Hasnain, 2016 - Obesity, More Than A Cosmetic Problem. Current Knowledge and Future Prospects of Human Obesity Genetics

Biochem Genet (2016) 54:1–28
DOI 10.1007/s10528-015-9700-2
REVIEW
Obesity, More than a ‘Cosmetic’ Problem. Current

Knowledge and Future Prospects of Human Obesity
Genetics
Shabana1 • Shahida Hasnain1,2
Received: 6 October 2015 / Accepted: 30 October 2015 / Published online: 18 November 2015
Ó Springer Science+Business Media New York 2015
Abstract Obesity has been designated as a global epidemic by WHO as its

prevalence has increased at an alarming rate in the last few decades worldwide. It is
a risk factor for diabetes, hypertension, cardiovascular problems, etc. The contri-
bution of genes to the development of obesity was confirmed in late twentieth
century. The concept of monogenic obesity came with the identification of leptin,
and mutations in its gene, followed by the discovery of more single gene mutations.
However, the recent explosion of obesity could not be explained on the basis of
these rare mutations and it was after the first genome-wide association study in 2007
that made possible the identification of different effect size variants in many can-
didate and non-candidate genes acting in a quantitative way to add to body weight.
These studies laid down the basis for polygenic cause of common forms of obesity.
The role of epigenetic regulation in the modulation of energy regulation pathway
was another important explanation put forward in the latter half of the past decade.
Taking into account the quantitative contribution of different variants has given the
concept of obesity risk scoring in order to score individuals into different risk
groups so as to decide for treatment options.
Keywords Obesity Epidemic Monogenic Polygenic
& Shabana
shabana.mmg@pu.edu.pk
1
Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore 54590,
Pakistan
2
The Women University Multan, Multan, Pakistan
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Introduction
Obesity is defined as excess of body weight and results from accumulation of body
fat over time because of excess of energy intake or a lack of energy
expenditure.(Cheung and Mao 2012) It has emerged as an important public health
problem in past few years. Previously, it was thought to be a problem of western
society mainly reflected in the National Center for Health statistics that about 61 %
of US adults are overweight and 26 % are obese, but by 2013 it was accepted that
obesity has now become a worldwide problem with over one billion people either
obese or overweight all over the world (Kelly et al. 2008; Castetbon 2015). Apart
from lifestyle and environmental factors, such reports relied on data that were
available only for high income countries with more diagnosis rate and healthcare
facilities compared to developing world (Yusuf et al. 2005). The trend of obesity has
increased in the developing world mainly because of adopting a more ‘Westernized’
lifestyle (Friedrich 2002; Bell et al. 2005). Obesity has been declared as ‘global
epidemic’ by World Health Organization evidenced on the rapid increase in the
obese individuals. According to WHO, there were approximately 1.6 billion
overweight and 400 million obese individuals in 2005, and the numbers are
expected to rise to 2.3 billion overweight and over 700 million obese individuals by
2015 (Cheung and Mao 2012). The condition is of concern not only because of its
global explosion but also due to the fact that childhood obesity is increasing at an
alarming rate with higher numbers concentrated still in the west, e.g., the number of
obese children increased fivefold in France during last decade of twentieth century
and doubled in USA in the last quarter of twentieth century (Cummings and
Schwartz 2003; Hedley et al. 2004; Castetbon 2015).
Body Mass Index as a Measure of Obesity
Body mass index (BMI, weight in kilograms divided by height in square meter) is
conventionally used for classifying obesity into different categories and has been the
most important epidemiological measure for tracking increase in the overall burden
of obesity globally(Heber 2010). A BMI \18 as underweight, 18–24.5 as normal
weight, 24.6–29.9 as overweight,[30 and\40 as obese, and[40 as morbidly obese
for Caucasians but for Asian lower BMI cut offs are used (Javed et al. 2015;
Shabana et al. 2015). The use and value of BMI are, however, questioned in many
studies because of ethnic differences in body weight distribution (Yusuf et al. 2005;
Heber 2010). Athletes often have greater than average muscle mass (not fat mass, a
measure for obesity) that increases the body weight, whereas asthenic individuals
who limit their dietary intake to have desirable body shape may have a normal body
weight with less muscle and greater fat mass. Relying solely on BMI for obesity
classification in these and related situations may lead to under or overestimating
obesity (Heber et al. 1996). Despite its limitation, however, BMI is routinely used
due to its robustness. Many others methods used to measure body fat are
summarized in Table 1 (Deurenberg and Yap 1999).
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Table 1 Phenotypes that are commonly used in obesity genetics research
Phenotypes Measurement methods Comments
Physical phenotypes
Weight Scales Quick, easy, cheap. Self-reported, so can be inaccurate
Waist circumference Tape measure Quick, easy, cheap. Used to define central obesity. Correlates well
Waist–hip ratio with BMI, visceral fatness and total body fatness
Body mass index (BMI) Scales and tape measure Quick, easy, cheap. Used to define clinical obesity that is due to
high correlation with fatness. Often calculated retrospectively for
study groups that have been recruited for other reasons

