, G.; Vidal-Puig, A.; Grujic, D.; Flier, J.; Lowell, B. B.
The Human Uncouplin Protein-3 Gene. J. Biol. Chem. 1997,
272, 25433–25436.
213. Pecqueur, C.; Cassard-Doulcier, A. M.; Raimbault, S.;
­Miroux, B.; Fleury, C.; Gelly, C.; Bouillaud, F.; Ricquier, D.
Functional Organization of the Human Uncoupling ­Protein-2
Gene, and Juxtaposition to the Uncoupling ­Protein-3 Gene.
Biochem. Biophys. Res. Commun. 1999, 255, 40–46.
214. Schrauwen, P.; Xia, J.; Bogardus, C.; Pratley, R. E.; ­Ravussin,
E. Skeletal Muscle Uncoupling Protein 3 Expression Is a
Determinant of Energy Expenditure in Pima Indians. Diabe-
tes 1999, 48, 146–149.
215. Vidal-Puig, A.; Grujic, D.; Zhang, C. Y.; Hagen, T.; Boss, O.;
Ido, Y.; Szczepanik, A.; Wade, J.; Mootha, V.; Cortright, R.;
Muoio, D.; Lowell, B. B. Energy Metabolism in Uncou-
pling Protein 3 Knockout Mice. J. Biol. Chem. 2000, 275,
16258–16266.
216. Urhammer, S.; Fridberg, M.; Sorensen, T.; Echwald, S. M.;
Andersen, T.; Tybjaerg-Hansen, A.; Clausen, J. O.; Pedersen,
O. Studies of Genetic Variability of the Uncoupling Protein 1
Gene in Caucasian Subjects with Juvenile-Onset Obesity. J.
Clin. Endocrinol. Metab. 1997, 82, 4069–4074.
217. Otabe, S.; Clement, K.; Rich, N.; Warden, C.; Pecqueur, C.;
Neverova, M.; Raimbault, S.; Guy-Grand, B.; Basdevant, A.;
Ricquier, D., et al. Mutation Screening of the Human UCP-2
Gene in Normoglycemic and NIDDM Morbidly Obese
Patients: Lack of Association Between New UCP-2 Polymor-
phisms and Obesity in French Caucasians. Diabetes 1998,
47, 840–842.
218. Argyropoulos, G.; Brown, A.; Peterson, R.; Likes, C.;
­Watson, D.; Garvey, W. Structure and Organization of
the Human Uncoupling Protein 2 Gene and Identification
of a Common Biallelic Variant in Caucasian and African-­
American Subjects. Diabetes 1998, 47, 685–687.
219. Yanovski, J. A.; Diament, A.; Sovik, K.; Nguyen, T.; Li, H.;
Sebring, N.; Warden, C. Associations Between Uncoupling
Protein 2, Body Composition, and Resting Energy Expendi-
ture in Lean and Obese African American, White, and Asian
Children. Am. J. Clin. Nutr. 2000, 71, 1405–1412.
220. Esterbauer, H.; Schneitler, C.; Oberkofler, H.; Ebenbichler, C.;
Paulweber, B.; Sandhofer, F.; Ladurner, G.; Hell, E.; Strosberg,
A. D.; Patsch, J. R., et  al. A Common Polymorphism in the
Promoter of UCP2 Is Associated with Decreased Risk of Obe-
sity in Middle-Aged Humans. Nat. Genet. 2001, 28, 178–183.
30 CHAPTER 90  Disorders of the Body Mass
221. Kimm, S. Y.; Glynn, N. W.; Aston, C. E.; Damcott, C. M.;
Poehlman, E. T.; Daniels, S. R.; Ferrell, R. E. Racial Differ-
ences in the Relation Between Uncoupling Protein Genes and
Resting Energy Expenditure. Am. J. Clin. Nutr. 2002, 75 (4),
714–719.
222. Schonfeld-Warden, N. A. Warden CH Physiological Effects
of Variants in Human Uncoupling Proteins: UCP2 Influ-
ences Body-Mass Index. Biochem. Soc. Trans. 2001, 29,
777–784.
223. Uehara, Y.; Shimizu, H.; Ohtani, K.; Sato, N.; Mori, M.
Hypothalamic Corticotropin-releasing Hormone Is a Media-
tor of the Anorexigenic Effect of Leptin. Diabetes 1998, 47,
890–893.
224. Bell, C. G.; Walley, A. J.; Froguel, P. The Genetics of Human
Obesity. Nat. Rev. Genet. 2005, 6, 221–234.
225. Korner, J.; Leibel, R. L. To Eat Ornot to Eat—How the Gut
Talks to the Brain. N. Engl. J. Med. 2003, 349, 926–928.
226. Horvath, T. L.; Diano, S.; Sotonyi, P.; Heiman, M.; Tschop,
M. Minireview: Ghrelin and the Regulation of Energy
­Balance—A Hypothalamic Perspective. Endocrinology
2001, 142 (10), 4163–4169.
227. Haqq, A. M.; Farooqi, I. S.; O’Rahilly, S.; Stadler, D. D.;
Rosenfeld, R. G.; Pratt, K. L.; LaFranchi, S. H.; Purnell, J.
Q. Serum Ghrelin Levels Are Inversely Correlated with Body
Mass Index, Age, and Insulin Concentrations in Normal
Children and are Markedly Increased in Prader–Willi Syn-
drome. J. Clin. Endocrinol. Metab. 2003, 88 (1), 174–178.
228. English, P. J.; Ghatei, M. A.; Malik, I. A.; Bloom, S. R.;
­Wilding, J. P. H. Food Fails to Suppress Ghrelin Levels in
Obese Humans. J. Clin. Endocrinol. Metab. 2002, 87 (6),
2984.
229. Sun, A. Deletion of Ghrelin Impairs neither Growth nor
Appetite. Mol. Cell. Biol. 2003, 23 (22), 7973–7981.
230. Korbonits, M.; Gueorguiev, M.; O’Grady, E.; Lecoeur, C.;
Swan, D. C.; Mein, C. A.; Weill, J.; Grossman, A. B.; Froguel,
P. A Variation in the Ghrelin Gene Increases Weight and
Decreases Insulin Secretion in Tall, Obese Children. J. Clin.
Endocrinol. Metab. 2002, 87 (8), 4005–4008.
231. Wu, J. T.; Kral, J. G. Ghrelin: Integrative Neuroendocrine
Paptide in Health and Disease. Ann. Surg. 2004, 239,
464–474.
232. Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Seeley, R. J.;
Baskin, D. Central Nervous System Control of Food Intake.
Nature 2000, 404, 661–671.
233. Sainsbury, A.; Cusin, I.; Rohner-Jeanrenaud, F.; Jeanrenaud,
B. Adrenalectomy Prevents the Obesity Syndrome Produced
by Chronic Central Neuropeptide Y Infusion in Normal
Rats. Diabetes 1997, 46, 209–214.
234. Erickson, J. C.; Hollopeter, G.; Palmiter, R. D. Attenuation
of the Obesity Syndrome of ob/ob Mice by the Loss of Neu-
ropeptide Y. Science 1996, 274, 1704–1707, (6 December).
235. Erickson, J. C.; Ahima, R. S.; Hollopeter, G.; Flier, J.;
­Palmiter, R. D. Endocrine Function of Neuropeptide Y
Knockout Mice. Regul. Pept. 1997, 70, 199–202.
236. Bannon, A.; Seda, J.; Carmouche, M.; Francis, J.; Norman,
M.; Karbon, B.; McCaleb, M. Behavioral Characterization
of Neuropeptide Y Knockout Mice. Brain. Res. 2000, 868,
79–87.
237. Kanatani, A.; Mashiko, S.; Murai, N.; Sugimoto, N.; Ito, J.;
Fukuroda, T.; Fukami, T.; Morin, N.; MacNeil, D.; Van der
Ploeg, L., et  al. Role of the Y1 Receptor in the Reguation
of Neuropeptide Y-Mediated Feeding: Comparison of Wild-
type, Y1 Receptor-Deficient, and Y5 Receptor-Deficient
Mice. Endocrinology 2000, 141, 1011–1016.
238. Antonijevic, I.; Murck, H.; Bohlhalter, S.; Frieboes, R.; Hols-
boer, F.; Steiger, A. Neuropeptide Y Promotes Sleep and
Inhibits ACTH and Cortisol Release in Young Men. Neuro-
pharmacology 2000, 39, 1474–1481.
239. Bray, M.; Boerwinkle, E.; Hanis, C. L. Linkage Analysis of
Candidate Obesity Genes Among the Mexican-American
Population of Starr County, Texas. Genet. Epidemiol. 2000,
16, 397–411.