Caloric intake Questionnaire or subject recall observation Cheap and relatively simple if it is questionnaire-based. Complex
and time-consuming if observation is required in controlled
conditions
Feeding behavior Questionnaire or subject recall observation Cheap and relatively simple if it is questionnaire-based. Complex
and time-consuming if observation is required in controlled
conditions
Skin fold thickness Skin calipers A relatively simple measure of subcutaneous fat. Usually used as
the sum of several measures or as a ratio of thicknesses
Central fat mass (CFM) DEXA Precise and accurate, but expensive, complex and time-consuming.
Visceral fat mass (VFM) Unsuitable for large-scale screening
CFM–VFM ratio
Body fat distribution CT Precise and accurate, but expensive, complex and time-consuming
MRI Unsuitable for large-scale screening
Molecular phenotypes
Hormone levels ELISA Typically assessed in blood samples. Difficult to do in vivo for
differentiated
RIA Organs and tissues; for example, adipose tissue. Reflects the sum of
all influences on a particular hormone. Expensive for large-scale
studies
3
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4
Table 1 continued
Phenotypes Measurement methods Comments
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Transcription levels Real-time PCR A wide range of tissues can be investigated; comparisons of
Microarray different physiological states are possible. Only small numbers
are used as it is currently expensive. Large datasets present
analytical challenges
Measures relative RNA levels and not levels of biologically active
proteins
Metabolic profiling HPLC Typically assessed in body fluids. Sample acquisition is relatively
NMR easy but generates a complex metabolic profile, is expensive and
is not easily applicable to solid tissues
This is a list of categories of phenotypes that are used in many obesity genetics studies. Most are relatively broad, but demonstrate the relative strengths and weaknesses of
each
CT computed tomography, DEXA dual energy X-ray absorptiometry, ELISA enzyme-linked immunosorbent assay, HPLC high-performance liquid chromatography, MRI
magnetic resonance imaging, NMR nuclear magnetic resonance, RIA radioimmunoassay, RT-PCR reverse-transcriptase PCR (Bray 1992)
Biochem Genet (2016) 54:1–28 5
Use of Waist to Hip Ratio (WHR) Rather than BMI?
It has been proposed that waist circumference or waist to hip ratio is a better marker
for central adiposity than BMI (Dagenais et al. 2005). Yusuf et al. found in the
INTERHEART study that mean BMI was lowest in South Asia, China and
Southeast Asia, intermediate in eastern, central and Western Europe and highest in
Australia, New Zealand, middle east and North America with striking differences in
proportions of obese and overweight individuals in different regions. However, if
the same data are analyzed using waist to hip ratio as a measure of central adiposity,
a different pattern is observed from BMI, with WHR highest in Middle East and
North America, lowest in China and intermediate in the rest of the regions. They
also adjusted the data for age, gender, and other risk factors which reduced the BMI
cut offs, but the association of WHR with obesity remained unchanged even after all
risk factors were adjusted (Yusuf et al. 2005).
Apart from these commonly used parameters, a number of other methods are
used to measure fat mass and obesity. Table 1 summarizes the common methods
with their advantages and disadvantages.
Pathophysiology of Obesity
A complex physiological system that integrates peripheral body signals and brain
controls food intake and utilization. This biological regulation is known as energy
homeostasis and balances and maintains cumulative energy intake and utilization
over long time periods, despite daily imbalances between energy consumed and
utilized. It senses any perturbations of body weight beyond the threshold limit and
engages body for adaptive responses such as energy intake or energy expenditure,
e.g., reduction in body weight is compensated by increased hunger and decrease in
metabolic rate. Peripheral body signals, mainly neuronal and hormonal, are sent to
hypothalamus, which is the central regulator of this system and receives long- and
short-term feedback regarding energy intake and expenditure from the periphery. It
integrates these signals and acts as a master regulator of satiety. Various tissue
nuclei of hypothalamus (ventro-medial, paraventricular, arcuate) and lateral
hypothalamic area respond to these signals. The signals received in hypothalamus
can be broadly categorized into anorexigenic and orexigenic, each involving both
hormones and neurons (O’rourke 2015).
Anorexigenic Signals
The hormones involved in the transmission of anorexigenic signals are leptin and
insulin, while the neurons are pro-opiomelanocortin (POMC) receptor and cocaine
and amphetamine-related transcript (CART), while orexigenic signal transmission
involves ghrelin as the major hormone and agouti-related peptide (AGRP) and
neuropeptide-Y (NPY) neurons.
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Leptin
Leptin is a hormone produced by adipocytes and acts as an anorexigenic signal to