240. Roche, F.; Boutin, P.; Dina, C.; Gyapay, G.; Basdevant, A.;
Hager, J.; Guy-Grand, B.; Clement, K. Frogu Genetic Stud-
ies of Neuropeptide Y and Neuropeptide Y Receptors Y1
and Y5 Regions in Morbid Obesity. Diabetologia 1997, 40,
671–675.
241. Herzog, H.; Darby, K.; Ball, H.; Hort, Y.; Beck-Sickinger, A.;
Shine, J. Overlapping Gene Structure of the Human Neuro-
peptide Y Receptor Subtypes Y1 and Y5 Suggests Coordinate
Transcriptional Regulation. Genomics 1997, 41, 315–319.
242. Rosenkranz, K.; Hinney, A.; Ziegler, A.; von Prittwitz, S.;
Barth, N.; Roth, H.; Mayer, H.; Siegfried, W.; Lehmkuhl, G.;
Poutska, F., et al. Screening for Mutations in the Neuropep-
tide Y Y5 Receptor Gene in Cohorts Belonging to Different
Weight Extremes. Int. J. Obes. 1998, 22, 157–163.
243. Sakuri, T.; Ameniya, A.; Ishii, M.; Matsuzaki, I.;
Chemelli, R. M.; Tanaka, H.; Williams, S. C.; Richardson, J.
A.; Kozlowski, G. P.; Wilson, S., et al. Orexins and Orexin
Receptors: A Family of Hypothalamic Neuropeptides and G
Protein-Coupled Receptors that Regulate Feeding Behavior.
Cell 1998, 92, 573–585.
244. Chemelli, R. M.; Willie, J.; Sinton, C.; Elmquist, J.;
Scammell, T.; Lee, C.; Richardson, J. A.; Williams, S.; Xiong,
Y.; Kisanuki, Y., et  al. Narcolepsy in Orexin Knock-Out
Mice: Molecular Genetics of Sleep Regulation. Cell 1999,
98, 437–451.
245. Blanco, M.; Lopez, M.; GarcIa-Caballero, T.; Gallego, R.;
Vazquez-Boquete, A.; Morel, G.; SenarIs, R.; Casanueva,
F.; Dieguez, C.; Beiras, A. Cellular Localization of Orexin
Receptors in Human Pituitary. J. Clin. Endocrinol. Metab.
2001, 86 (4), 1616–1619.
246. Mazzocchi, G.; Malendowicz, L. K.; Aragona, F.; Rebuffat, P.;
Gottardo, L.; Nussdorfer, G. G. Human Pheochromocytomas
Express Orexin Receptor Type 2 Gene and Display an in Vitro
Secretory Response to Orexins A and B. J. Clin. Endocrinol.
Metab. 2001, 86 (10), 4818–4821.
247. Plotsky, P. M.; Thrivikraman, K. V.; Watts, A. G.; Hauger,
R. L. Hypothalamic–Pituitary–Adrenal Axis Function in the
Zucker Obese Rat. Endocrinology 1992, 130, 1931–1941.
248. Moreau, J.; Kilpatrick, G.; Jenck, F. Urocortin, a Novel Neu-
ropeptide with Anxiogenic-Like Properties. NeuroReport
1997, 8, 1697–1701.
249. Spina, M.; Merlo-Pich, E.; Chan, R.; Basso, A. M.; Rivier,
J.; Vale, W.; Koob, G. F. Appetite-Suppressing Effects of
Urocortin, a CRF-related Neuropeptide. Science 1996, 273,
1561–1564.
250. Rohner-Jeanrenaud, F.; Walker, C. D.; Greco-Perotto, R.;
Jeanrenaud, B. Central Corticotropin-Releasing Factor Admin-
istration Prevents the Excessive Body Weight Gain of Geneti-
cally Obese (fa/fa) Rats. Endocrinology 1989, 124, 733–739.
251. Spina, M.; Merlo-Pich, E.; Chan, R. K. W.; Basso, A. M.;
Rivier, J.; Vale, W.; Koob, G. F. Appetite-Suppressing Effects
of Urocortin, a CRF-related Neuropeptide. Science 1996,
273, 1561–1564, (13 September).
252. Heiman, M. L.; Ahima, R. S.; Craft, L. S.; Schoner, B.;
Stephens, T. W.; Flier, J. Leptin Inhibition of the
­Hypothalamic–Pituitary–Adrenal Axis in Response to
Stress. Endocrinology 1997, 138, 3859–3863.
253. Boston, B.; Blaydon, K. M.; Varnerin, J.; Cone, R. D.
­Independent and Additive Effects of Central POMC and
Leptin Pathways on Murine Obesity. Science 1997, 278,
1641–1644.
254. Glasow, A.; Haidan, A.; Hilbers, U.; Breidert, M.; ­Gillespie, J.;
Scherbaum, W. A.; Bornstein, S. R.; Chrousos, G. P.
Expression of Ob Receptor in Normal Human Adrenals:

Differential Regulation of Adrenocortical and Adrenomedul-
lary Function by Leptin. J. Clin. Endocrinol. Metab. 1998, 83,
4459–4466.
255. Huizenga, N.; Koper, J.; De Lange, P.; Pols, H.; Stolk, R.;
Burger, H.; Grobbee, D.; Brinkmann, A.; De Jong, F.; Lam-
berts, S. A Polymorphism in the Glucocorticoid Receptor
Gene May Be Associated with an Increased Sensitivity to
Glucocorticoids In Vivo. J. Clin. Endocrinol. Metab. 1998,
83, 144–151.
256. White, P. C.; Tomoatsu, M.; Agarwal, A. K.
11β-Hydroxysteroid Dehydrogenase and the Syndrome of
Apparent Mineralocorticoid Excess. Endocr. Rev. 1997, 18,
135–156.
257. Farese, R. V., Jr.; Biglieri, E. G.; Shackleton, C. H. L.;
Irony, I.; Gomez-Fontes, R. Licorice-Induced Hyperminer-
alocorticoidism. N. Engl. J. Med. 1991, 325, 1223.
258. Armanini D; Francini-Pesenti F; Battagin G; Fiore C;
Mariniello B; Sartorato P; Nacamulli D. Effect of a Cream
with Glycyrrhetinic Acid on the Reduction of Subcutaneous
Fat Layer in Women. The Endocrine Society 85th Annual
Meeting, 583, 2003. Ref Type: Abstract.
259. Armanini, D.; DePalo, C. B.; Mattarello, M. J.; Spinella, P.;
Zaccaria, M.; Ermolao, A.; Palermo, M.; Fiore, C.; Sartor-
ato, P.; Francini-Pesenti, F., et  al. Effect of Licorice in the
Reduction of Body Fat Mass in Healthy Subjects. J. Endocri-
nol. Invest. 2003, 26, 646–650.
260. Nordström, A.; Marcus, C.; Axelson, M.; Wedell, A.;
Ritzén, M. Failure of Conrtisone Acetate Treatment of
Congeital Adrenal Hyperplasia Because of Defective
11β-Hydroxysteroid Dehydrogenase Reductase Activity. J.
Clin. Endocrinol. Metab. 1999, 84, 1210–1213.
261. Jamieson, A.; Wallace, A. M.; Andrew, R.; Nunez, B. S.;
Walker, B. R.; Fraser, R.; White, P. C.; Connell, J. M. C.
Apparent Cortisone Reductase Deficiency: A Functional
Defect in 11β-Hydroxysteroid Dehydrogenase Type 1. J.
Clin. Endocrinol. Metab. 1999, 84, 3570–3574.
262. Masuzaki, H.; Paterson, J.; Shinyama, H.; Morton, N. M.;
Mullins, J. J.; Seckl, J. R.; Flier, J. S. A Transgenic Model of
Visceral Obesity and the Metabolic Syndrome. Science 2001,
294, 2166–2170.
263. Tiosano, D.; Einsentein, I.; Militianu, D.; Hrousos, G. P.;
Hochberg, Z. 11β-Hydroxysteroid Dehydrogenase Activity
in Hypothalamic Obesity. J. Clin. Endocrinol. Metab. 2003,
88, 379–384.
264. Rask, E.; Olsson, T.; Söderberg; Andrew, R.; Livingstone, D.
E.W.; Johnson, O.; Walker, B. R. Tissue-Specific Dysregu-
lation of Cortisol Metabolism in Human Obesity. J. Clin.
Endocrinol. Metab. 2003, 86, 1418–1421.
265. Bujalska, I. J.; Kumar, S. Does Central Obesity Reflect
“Cushing’s Disease of the Omentum?” Lancet 1997, 349,
1210–1215.
266. Draper, N.; Echwald, S. M.; Lavery, G. G.; Walker, E. A.;
Fraser, R.; Davies, E.; Sørensen, T. I. A.; Astrup, A.; Adam-
ski, J.; Hewison, M., et  al. Association Studies Between
Microsatellite Markers within the Gene Encoding Human
11β-Hydroxysteroid Dehydrogenase Type 1 and Body Mass
Index, Waist to Hip Ratio, and Glucocorticoid Metabolism.
J. Clin. Endocrinol. Metab. 2002, 87, 4984–4990.
267. Gelernter-Yaniv, L.; Feng, N.; Sebring, N. G.; Hochberg, Z.;
Yanovski, J. A. Associations Between a Ploymorphism in the
11 Beta Hydorxysteroid Dehydrogenase Type 1 Gene and
Body Composition. Int. J. Obes. 2003, 27, 983–986.
268. Diamond, F. The Endocrine Function of Adipose Tissue.
Growth Genet. Horm. 2002, 18, 17–22.
269. Comuzzie, A. G.; Funahashi, T.; Sonnenberg, G.; Martin, L.
J.; Jacob, H. J.; Black, A. E. K.; Maas, D.; Takahashi, M.;
Kihara, S.; Tanaka, S., et  al. The Genetic Basis of Plasma
Variation in Adiponectin, a Global Endophenotype for
CHAPTER 90  Disorders of the Body Mass 31
Obesity and the Metabolic Syndrome. J. Clin. Endocrinol.
Metab. 2001, 86 (9), 4321–4325.
270. Levine, J. A.; Jensen, M.; Eberhardt, N. L.; O’Brien, T.
­Adipocyte Macrophage Colony-Stimulating Factor Is a
Mediator of Adipose Tissue Growth. J. Clin. Invest. 1998,
101, 1557–1564.
271. Magre, J.; Laurell, H.; Fizames, C.; Antoinne, P. J.; Dib, C.;
Vigouroux, C.; Bourot, C.; Capeau, J.; Weissenbach, J.;
­Langin, D. Human Hormone-Sensitive Lipase: Genetic
Mapping, Identification of a New Dinucleotide Repeat, and
Association with Obesity and NIDDM. Diabetes 1998, 47,
284–286.
272. Spiegelman, B. M. PPAR-γ: Adipogenic Regulator and Thia-
zolidinedione Receptor. Diabetes 1998, 47, 507–514.
273. Adams, M.; Montague, C. T.; Prins, J. B.; Holder, J.;
Smith, S.; Sanders, L.; Digby, J. E.; Sewter, C. P.; Lazar,
M.; Chatterjee, K., et al. Activators of Peroxisome Prolif-
erator–Activated Receptor γ have Depot-Specific Effects on
Human Preadipocyte Differentiation. J. Clin. Invest. 1997,
100, 3149–3153.
274. Tontonoa, P.; Singer, S.; Forman, B.; Sarraf, P.; Fletcher, J.;
Fletcher, C.; Brun, R.; Mueller, E.; Altiok, S.; Oppenheim, H.,
et al. Terminal Differentiation of Human Liposarcoma Cells
Induced by Ligands for Peroxisome ­Proliferator-Activated
Receptor γ and the Retionoid X Receptor. Proc. Natl. Acad.
Sci. U.S.A. 1997, 94, 237–241.
275. Kubota, N.; Terauchi, Y.; Miki, H.; Tamemoto, H.;
­Yamauchi, T.; Komeda, K.; Satoh, S.; Nakano, R.; Ishii, C.,
et al. PPAR Gamma Mediates High-fat Diet-Induced Adipo-
cyte Hypertrophy and Insulin Resistance. Mol. Cell. 1999, 4,
597–609.
276. Norris, A. W.; Chen, L.; Fisher, S. J.; Szanto, I.; Ristow, M.;
Jozsi, A. C.; Hirshman, M. F.; Rosen, E. D.; Goodyear, L.
J.; Gonzalez, F. J., et  al. Muscle-Specific PPAR­{Gamma}-
Deficient Mice Develop Increased Adiposity and Insulin
Resistance But Respond to Thiazolidinediones. J. Clin.
Invest. 2003, 112 (4), 608–618.
277. Vigouroux, C.; Fajas, L.; Khallouf, E.; Meier, M.; Gyapay, G.;
Lascols, O.; Auwerx, J.; Weissenbach, J.; Capeau, J.; Magre,
J. Human Peroxisome Proliferator-Activated Receptor-γ2:
Genetic Mapping, Identification of a Variant in the Cod-
ing Sequence, and Exclusion as the Gene Responsible for
Lipoatrophic Diabetes. Diabetes 1998, 47, 490–492.
278. Ristow, M.; Müller-Wieland, D.; Pfeiffer, A.; Krone, W.;
Kahn, C. Obesity Associated with a Mutation in a Genetic
Regulator of Adipocyte Differentiation. N. Engl. J. Med.
1998, 339, 953–959.
279. Hamann, A.; Munzberg, H.; Buttron, P.; Busing, B.;
Hinney, A.; Mayer, H.; Siegfried, W.; Hebebrand, J.;
­Greten, H. Missense Variants in the Human Peroxisome
­Proliferator-Activated Receptor Gamma 2 Gene in Lean and
Obese Subjects. Eur. J. Endocrinol. 1999, 141, 90–92.
280. Ek, J.; Urhammer, S.; Sorensen, T.; Andersen, T.;
Auwerx, J.; Pedersen, O. Homozygosity of the Pro12Ala
Variant of the Peroxisome Proliferative-Activated Receptor
Gamma 2 (PPAR-γ2): Divergent Modulating Effects on Body
Mass Index in Obese and Lean Caucasian men. Diabetologia
1999, 42, 892–895.
281. Beamer, B. A.; Yen, C. J.; Andersen, R. E.; Muller, D.;
Elahi, D.; Cheskin, L. J.; Andres, R.; Roth, J.; Shuldiner, A.
R. Association of the Pro12Ala Variant in the Peroxisome
­Proliferator-Activated Receptor-γ2 Gene with Obesity in
Two Caucasian Populations. Diabetes 1998, 47, 1806–1808.
282. Meirhaeghe, A.; Fajas, L.; Helbecque, N.; Cottel, D.;
­Auwerx, J.; Deeb, S.; Amouyel, P. Impact of the Peroxisome
Proliferator-Activated Receptor Gamma 2 Pro12Ala Poly-
morphism on Adiposity, Lipids, and Non-Insulin-Dependent
Diabetes Mellitus. Int. J. Obes. 2000, 24, 195–199.
32 CHAPTER 90  Disorders of the Body Mass
283. Ringel, J.; Engeli, S.; Distler, A.; Sharma, A. Pro12Ala Mis-
sense Mutation of the Peroxisome Proliferator-Activated
Receptor Gamma and Diabetes Mellitus. Biochem. Biophys.
Res. Commun. 1999, 254, 450–453.
284. Cole, S.; Mitchell, B. D.; Hsueh, W.; Pineda, P.; Beamer, B.
A.; Shuldiner, A. R. The Pro12Ala Variant of Peroxisome
­Proliferator-Activated Receptor-gamma 2 (PPAR-γ2) Is Asso-
ciated with Measures of Obesity in Mexican Americans. Int.
J. Obes. 2000, 24, 522–524.
285. Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M. Adi-
pose Expression of Tumor Necrosis Factor-α: Direct Role
in Obesity-Linked Insulin Resistance. Science 1993, 259,
87–91, (1 January).
286. Liu, L.; Spelleken, M.; Röhrig, K.; Hauner, H.; Eckel, J.
Tumor Necrosis Factor-α Inhibits Insulin Signalling in
Human Adipocytes. Diabetes 1998, 47, 515–522.
287. Prins, J. B.; Niesler, C.; Winterford, C.; Bright, N.;
Siddle, K.; O’Rahilly, S.; Walker, N.; Cameron, D. Tumor
Necrosis Factor-α Induces Apoptosis of Human Adipose
Cells. Diabetes 1997, 46, 1939–1944.
288. Nisoli, E.; Briscini, L.; Tonello, C.; Degiulimorghen, C.;
Carruba, M. Tumor Necrosis Factor-α Induces Apoptosis
in Rat Brown Adipocytes. Cell. Death. Differ. 1997, 4,
771–778.
289. Kirchgessner, T.; Uysal, K.; Wiesbrock, S.; Marino, M.;
Hotamisligil, G. S. Tumor Necrosis Factor-α Contributes
to Obesity-Related Hyperleptinemia by Regulating Leptin
Release from Adipocytes. J. Clin. Invest. 1997, 100,
2777–2782.
290. Mantzoros, C. S.; Moschos, S.; Avramopoulos, I.; ­Kaklamani,
V.; Liolios, A.; Dougerakis, D.; Griveas, I.; Katsilambros,
N.; Flier, J. Leptin Concentrations in Relation to Body Mass
Index and the Tumor Necrosis Factor-α System in Humans.