reduce energy intake. Leptin stimulates the conversion of POMC in the arcuate
nucleus into a-melanocyte stimulating hormone (MSH) which binds to melano-
cortin-4-receptor (MC4R). MC4R is a key receptor in energy regulation pathway
and mice knockout for MC4R gene are hyperphagic and obese. MC4R mutations are
the most frequent and account for *5.8 % forms of severe childhood early onset
obesity (Farooqi et al. 2003). 2–3 % cases of severe obesity are due to low
frequency coding variants in MC4R gene and some common variants are associated
with fat mass, obesity, and increased tendency of weight gain (Larsen et al. 2005;
Loos et al. 2008). It has been shown that MC4R agonists can maintain appetite, lean
body mass, and energy expenditure in rodents thereby offering MC4R agonists a
therapeutic option to treat obesity in future (Mak et al. 2005; Cheung et al. 2007).
POMC is cleaved by specific endoproteases which are different in different
tissues, and the product of this tissue specific post-translational cleavage depends on
the type of endoprotease. Its deficiency can lead to obesity due to inability of MC4R
to bind in the brain, to hypercortisolism in kidneys due to inability of ACTH and
MC2R to bind to appropriate receptor and to pigment alteration due to inability of
MC1R to bind to it in skin, a syndrome collectively defined as severe early onset
obesity, adrenal insufficiency, and red hair (Loos et al. 2008).
Sequelae of Obesity
Social and psychological aspects of obesity show it more like a ‘cosmetic’ problem;
however, it predisposes to serious medical conditions, including type II diabetes,
hypertension, cardiovascular diseases, many forms of cancer, pulmonary afflictions,
osteoarthritis, etc. (Calle et al. 2003; Shabana and Hasnain 2015b, 2015c). If the
current trends in obesity kinetics continue at the same rate and in the same direction,
it is expected that in the next few years in USA, it will surpass the leading risk
factor, smoking, for mortality (Mokdad et al. 2004). As the number of children
becoming obese is increasing steadily, reduction in average life expectancy is even
more pronounced (Fontaine et al. 2003). Many studies have proved that increase in
mortality rate occurs as function of increasing body weight; therefore, it is argued
that obesity may overtake infectious diseases and under nutrition as most important
contributor to illness all over the world (Kopelman 2000).
Obesity—A Multifactorial Etiology
Understanding the complex interaction of human behavior, environment, and

genetics in the development of obesity and the contribution and extent of each factor
has been the area of much interest and research. A lot of effort, time, and money
have been invested to understand the physiological basis of obesity and the energy
regulation and homeostatic pathways that lead to obesity. Physiological processes,
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as the body’s control of amount and frequency of ingestion, subsequent digestion,

absorption, and metabolism of utilized meal and distribution of nutrients to various
compartments of body, are being continuously studied and explored to minute
details. In addition, how genetics plays a role in the predisposition and development
of obesity has gained attention of scientific society. As stated earlier, the rapid rise
in obesity is largely attributed to lifestyle and environment, they cannot solely
determine the individual’s risk of obesity, and thus genetic predisposition has a vital
role in the development of obesity phenotype (Shabana et al. 2015). Here we discuss
each of these factors independently (Fig. 1).
Effect of Lifestyle on Obesity
The recent explosion of obesity is attributed to an abundance of calorie-rich food,

ease to access it, and reduced physical activity due to increasing urbanization and
industrialization. Such an environment with plenty of food and sedentary lifestyle is
termed as ‘obesogenic’ (Chaput et al. 2011). It was thus previously proposed that fat
accumulation in such an environment should not be considered a disease as it is not
due to an individual’s biological abnormality, but due to an adaptation to a
pathological environmental pressure to eat more and exercise little (French et al.
2001; Bell et al. 2005).
Effect of Behavior on Obesity
Considered as an eating disorder previously, obesity is now viewed as a