J. Clin. Endocrinol. Metab. 1997, 82, 3408–3413.
291. Zumbach, M.; Boehme, M.; Wahl, P.; Stremmel, W.;
Ziegler, R.; Nawroth, P. Tumor Necrosis Factor Increases
Serum Leptin Levels in Humans. J. Endocrinol. Invest. 1997,
82, 4080–4082.
292. Hotamisligil, G. S.; Johnson, R. S.; Distel, R. J.; Ellis, R.;
Papaioannou, V. E.; Spiegelman, B. M. Uncoupling of Obe-
sity from Insulin Resistance through a Targeted Mutation in
aP2, the Adipocyte Fatty Acid Binding Protein. Science 1996,
274, 1377–1379, (22 November).
293. Ventre, J.; Doebbler, T.; Wu, M.; MacNaul, K.; Stevens, K.;
Pasparakis, M.; Kollias, G.; Moller, D. Targeted Disruption
of the Tumor Necrosis Factor-α Gene. Diabetes 1997, 46,
1526–1531.
294. Scheyer, S.; Chua, S.; Leboeuf, R. Obesity and Diabetes in
TNF-Alpha Receptor-Deficient Mice. J. Clin. Invest. 1998,
102, 402–411.
295. Carroll, M. C.; Katzman, P.; Alicot, E.; Koller, B.; Geraghty,
D.; Orr, H.; Strominger, J. L.; Spies, T. Linkage Map of the
Major Histocompatibility Complex Including the Tumor
Necrosis Factor Genes. Proc. Natl. Acad. Sci. U.S.A. 1987, 84,
8535–8539.
296. Norman, R. A.; Bogardus, C.; Ravussin, E. Linkage Between
Obesity and a Marker Near the Tumor Necrosis Factor-α
Locus in Pima Indians. J. Clin. Invest. 1995, 96, 158–162.
297. Fernandez-Real, J. M.; Gutierrez, C.; Ricart, W.; ­Casamitjana,
R.; Fernandez-Castaner, M.; Vendrell, J.; Richart, C.;
Soler, J. The TNF-α Gene Nco I Polymorphism Influences
the Relationship Among Insulin Resistance, Percent Body
Fat, and Increased Serum Leptin Levels. Diabetes 1998, 46,
1468–1472.
298. Berg, A. H.; Combs, T. P.; Scherer, P. E. ACRP30/Adiponec-
tin: An Adipokine Regulating Glucose and Lipid Metabo-
lism. Trends. Endocrinol. Metab. 2002, 13, 84–89.
299. Maeda, K.; Okubo, K.; Shimomura, I.; Funahashi, T.;
­Matsuzawa, Y.; Matsubara, K. cDNA Cloning and
Expression of a Novel Adipose Specific Collagen-Like Fac-
tor, apM1(Adipose Most Abundant Gene Transcript 1). Bio-
chem. Biophys. Res. Commun. 1996, 221, 286–289.
300. Silha, J. F.; Krsek, M.; Skrha, J. V.; Sucharda, P.; Nyomba,
B. L. G.; Murphy, L. J. Plasma Resistin, Adiponectin and
Leptin Levels in Lean and Obese Subjects: Correlations
with Insulin Resistance. Eur. J. Endocrinol. 2003, 149 (4),
331–335.
301. Fasshauer, M.; Kralisch, S.; Klier, M.; Lossner, U.;
Bluher, M.; Klein, J.; Paschke, R. Adiponectin Gene Expres-
sion and Secretion Is Inhibited by Interleukin-6 in 3T3-L1
Adipocytes. Biochem. Biophy. Res. Commun. 2003, 301
(4), 1045–1050.
302. Qi, Y.; Takahashi, N.; Hileman, S. M.; Patel, H. R.; Berg, A.
H.; Pajvani, U. B.; Scherer, P. E.; Ahima, R. S. Adiponectin
Acts in the Brain to Decrease Body Weight. Nat. Med. 2004,
10 (5), 524–529.
303. Takahashi, M.; Arita, Y.; Yamagata, K.; Matsukawa, Y.;
Okutomi, K.; Horie, M.; Shimomura, I.; Hotta, K.; Kuri-
yama, H.; Kihara, S., et  al. Genomic Structure and Muta-
tions in Adipose-Specific Gene, Adiponectin. Int. J. Obes.
2000, 24, 861–868.
304. Schaffler, A.; Barth, N.; Palitzsch, K. D.; Drobnik, W.;
S­cholmerich, J.; Schmitz, G. Mutation Analysis of the
Human Adipocyte-Specific apM-1 Gene. Eur. J. Clin. Invest.
2000, 30 (10), 879–887.
305. Ukkola, O.; Ravussin, E.; Jacobson, P.; Sjöström, L.;
Bouchard, C. Mutations in the Adiponectin Gene in Lean
and Obese Subjects from the Swedish Obese Subjects Cohort.
Metab. Clin. Exp. 2003, 52 (7), 881–884.
306. Poitou, C.; Lacorte, J.-M.; Coupaye, M.; Bertrais, S.; Bedel,
J.-F.; Lafon, N.; Bouillot, J.-L.; Galan, P.; Borson-Chazot, F.;
Basdevant, A., et al. Relationship Between Single Nucleotide
Polymorphisms in Leptin, IL6 and Adiponectin Genes and
their Circulating Product in Morbidly Obese Subjects Before
and After Gastric Banding Surgery. Obes. Surg. 2005, 15,
11–23.
307. Samal, B.; Sun, Y.; Stearns, G.; Xie, C.; Suggs, S.; McNiece, I.
Cloning and Characterization of the cDNA Incoding a Novel
Pre-B-Cell Colony-Enhancing Factor. Mol. Cell. Biol. 1994,
14, 1431–1437.
308. Strowski, M. Z.; Li, Z.; Szalkowski, D.; Shen, X.; Guan, X.
M.; Juttner, S.; Moller, D. E.; Zhang, B. B. Small-Molecule
Insulin Mimetic Reduces Hyperglycemia and Obesity in a
Nongenetic Mouse Model of Type 2 Diabetes. Endocrinol-
ogy 2004, 145 (11), 5259–5268.
309. Fukuhara, A.; Matsuda, M.; Nishizawa, M.; Segawa,
K.; Tanaka, M.; Kishimoto, K.; Matsuki, Y.; Murakami,
M.; Ichisaka, T.; Murakami, H., et  al. Visfatin: A Protein
Secreted by Visceral Fat That Mimics the Effects of Insulin.
Science 2005, 307 (5708), 426–430.
310. Air, E. L.; Strowski, M. Z.; Benoit, S. C.; Conarello, S. L.;
Salitro, G. M.; Guan, X. -M.; Liu, K.; Woods, S. C.; Zhang,
B. B. Small Molecule Insulin Mimetics Reduce Food Intake
and Body Weight and Prevent Development of Obesity. Nat.
Med. 2002, 8, 179–183.
311. Warden, C. H.; Fisler, J. S.; Pace, M. J.; Svenson, K. L.;
Lusis, A. J. Coincidence of Genetic Loci for Plasma Choles-
terol Levels and Obesity in a Multifactorial Mouse Model. J.
Clin. Invest. 1993, 92, 773–779.
312. Warden, C. H.; Fisler, J. S.; Shoemaker, S. M.; Wen, P.-Z.;
Svenson, K. L. Identification of Four Chromosomal Loci
Determining Obesity in a Multifactorial Mouse Model. J.
Clin. Invest. 1995, 95, 1545–1552.
313. Taylor, B. A.; Phillips, S. J. Obesity QTLs on Mouse Chro-
mosomes 2 and 17. Genomics 1997, 43, 249–257.
314. York, B.; Kailian, L.; West, D. B. Inherited Non-Autosomal
Effects on Body Fat in F2 Mice Derived from an AKR/J ×
SWR/J Cross. Mamm. Genome. 1997, 8, 726–730.

315. West, D. B.; Goudey-Lefevre, J.; York, B.; Truett, G. E.
Dietary Obesity Linked to Genetic Loci on Chromosomes 9
and 15 in a Polygenic Mouse Model. J Clin Invest 1994, 94,
1410–1416.
316. Frederich, R. C.; Hamann, A.; Anderson, S.; Lollmann, B.;
Lowell, B. B.; Flier, J. S. Leptin Levels Reflect Body Lipid
Content in Mice: Evidence for Diet-Induced Resistance to
Leptin Action. Nat. Med. 1995, 1, 1311–1314.
317. Chung, W. K.; Zheng, M.; Chua, M.; Kershaw, E.;
­Power-Kehoe, E.; Tsuji, M.; Wupeng, X. S.; Williams, J.;
Chua, S. C.; Leibel, R. L. Genetic Modifiers of Lepr (fa)
Associated with Variability in Insulin Production and
­Susceptibility to NIDDM. Genomics 1997, 41, 332–344.
318. Meirhaeghe, A.; Heibecque, N.; Cottel, D.; Amouyel, P.
β2-Adrenoreceptor Gene Polymorphism, Body Weight, and
Physical Activity. Lancet 1999, 353, 896.