neurobehavioral or psychiatric disorder because the pathogenesis involves majority
of those genes controlling appetite and food intake (Walley et al. 2009). Such
statements are largely true as obesity definitely has behavioral basis. The fact is
supported by the recent advances in biomedical research that clearly shows that
brain and particularly hypothalamus are involved in regulation of appetite, satiety,
physical activity, and body weight. The involvement of neurotransmitter and
neuropeptide pathways in both obesity and psychological diseases is another proof
in the link of obesity with psychological basis, but the quantitative nature of weight
gain is opposed to psychological disorders which are largely qualitative. Such
similarities and differences can be elucidated with further research using large
sample size (Hinney et al. 2010).
Do the Genes Contribute to Obesity?
Although an exact consensus is still lacking, there are a few hypotheses explaining
how genes may contribute toward predisposition and development of obesity.
The thrifty gene hypothesis focuses on the evolutionary process in context of an
environment where food is scarce, food resources are not easy to approach and the
socioeconomic status of humans is low. This was the case early in human history
whereby not only food crops were limited and not available throughout the year, but
also there were frequent famines; therefore, there were needed genes that favored
weight gain to cope with nutrient poor environment and such physiological
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Fig. 1 Physiological regulation of energy balance. The neuropeptide-Y (NPY)/agouti-related protein

(AGRP) neurons, and the pro-opiomelanocortin (POMC)/cocaine and amphetamine-related transcript
(CART) neurons in the arcuate nucleus of the hypothalamus have key roles in the regulation of energy
balance. Activation of the NPY/AGRP neurons has an orexigenic effect, promoting food intake, whereas the
POMC/CART neurons have the opposite anorexigenic effect. POMC is activated through its post-
translational modification to a-melanocyte stimulating hormone (a-MSH; not shown). These two sets of
neurons receive input from several endocrine hormones as follows. Leptin is secreted from adipose tissue,
circulating at levels that are proportional to body adipose stores, and exerts its effects through the leptin
receptor (LEPR), inhibiting the NPY/AGRP neurons and stimulating the POMC/CART neurons. The
pancreas secretes insulin, which has an anorexigenic influence on the arcuate nucleus. Ghrelin is produced by
the stomach and duodenum, and stimulates the NPY/AGRP neurons through their growth hormone
secretagogue receptors (GHSRs). The peptide YY3–36 (PYY3–36) is secreted from the distal gastrointestinal
tract and signals through Y2 receptors (Y2Rs) to produce an inhibitory effect on the NPY/AGRP neurons.
The NPY/AGRP neurons also have an inhibitory effect on the POMC/CART neurons through the release of
c-aminobutyric acid (GABA), which might be stimulated by the binding of ghrelin to GHSRs. The
orexigenic and anorexigenic signals that are produced by the NPY/AGRP and POMC/CART neurons are
then sent to second-order downstream effector neurons, which also receive modifying inputs from
dopamine, serotonin, and endocannabinoid signals. These effector neurons express receptors that include the
Y1 receptor (Y1R) and the melanocortin 4 receptor (MC4R). These various inputs come together to provide
the overall balance between food intake and energy expenditure (Farooqi et al. 2003)
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mechanisms that could prevent starvation. Such a system led to weight gain when
food was plentiful and use that stored energy when food was scarce. In modern
world due to extensive biotechnology development, food is plentiful and available
throughout the year; such a physiological and genetic system may have led to the
explosion of overweight and obesity (Speakman 2008).
The fetal programming hypothesis points toward the importance of intrauterine
environment and mother’s nutritional status in deciding fetal weight gain tendency
in future life and takes into account that epigenetic regulation of energy regulation
pathway genes may be important in this regard. The predation release hypothesis
states that in earlier times, obese or overweight individuals may have been selected
against because they were more easily caught by predators but with more
civilization as man became more urbanized and learnt ways how to defend himself
from wild animals that resulted in increased survival of overweight and obese
individuals and a random genetic shift toward the accumulation of genes
predisposing to obesity. This hypothesis is different from thrifty gene hypothesis
in that it does not consider famines as a strong evolutionary pressure in human
history (Mcardle et al. 2006).
The sedentary lifestyle hypothesis is based on the last five decades’ change in the
availability of food and proportion of physical activity patterns. Fat-rich, calorie
dense foods have been plentiful in the last 50 years with less and less physical
activity resulting in predisposition to fat accumulation; however, awareness
campaigns have resulted in a change of exercise behavior resulting in increased
physical activity thereby leaving only dietary habits as a major reason and
emphasizing the importance of enzymes involved in energy regulation pathway in
susceptibility to obesity (Blümel et al. 2015).
The ethnic shift hypothesis makes use of the fact that obesity is more prevalent in
certain ethnic groups, e.g., Hispanic Americans as compared to others, e.g.,
European Americans, and the increase in population of the ethnic group with more
obese individuals will ultimately result in the overall increase in obesity. The
increased reproductive fitness hypothesis relies on the fact that adiposity increases
fecundity and women with more number of offsprings have high BMI resulting in
selection of genetic variants that predispose to obesity (Burke et al. 2010).
A low but statistically significant correlation between the BMI of spouses is the
basis for the assortive mating hypothesis and is due to assertive mating which may
result in the increase in overall obesity over time (Hebebrand et al. 2000).
The complex hypothesis states that there is no single cause of obesity and all the
hypotheses discussed above contribute to the overall increase in obesity (Walley
et al. 2009; Heber 2010; Mao 2012).
Initial Studies to Explore Obesity Genetics
Although environmental factors play significant role in development of obese