319. Donohoue, P. A.; Mendoza, M. B.; Collins, M. M.;
Hamilton, W. L.; Burns, T. L. The Association of Geno-
type, Physical Activity, and their Interaction on Age/Gender
Adjusted Body Mass Index (BMI): The Muscatine Study.
Pediatr. Res. 2001, 49.
320. Garenc, C.; Perusse, L.; Bergeron, J.; Gagnon, J.; Chagnon,
Y. C.; Borecki, I. B.; Leon, A. S.; Skinner, J. S.; Wilmore, J.
H.; Rao, D. C., et al. Evidence of LPL Gene-Exercise Interac-
tion for Body Fat and LPL Activity: The HERITAGE Family
Study. J. Appl. Phys. 2001, 91 (3), 1334–1340.
321. Lowell, BB.; Bachman, E. S. β-Adrenergic Receptors, Diet-
Induced Thermogenesis, and Obesity. J. Biol. Chem. 2003,
278, 29385–29388.
322. Perusse, B. Gene–Diet Interactions in Obesity. Am. J. Clin.
Nutr. 2000, 72 (5), 1285S–1290S.
323. De Luca, M.; Chambers, M. M.; Casazza, K.; Lok, K. H.;
Hunter, G. R.; Gower, B. A.; Fernández, J. R. Genetic Varia-
tion in a Member of the Laminin Gene Family Affects Varia-
tion in Body Composition in Drosophila and Humans. BMC.
Genet. 2008, 11 (9), 52.
324. De Luca, M.; Crocco, P.; Wiener, H.; Tiwari, H. K.;
­Passarino, G.; Rose, G. Association of a Common LAMA5
Variant with Anthropometric and Metabolic Traits in an
Italian Cohort of Healthy Elderly Subjects. Exp. Gerentol.
2011, 46 (1), 60–64.
325. De Luca, M.; Klimentidis, Y. C.; Casazza, K.; Chambers, M.
M.; Cho, R.; Harbison, S. T.; Jumbo-Lucioni, P.; Zhang, S.;
Leips, J.; Fernández, J. R. A Conserved Role for Syndecan
Family Members in the Regulation of Whole-Body Energy
Metabolism. PLoS One 2010, 5 (6), e11286.
326. Blechman, J.; Amir-Zilberstein, L.; Gutnick, A.; Ben-Dor, S.;
Levkowitz, G. The Metabolic Regulator PGC-1 Alpha
Directly Controls the Expression of the Hypothalamic
­Neuropeptide Oxytocin. J. Neurosci. 2011, 31 (42),
14835–14840.
327. Jones, K. T.; Ashrafi, K. Caenorhabditis Elegans as an
Emerging Model for Studying the Basic Biology of Obesity.
Dis. Model Mech. 2011, 2 (5–6), 224–229.
328. Ashrafi, K.; Chang, F. Y.; Watts, J. L.; Fraser, A. G.; Kamath,
R. S.; Ahringer, J.; Ruvkun, G. Genome-Wide RNAi Analy-
sis of Caenorhabditis Elegans Fat Regulatory Genes. Nature
2003, 421 (6920), 268–272.
329. Birkenfeld, A. L.; Lee, H. Y.; Guebre-Egziabher, F.; Alves,
T. C.; Jurczak, M. J.; Momauvaz, F. R., et  al. Deletion of
the Mammalian INDY Homolog Mimics Aspects of Dietary
Restriction and Protects Against Adiposity and Insulin Resis-
tance in Mice. Cell. Metab. 2011, 14 (2), 184–195.
330. Gibson, T.; Farooqi, I. S.; Moreau, M.; DePoli, A. M.;
Lwrence, E.; O’Rahilly, S.; Trussell, R. A. Congenital
Leptin Deficiency Due to Homozygosity for the DELTA
133 G Mutation: Report of Another Case and Evaluation of
Response to Four Years of Leptin Therapy. J. Clin. Endocri-
nol. Metab. 2004, 89 (10), 4821–4826.
CHAPTER 90  Disorders of the Body Mass 33
331. Farooqi, I. S.; Matarese, G.; Lord, G. M.; Keogh, J. M.;
Lawrence, E.; Agwu, C.; Sanna, V., et al. Beneficial Effects
of Letpin on Obesity, T Cell Hyporesponsiveness, and Neu-
roendocrine/Metabolic Dysfunction of Human Congenital
Leptin Deficiency. J. Clin. Invest. 2002, 110, 1093–1103.
332. Licinio, J.; Caglayan, S.; Ozata, M.; Yildiz, B. O.;
de Miranda, P. B.; O’Kirwan, F., et al. Phenotypic Effects of
Leptin Replacement on Morbid Obesity, Diabetes Mellitus,
Hypogonadism, and Behavior in Leptin-Deficient Adults.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 4531–4536.
333. Fischer-Posovoszky, P.; von Schnurbein, J.; Moepps, B.;
Lahr, G.; Strauss, G.; Barth, T. F., et  al. A New Missense
Mutation in the Leptin Gene Causes Mild Obesity and
Hypogonadism without Affecting T Cell Responsiveness. J.
Clin. Endocrinol. Metab. 2010, 95 (6), 2836–2840.
334. Farooqi, I. S.; Wangensteen, T.; Collins, S.; Kimber, W.;
Matarese, G.; Keogh, J. M.; Lank, E.; Bottomley, B.;
Lopez-Fernandez, J., et  al. Clinical and Molecular Genetic
Spectrum of Congenital Deficiency of the Leptin Receptor.
N. Engl. J. Med. 2007, 96 (5), 237–247.
335. Santini, F.; Maffei, M.; Pelosini, C.; Salvetti, G.; Scartabelli, G.;
Pinchera, A. Melanocortin-4 Receptor Mutations in Obesity.
Am. J. Clin. Nutr. 2009, 49, 95–109.
336. Miraglia Del Giudice, E.; Cirillo, G.; Nigro, V.; Santoro, N.;
D’Urso, L.; Raimondo, P.; Cozzolino, D.; Scafato, D. Per-
rone L Low Frequency of Melanocortin-4 Receptor (MC4R)
Mutations in a Mediterranean Population with Early Onset
Obesity. Int. J. Obes. Relat. Metab. Disord. 2002, 26 (5),
647–651.
337. Nowacka-Woszuk, J.; Cieslak, J.; Skowronska, B.;
­Majewska, K. A.; Stankiewicz, W.; Fichna, P.; Switonski, M.
Missense Mutations and Polymorhisms of the MC4R Gene
in Polish Obese Children and Adolescents in Relation to the
Relative Body Mass Index. J. Appl. Genet. 2011, 52 (3),
319–323.
338. Mendiratta, M. S.; Yang, Y.; Balazs, A. E.; Willis, A. S.;
Eng, C. M.; Karaviti, L. P.; Potocki, L. C. Early Onset Obe-
sity and Adrenal Insufficiency Associated with a Homozygous
POMC Mutation. Int. J. Pediatr. Endocrinol. 2011, 5 (1).
339. Clément, K.; Dubern, B.; Mencarelli, M.; Czernichow, P.;
Ito, S.; Wakamatsu, K.; Barsh, G. S.; Vaisse, C.; Leger, J.
Unexpected Endocrine Features and Normal Pigmentation
in a Young Adult Patient Carrying a Novel Homozygous
Mutation in the POMC Gene. J. Clin. Endocrinol. Metab.
2008, 93 (12), 4955–4962.
340. Jackson, R. S.; Creemers, J. W.; Farooqi, I. S.; Raffin-Sanson,
M. L.; Varro, A.; Dockray, G. J.; Holst, J. J.; Brubaker, P. L.,
et  al. Small-Intestinal Dysfunction Accompanies the Com-
plex Endocrinopathy of Human Proprotein Convertase 1
Deficiency. J. Clin. Invest. 2003, 112 (10), 1550–1560.
341. Douzgou, S.; Petersen, M. B. Clinical Variability of Genetic Iso-
lates of Cohen Syndrome. Clin. Genet. 2011, 79 (6), 501–506.
342. Marshall, J. D.; Maffei, P.; Collin, G. B.; Naggert, J. K.
Alström Syndrome: Genetics and Clinical Overview. Curr.
Genomics. 2011, 12 (3), 225–235.
343. Girard, D.; Petrovsky, N. Alström Syndrome: Insights into
the Pathogenesis of Metabolic Disorders. Nat. Rev. Endocri-
nol. 2011, 7 (2), 77–88.
344. Wang, J. C.; Turner, L.; Lomax, B.; Eydoux, P. A 5-Mb
Microdeletion at 6q16.1-q16.3 with SIM Gene Deletion and
Obesity. Am. J. Med. Genet. 2008, 146A (22), 2975–2978.
345. Gray, J.; Yeo, G.; Hung, C.; Keogh, J.; Clayton, P.; Baner-
jee, K.; McAulay, A.; O’Rahilly, S.; Farooqi, I. S. Functional
Charaterization of Human NTRK2 Mutations Identified in
Patients with Severe Early-Onset Obesity. Int. J. Obes. 2007,
31 (2), 359–364.
346. Buiting, K. Prader–Willi Syndrome and Angelman Syndrome.
Am. J. Med. Genet. C Semin. Med. Genet. 2010, 154C (3),
365–376.
34 CHAPTER 90  Disorders of the Body Mass
347. Cassidy, S. B.; Driscoll, D. J. Prader–Willi Syndrome. Eur. J.
Hum. Genet. 2009, 17, 3–13.
348. Butler, M. G. Prader–Willi Syndrome: Obesity Due to
Genomic Imprinting. Curr. Genomics. 2011, 12 (3), 204–215.
349. Duker, A. L.; Balllif, B. C.; Bawle, E. V.; Person, R. E.;
Mahadevan, S.; Alliman, S.; Thompson, R.; Traylor,
R.; Bejjani, B. A.; Shaffer, L. G., et  al. Paternally Inher-
ited Microdeletion at 15q11.2 Confirms a Significant
Role for the SNORD116 C/D box snoRNA Cluster in
Prader–Willi Syndrome. Eur. J. Hum. Genet. 2010, 18 (11),
1196–1201.
350. Janssen, S.; Ramaswami, G.; Davis, E. E.; Hurd, T.;
Airik, R.; Kasanuki, J. M.; Van Der Kraak, L.; Allen, S.
J.; Beales, B. A.; Katsanis, N., et al. Mutation Analysis in
Bardet–Biedl Syndrome by DNA Pooling and Massively
Parallel Resequencing in 105 Individuals. J. Appl. Genet.
2011, 129 (1), 79–90.
351. Muller, J.; Stoetzel, C.; Vincent, M. C.; Leitch, C. C.;
Laurier, V.; Danse, J. M.; Hellé, S.; Marion, V.; Bennouna-
Greene, V., et al. Identification of 28 Novel Mutations in the
Bardet–Biedl Syndrome Genes: The Burden of Private Muta-
tions in an Extensively Heterogeneous Disease. Hum. Genet.
2010, 127 (5), 583–593.
352. Aliferis, K.; Hellé, S.; Gyapay, G.; Duchatelet, S.; Stoetzel,
C.; Mandel, J. L.; Dollfus, H. Differentiating Alström from
Bardet–Biedl Syndrome (BBS) Using Systematic Ciliopathy
Genes Sequencing. Ophthalmic. Genet. Oct 17, 2011, e pub
ahead of print.
353. Sapp, J. C.; Nishimura, D.; Johnston, J. J.; Stone, E. M.;
Heon, E.; Sheffield, V. C.; Biesecker, L. G. Recurrence Risks
for Bardet–Biedl Syndrome: Implications of Locus Heteroge-
neity. Genet. Med. 2010, 12 (10), 623–627.
354. Han, J. C.; Liu, Q. R.; Jones, M.; Levinn, R. L.;
Menzie, C. M.; Jefferson-George, K. S.; Adler-Wailles, D.
C., et  al. Brain-Derived Neurotrophic Factor and Obesity
in the WAGR Syndrome. N. Engl. J. Med. 2008, 359 (9),
918–927.
355. Bochukova, E. G.; Huang, N.; Keogh, J.; Henning, E.;
­Purmann, C.; Blaszczyk, K.; Saeed, S.; Hamilton-Shield, J.;
Clayton-Smith, J.; O’Rahilly, S., et al. Large, Rare Chromo-
somal Deletions Associated with Severe Early-Onset Obesity.
Nature 2010, 463 (7281), 666–670.
356. Kissebah, A. H.; Sonnenberg, G. E.; Myklebust, J.; ­Goldstein,
M.; Broman, K., et  al. Quantitative Trait Loci on Chro-
mosomes 3 and 17 Influence Phenotypes of the Metabolic
Syndrome. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (26),
14478–14483.
357. Frayling, T. M.; Timpson, N. J.; Weedon, M. N., et  al. A
Common Variant in the FTO Gene Is Associated with Body
Mass Index and Predisposes to Childhood and Adult Obe-
sity. Science 2007, 316, 889–894.
358. Tung, Y. C.; Yeo, G. S. From GWAS to Biology: Lessons
from FTO. Ann. NY Acad. Sci. 2011, 1220, 162–171.
359. Van d Hoeven, F.; Schimmang, T.; Volkmann, A., et al. Pro-
grammed Cell Death is Affected in the Novel Mouse Mutant
Fused Toes (Ft). Development 1994, 120, 2601–2607.
360. Church, C.; Lee, S.; Bagg, E. A., et al. A Mouse Model for
the Metabolic Effects of the Human Fat Mass and Obesity
Associated FTO Gene. PLoS Genet. 2009, 5, e1000599.
361. Tung, Y. C.; Ayuso, E.; Shan, X., et  al. Hypothalamic-
Specific Manipulation of Fto, the Ortholog of the Human
Obesity Gene FTO, Affects Food Intake in Rats. PLoS One
2010, 5, e8771.
362. Jia, G.; Yang, G. G.; Yang, S., et al. Oxidative Demthylation
of 3-Methylthymine and 3-Methyluracil in Single-Stranded
DNA and RNA by Mouse and Human FTO. FEBS. Lett.
2008, 582, 3313–3319.
363. Deeb, S. S.; Fajas, L.; Nemoto, M.; Pihlajamäki, J.;
­Mykkänen, L.; Kuusisto, J.; Laakso, M.; Fujimoto, W.;
Auwerx, J. A. Pro12Ala Substitution in PPARgamma2 Asso-
ciated with Decreased Receptor Activity, Lower Body Mass
Index and Improved Insulin Sensitivity. Nat. Genet. 1998,
20 (3), 284–287.
364. Lei, H. H.; Chen, M. H.; Yang, W. S.; Chiu, M. C.;
Chen, M. C.; Tai, T. Y.; Chuang, L. M. Peroxisome
­Proliferator-Activated Receptor Gamma 2 Pro12Ala Gene
Variant Is Strongly Associated with Larger Body Mass in the
Taiwanese. Metabolism 2000, 49 (10), 1267–1270.
365. Kawasaki, I.; Tahara, H.; Emoto, M.; Shoji, T.; Okuno,
Y.; Inaba, M.; Nishizawa, Y. Impact of Pro12Ala Variant
in the Peroxisome Proliferative-Activated Receptor (PPAR)
Gamma2 on Obesity and Insulin Resistance in Japanese Type
2 Diabetic and Healthy Subjects. Osaka City Med. 2002, 48
(1), 23–28.
366. Ishiyama-Shigemoto, S.; Yamada, K.; Yuan, X.; Ichikawa,
F.; Nonaka, K. Association of Polymorphisms in the Beta2-
Adrenergic Receptor Gene with Obesity, Hypertriglyceri-
demia, and Diabetes Mellitus. Diabetologia 1999, 42 (1),
98–101.
367. Masuo, K.; Katsuya, T.; Kawaguchi, H.; Fu, Y.;
Rakugi, H.; Ogihara, T.; Tuck, M. L. Beta2-Adrenoceptor
Polymorphisms Relate to Obesity through Blunted Leptin-
Medicated Sympathetic Activation. Am. J. Hypertens. 2006,
19 (10), 1084–1091.
368. Masuo, K.; Katsuya, T.; Fu, Y.; Rakugi, H.; Ogihara, T.;
Tuck, M. L. Beta2- and Beta3-Adrenergic Receptor Polymor-
phisms Are Related to the Onset of Weight Gain and Blood
Pressure Elevation Over 5 Years. Circulation 2005, 111 (25),
3429–3434.
369. Santos, J. L.; Pérez-Bravo, F.; Martinez, J. A.; Montalvo,
D.; Albala, C.; Carrasco, E. No Evidence for an Association
Between Genetic Polymorphisms of Beta(2)- and Beta(3)-
Adrenergic Receptor Genes with Body Mass Index in Aymara
Natives from Chile. Nutrition 2002, 18 (3), 255–258.
370. Lowe, W. L., Jr.; Rotimi, C.; Luke, A.; Guo, X.; Zhu, X.;
Comuzzie, A. G.; Schuh, T. S.; Halback, S.; Kotlar, T. J.;
Cooper, R. S. The Beta 3-Adrenergic Receptor Gene and
Opbesity in a Population Sample of African Americans. Int.