phenotype, it was accepted from the beginning that influence of genetic components
is not less significant. It is estimated that [40 % variation within a population is
accounted for by genetic factors (Stunkard et al. 1986; Fagnani et al. 2008).
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Twin, Family and Adoption Studies
These studies demonstrate that parental BMI is a strong predictive of later adulthood
risk of obesity than environmental factors (Stunkard and Sørenson 1993; Maes et al.
1997). If both parents are obese, the future risk becomes the greatest. It has been
shown that maternal BMI has a stronger effect that paternal BMI reflecting pre and
post-natal factors and gender-related differences in genetic mechanisms. In addition,
weight gain during pregnancy positively correlates with child’s future weight gain
(Reilly et al. 2005; Mamun et al. 2009). Twin studies have indicated that 60–90 %
BMI variation within population is due to genetic factors. Twins that are reared
apart have similar heritability estimates (0.7) as the twins reared together. A
significant contribution to these heritability estimates have been made by non-
additive genetic models. However, many of these twin pairs reared apart were not
separated immediately after birth and shared a uterine and early post-natal
environment that could have inflated heritability estimates to some extent
(Hebebrand et al. 2000). In addition to uterine and post-natal environment, age
affects BMI heritability estimates, although to a minor degree. Twin studies have
pointed out that intrauterine environment as a strong influence on birth weight,
especially for monozygotic twins. The correlation is less well in infancy and
becomes progressively stronger in childhood (heritability estimates shown to
increase from 0.48 at age 4 to 0.78 at age 11). According to another study,
heritability is the highest in late adolescence (0.9) (Haworth et al. 2008). Thus, the
behavioral basis of obesity is complex and involves many aspects of energy
metabolism and regulation, with 0.20–0.55 heritability estimates for such behavioral
features as restricted eating to gain a desirable and thin body shape. The children,
separated from their biological parents (adoption studies), show linear correlation in
BMI with their biological parents (Barsh et al. 2000; Cummings and Schwartz
2003).
Epigenetic Regulation
Epigenetic regulation (changes due to DNA modification, e.g., methylation, not the
DNA sequence), is also assumed to contribute to the recent epidemic of obesity.
Changes in lifestyle in the modern world may affect methylation pattern of some
genes that may alter the risk to obesity. One study observed that monozygotic twins
have epigenetically indistinguishable DNA modification pattern in early years of
life; however, differences in content and distribution of 5-methylcytosine DNA and
histone acetylation can be observed with increasing age, which obviously affect the
level of gene expression. It can be appreciated that these changes are related to
environmental triggers, resulting in individual BMI differences. Such epigenetic
differences are obviously much more pronounced in dizygotic (fraternal) twins
(Fraga et al. 2005).
Twin, family and adoption studies have thus provided ample information
regarding heritability of BMI, while current research focuses on variations on DNA
level. Research in the field of epigenetic modifications and their impact on obesity
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Biochem Genet (2016) 54:1–28 11
will definitely add information to ultimately settle the contribution of genetic