J. Obes. Relat. Metab. Disord. 2001, 25 (1), 54–60.
371. Fogelholm, M.; Valve, R.; Kukkonen-Harjula, K.; Nenonen, A.;
Hakkarainen, V.; Laakso, M.; Uusitupa, M. Additive Effects of
the Mutations in the {beta}3-Adrenergic Receptor and Uncou-
pling Protein-1 Genes on Weight Loss and Weight Maintenance
in Finnish Women. J. Clin. Endocrinol. Metab. 1998, 83 (12),
4246–4250.
372. Sivenius, V. L. N. L. U. Synergistic Effect of Polymorphisms
in Uncoupling Protein 1 and Beta3-Adrenergic Receptor
Genes on Long-Term Body Weight Change in Finnish Type
2 Diabetic and Non-Diabetic Control Subjects. Int. J. Obes.
2000, 24 (4), 514–519.
373. Kring, S. I.; Holst, C.; Toubro, S.; Astrup, A.; Hansen, T.;
Pedersen, O.; Sørensen, T. I. Common Variants Near MC4R
in Relation to Body Fat, Body Fat Distribution, Metabolic
Traits and Energy Expenditure. Int. J. Obes. 2010, 34 (1),
182–189.
374. Loos, R. J.; Lindgren, C. M.; Li, S., et al. Common Variants
Near MC4R Are Associated with Fat Mass, Weigth and Risk
of Obesity. Nat. Genet. 2008, 40 (6), 768–775.
375. Herrera, B. M.; Keildson, S.; Lindgren, C. M. Genetics and
Epigenetics of Obesity. Maturitas 2011, 69 (1), 41–49.
376. Ichihara, S.; Yamada, Y. Genetic Factors for Human Obe-
sity. Cell. Mol. Life. Sci. 2008, 65 (7–8), 1086–1098.
377. Clarke, W. R.; Schrott, H. G.; Leaverton, P. E.; Connor, W. E.;
Lauer, R. M. Tracking of Blood Lipids and Blood Pressures in

School Age Children: The Muscatine Study. Circulation 1978,
58, 626–634, (October).
378. He, Q.; Karlberg, J. Prediction of Adult Overweight During
the Pediatric Years. Pediatr. Res. 1999, 46, 697–703.
379. Mossberg, H.-O. 40-Year Follow-Up of Overweight Chil-
dren. Lancet 1989, 491–493, August 26, 1989.
380. Must, A.; Jacques, P. F.; Dallal, G. E.; Bajema, C. J.;
Dietz, W. H. Long-Term Morbidity and Mortality of
Overweight Adolescents. N. Engl. J. Med. 1992, 327,
1350–1355.
381. Whitaker, R. C.; Pepe, M. S.; Wright, J. A.; Seidel, K. D.;
Dietz, W. H. Early Adiposity Rebound and the Risk of Adult
Obesity. Pediatrics 1998, 101 (3), e5.
382. Dorosty, A. R.; Emmett, P. M.; Reilly, J. J. The ALSPAC
Study Team Factors Associated with Early Adiposity
Rebound. Pediatrics 2000, 105 (5), 1115–1118.
383. Morrison, J. A.; Sprecher, D. L.; Barton, B. A.; Waclawiw,
M. A.; Daniels, S. R. Overweight, Fat Patterning, and Car-
diovascular Disease Risk Factors in Black and White Girls:
The National Heart, Lung, and Blood Institute Growth and
Health Study. J. Pediatr. 1999, 135, 458–464.
384. Lauer, R. M.; Connor, W. E.; Leaverton, P. E.;
Reiter, M. A.; Clarke, W. R. Coronary Heart Disease Risk
Factors in School Children: The Muscatine Study. J. Pediatr.
1975, 86 (5), 697–706.
385. Figueroa-Colon, R.; Franklin, F.; Lee, J.; Aldridge, R.;
­Alexander, L. Prevalence of Obesity with Increased Blood
Pressure in Elementary School-Aged Children. South. Med.
J. 1997, 90, 806–813.
386. Young-Hyman, D.; Schlundt, D. G.; Herman, L.; De Luca, F.;
Counts, D. Evaluation of the Insulin Resistance Syndrome in
5- to 10-Year-Old Overweight/Obese African-American Chil-
dren. Diabetes Care 2001, 24 (8), 1359–1364.
387. Dietz, W. H. Health Consequences of Obesity in Youth:
Childhood Predictors of Adult Disease. Pediatrics 1997, 101
(supplement), 518–525.
388. Fagot-Campagna, A.; Pettitt, D. J.; Engelgau, M. M.;
­Burrows, N. R.; Geiss, L. S.; Valdez, R.; Beckles, G. L.A.;
Saadine, J.; Gregg, E. W.; Williamson, D. F., et  al. Type 2
Diabetes Among North American Children and Adolescents:
An Epidemiological Review and a Public Health Perspective.
J. Pediatr. 2000, 136, 664–672.
389. Strauss, R. S.; Knight, J. Influence of the Home Environment
on the Development of Obesity in Children. Pediatrics 1999,
103 (6), e85.
390. Whitaker, R. C.; Dietz, W. H. Role of the Prenatal Environment
in the Development of Obesity. J. Pediatr. 1998, 132, 768–776.
391. Whitaker, R. C.; Wright, J. A.; Pepe, M. S.; Seidel, K. D.;
Dietz, W. H. Predicting Obesity in Young Adulthood from
Childhood and Parental Obesity. N. Engl. J. Med. 1997, 337
(13), 869–873.
392. Andersen, R. E.; Crespo, C. J.; Bartlett, S. J.; Cheskin, L. J.;
Pratt, M. Relationship of Physical Activity and Television
Watching with Body Weight and Level of Fatness Among
Children. J. Am. Med. Assoc. 1998, 279, 938–942.
393. Robinson, T. N. Ruducing Children’s Television Viewing to
Prevent Obesity. J. Am. Med. Assoc. 1999, 282, 1561–1567.
394. Ludwig, D. S.; Pereira, M. A.; Kroenke, C. H.; Hilner, J. E.;
Horn, L. V.; Slattery, M. L.; Jacobs, D. R. Dietary Fiber,
Weight Gain, and Cardiovascular Disease Risk Factors in
Young Adults. J. Am. Med. Assoc. 1999, 282 (16), 1539–1546.
395. National Center for Chronic Disease Prevention and Health
Promotion Resource Guide for Nutrition and Physical Activ-
ity Interventions to Prevent Obesity and Other Chronic Dis-
eases. CDC 2003.
396. Von Kries, R.; Koletzko, B.; Sauerwald, T.; von Mutius,
E.; Barnert, D.; Grunert, V.; von Voss, H. Breast Feeding
CHAPTER 90  Disorders of the Body Mass 35
and Obesity: Cross Sectional Study. Br. Med. J. 1999, 319,
147–150.
397. Denke, M. A. Weight Loss as an Endpoint: Measuring the
Effectiveness of Treatment in Obesity. Endocrinologist
1996, 6, 375–383.
398. Abenhaim, L.; Moride, Y.; Brenot, F.; Rich, S.; Benichou, J.;
Kurz, X.; Higenbottam, T.; Oakley, C.; Wouters, E.; Aubier,
M., et  al. Appetite-Suppressant Drugs and the Risk of Pri-
mary Pulmonary Hypertension. N. Engl. J. Med. 1996, 335,
609–616.
399. Heymsfield, S. B.; Greenberg, A. S.; Fujioka, K.; Dixon, R.
M.; Kushner, R.; Hunt, T.; Lubina, J. A.; Patane, J.; Self,
B.; Hunt, P., et al. Recombinant Leptin for Weight Loss in
Obese and Lean Adults. J. Am. Med. Assoc. 1999, 282 (16),
1568–1575.
400. Farooqi, S.; Jebb, S. A.; Langmack, G.; Lawrence, E.;
Cheetham, C. H.; Prentice, A. M.; Hughes, I. A.; McCamish,
M.; O’Rahilly, S. Effects of Recombinant Leptin Therapy in
a Child with Congenital Leptin Deficiency. N. Engl. J. Med.
1999, 341, 879–884.
401. Loftus, T.; Jaworski, D.; Frehywot, G.; Townsend, C.;
­Ronnett, G.; Lane, M. D.; Kuhajga, F. Reduced Food Intake
and Body Weight in Mice Treated with Fatty Acid Synthase
Inhibitors. Science 2000, 288, 2379–2381.
402. Buchwald, H.; Avidor, Y.; Braunwald, E.; Jensen, M. D.;
Pories, W.; Fahrbach, K.; Schoelles, K. Bariatric Surgery: A
Systematic Review and Meta-Analysis. J. Am. Med. Assoc.
2004, 292 (14), 1724–1737.
403. Pugnale, N.; Giusti, V.; Suter, M.; Zysset, E.; Héraief, E.;
Gaillard, R. C.; Burckhardt, P. Bone Metabolism and Risk
of Secondary Hyperparathyroidism 12 Months After Gas-
tric Banding in Obese Pre-Menopausal Women. Int. J. Obes.
2002, 27, 110–116.
404. Sjostrom, C. D.; Peltonen, M.; Wedel, H.; Sjostrom, L. Dif-
ferentiated Long-Term Effects of Intentional Weight Loss
on Diabetes and Hypertension. Hypertension 2000, 36,
20–25.
405. MacDonald, K. G.; Long, S. D.; Swanson, M. S.; Brown,
B. M.; Morris, P.; Dohm, G. L.; Pories, W. J. The Gastric
Bypass Operation Reduces the Progression and Mortality of
Non-Insulin-Dependent Diabetes Mellitus. J. Gastrointest.
Surg. 1997, 1, 213–220.
406. Goldner, W.; O’Dorisio, T. M.; Dillon, J. S.; Mason, E. E.
Severe Metabolic Bone Disease as a Long-Term Complica-
tion of Obesity Surgery. Obes. Surg. 2002, 12, 685–692.
407. Mason, E. E. Development and Future of Gastroplasties.
Arch. Surg. 2003, 138, 361–366.
408. Mason, E. E. Bone Disease from Duodenal Exclusion. Obes.
Surg. 2000, 10, 585–586.
409. Newbury, L.; Dolan, K.; Hatzifotis, M.; Low, N.; Fielding,
G. Calcium and Vitamin D Depletion and Elevated Parathy-
roid Hormone Following Biliopancreatic Diversion. Obes.
Surg. 2003, 13, 893–895.
410. Committee on Nutrition American Academy of Pediatrics
Policy Statement: Prevention of Pediatric Overweight and
Obesity. Pediatrics 2003, 112, 424–430.
411. Ruffin, M. P.; Nicolaidis, S. Electrical Stimulation of the
Ventromedial Hypothalamus Enhances Both Fat Utili-
zation and Metabolic Rate that Precede and Parallel the
Inhibition of Feeding Behavior. Brain Res. 1999, 846 (1),
23–29.
412. Advisory Board for The Endocrine Society and The Hormone
Foundation. The Endocrine Society Weighs. In: A Handbook
on Obesity in America; 2005.
413. Sahu, A. Minireview: A Hypothalamic Role in Energy Bal-
ance with Special Emphasis on Leptin. Endocrinology 2004,
145 (6), 2613–2620.
36 CHAPTER 90  Disorders of the Body Mass
414. Tecott, L.; Sun, L.; Akana, S.; Strack, A.; Lowenstein, D.;
Dallman, M.; Julius, D. Eating Disorder and Epilepsy in
Mice Lacking 5-HT2c Serotonin Receptors. Nature 1995,
374, 542–546.
415. Stenzel-Poore, M.; Cameron, V.; Vaughan, J.; Sawchenko,
P.; Vale, W. Development of Cushing’s Syndrome in
­Corticotropin-Releasing Factor Transgenic Mice.
­Endocrinology 1992, 130, 3378–3386.
416. Melynk, A.; Himms-Hagen, J. Temperature-Dependent
Feeding: Lack of a Role for Leptin and Defects in Brown
Adipose Tissue-Ablated Obese Mice. Am. J. Phys. 1998,
274, R1131–R1135.
417. Morin, C.; Eckel, R. Transgenic and Knockout Rodents—
Novel Insights into Mechanisms of Body Weight Regulation.
J. Nutr. Biochem. 2000, 8, 702–706.
418. Good, D. J.; Porter, F. D.; Mahon, K. A.; Parlow, A. F.;
Westphal, H.; Kirsch, I. R. Hypogonadism and Obesity in
Mice with a Targeted Deletion of the Nhlh2 Gene. Nat.
Genet. 1997, 15, 397–401.
419. Drago, J.; Padungchaichot, P.; Accili, D.; Fuchs, S. Dopa-
mine Receptors and Dopamine Transporter in Brain Func-
tion and Addictive Behaviors: Insights from Targeted Mouse
Mutants. Dev. Neurosci. 1998, 20, 188–203.
420. Elchebly, M.; Payette, P.; Machaliszyn, E.; Cromlish, W.;
Collins, S.; Loy, A.; Normandin, D.; Cheng, A.; Himms-
Hagen, J.; Chan, C.-C., et  al. Increased Insulin Sensitivity
and Obesity Resistance in Mice Lacking the Protein Tyrosine
Phophatase-1B Gene. Science 2000, 283, 1544–1548.
421. Charron, M. J.; Katz, E. Metabolic and Therapeutic Lessons
from Genetic Manipulation of GLUT4. Mol. Cell. Biochem.
1998, 182, 143–152.
422. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.;
Maratos-Flier, E. Mice Lacking Melanin-Concentrating
Hormone Are Hypophagic and Lean. Nature 1998, 396,
670–674.
423. Cummings, D.; Brandon, E.; Planas, J.; Motamed, K.;
­Idzerda, R.; McKnight, G. Genetically Lean Mice Result
from Targeted Disruption of the RII Beta Subunit of Protein
Kinase A. Nature 1996, 382, 622–626.
424. Muglia, L.; Jacobson, L.; Dikkes, P.; Majzoub, J.
­Corticotropin-Releasing Hormone Deficiency Reveals Major
Fetal But Not Adult Glucocorticoid Need. Nature 1995,
373, 427–432.
425. Thorliefsson, G.; Walters, G. B.; Gudbjartsson, D. F., et al.
Genome-Wide Association Yields New Sequence Variants at
Seven Loci That Associate with Measures of Obesity. Nat.
Genet. 2009, 41, 18–24.
426. Scherag, A.; Dina, C.; Hinney, A., et al. Two New Loci for
Body-Weight Regulation Identified in a Joint Analysis of
Genome-Wide Association Studies for Early-Onset Extreme
Obesity in French and German Study Groups. PLoS Genet.
2010, 6, e1000916.
427. Willer, C. J.; Speliotes, E. K.; Loos, R. J., et  al. Six New
Loci Associated with Body Mass Index Highlight a Neuronal
Influence on Body Weight Regulation. Nat. Genet. 2009, 41,
25–34.
428. Meyre, D.; Delplanque, J.; Chevre, J. C., et al. Genome-Wide
Association Study for Early-Onset and Morbid Adult Obe-
sity Identifies Three New Risk Loci in European Populations.
Nat. Genet. 2009, 41, 157–159.
429. Gratacos, M.; Gonzalez, J. R.; Mercader, J. M., et  al.
Brain-Derived Neurotrophic Factor Val66Met and Psy-
chiatric Disorders: Meta-analysis of Case-Control Studies
Confirm ­Association to Substance-Related Disorders, Eat-
ing Disorders, and Schizophrenia. Biol. Psychiatry. 2007,
61, 911–922.
430. Chambers, J. C.; Elliott, P.; Zabaneh, D., et  al. Common
Genetic Variation Near MC4R Is Associated with Waist
­Circumference and Insulin Resistance. Nat. Genet. 2008, 40,
716–718.
 CHAPTER 90  Disorders of the Body Mass 37

Biographies

 atricia A Donohoue attended medical school at The Ohio State University, and completed her
P
internship in Pediatrics there at what is now known as Nationwide Children’s Hospital. She
completed her second and third years of pediatric residency at Rainbow Babies and Children’s
Hospital, Case Western Reserve University. Her Pediatric Endocrinology Fellowship was at
Johns Hopkins under the mentorship of Professor Claude Migeon and the late Professor Neil
Van Dop. She stayed there as a junior faculty member for 4 years before moving to the Univer-
sity of Iowa. At Iowa, she continued her NIH-funded laboratory research on the genetics of ste-
roid 21-hydroxylase deficiency, and then focused her interest on other inherited defects of the
hypothalamic–pituitary–adrenal axis, and eventually on the genetics of obesity. After 18 years
at the University of Iowa, she moved to the Medical College of Wisconsin in Milwaukee in
2008, where she is a Professor of Pediatrics and Section Chief of Pediatric Endocrinology and
Diabetes.

 mar Ali, MD attended medical school at King Edward Medical College in Lahore, Pakistan,
O
and completed his residency in pediatrics at Jersey City Medical Center. He then did a 1-year
fellowship in community pediatrics at the Children’s Hospital of Pittsburgh. He worked in
general pediatrics for the next 12 years, but then decided to do a fellowship in Pediatric Endo-
crinology at UCLA-Mattel Children’s Hospital under Dr Hassy Cohen. Subsequently, he joined
the Medical College of Wisconsin in 2006. He is an Assistant Professor of Pediatrics in the
Section of Pediatric Endocrinology and Diabetes, and Director of the Pediatric Endocrinology
Fellowship Program. His research interest is the genetics and epigenetics of obesity and the
metabolic syndrome, and he is currently working on grants funded by the NIH, the National
Children’s study and the Children’s Research Institute.