component to obesity (Kaminsky et al. 2009).
Approaches to Human Obesity Gene Identification
Human obesity susceptibility gene identification has been an arduous task with slow
progress and limited success until 2007 when first genome-wide association study
was performed, before which the two most common approaches used were
candidate gene approach and genome-wide linkage approach.
Candidate Gene Approach
As the name indicates this approach is hypothesis driven and uses the information
already available on the biology and pathophysiology of the disease to identify the
possible genes. A candidate gene for obesity is usually identified from studies such
as gene knockout and transgenic animal models, cellular models explaining glucose
metabolism pathways, and linkage and positional cloning studies in extremely obese
subjects. After a candidate gene is identified, a polymorphism or mutation within or
near it is studied to find out an association with obesity. As such variants or
mutations are expected to be rare, such studies need to be large scale in order to
have sufficient power to detect such an association (Tabor et al. 2002; Bell et al.
2005). A mutation (Leu34Phe) in a candidate gene for an endogenous satiety factor,
neuropeptide cocaine, and amphetamine regulated transcript (CART), was identified
using this approach in obese children and was found to be associated with less
resting energy expenditure resulting in obesity (Del Giudice et al. 2001). The same
mutation was later shown to be associated with higher anxiety and depression scores
in adolescents with severe early onset of obesity as compared to control subjects
suggesting a possible relationship between obesity and mental disorders that may
involve CART as a mediator (Miraglia Del Giudice et al. 2006; Mao 2011).
More recently, information from publicly available datasets is used to select
tagSNPs and then observe the association of all common variants in a gene
comprehensively to deduce whether any of the these variants is in high linkage
disequilibrium with tagSNPs as a high LD value is expected for a causal variant
(Vimaleswaran and Loos 2010; Taşan et al. 2015). Such a hunting strategy led to the
identification of leptin hormone gene in 1994 that is a key hormone in energy intake
and expenditure regulation (Margetic et al. 2002). It was a landmark discovery in
the field of obesity genetics after which a number of mutations in leptin and leptin
receptor gene were found and shown to be associated with mild to severe forms of
obesity (Montague et al., 1997a; Fischer-Posovszky et al. 2010). After identification
of leptin gene and its mutations, large-scale studies identified other genes, the
variants in which are associated strongly with obesity, these genes include
melanocortin-4-receptor (MC4R) gene, prohormone convertase 1 (PCSK1) gene,
adrenergic-b-receptor receptor (ADRB3) gene, brain-derived neurotrophic factor
(BDNF) gene and endocannabinoid receptor 1 (CNR1) gene. Of the list most
important to date have been those involved in leptin-melanocortin pathway thought
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to be critical in energy balance being responsible for most severe forms of obesity
(Morton et al. 2006; Bochukova et al. 2010; Perrone et al. 2010).
Genome-Wide Linkage Approach
This approach relies on blood relationships between study subjects and screens the
genomes of participants to observe for cosegregation of chromosomal regions
implicated in obesity across generations and to generate hypotheses to identify new,
unanticipated genomic genetic variants associated with obesity (Bell et al. 2005).
The genetic basis of many diseases was localized using this design; therefore, it was
then used for complex diseases as well. Using this approach, 250 quantitative trait
loci (QTLs) have been identified for obesity by 2006 (Rankinen et al. 2006). This
approach uses 400–600 highly polymorphic markers which are genotyped at 10 cM
intervals, and therefore, identifies large intervals that have to be further screened in
order to pinpoint the specific variants associated with obesity within areas of high
linkage signal. Positional cloning identified three promising candidate genes for
obesity, glutamate decarboxylase 2 (GAD2) that catalyzes the formation of gamma
butyric acid which regulates food intake, ectonucleotide pyrophosphatase/phospho-
diesterase 1 (ENPP1) that inhibits insulin receptor activity, and solute carrier family
6 (SLC6A14), a tryptophan transporter, as tryptophan is serotonin precursor that
controls appetite) (Boutin et al. 2003; Suviolahti et al. 2003; Meyre et al. 2005).
This method was first used in 1997 after which there has been an exponential
increase in the number of loci linked to obesity-related traits (Norman et al. 1997).
However, the drawback of the approach is that it has not been possible to replicate
the results of previous studies and pinpoint the specific variants underlying a high
linkage signal in even very large studies, e.g., 37 genome-wide linkage studies have
been meta-analyzed with more than 31,000 participants’ data belonging to 10,000
European families could not identify a single locus associated with obesity or BMI
(Saunders et al. 2007). This failure to achieve a linkage peak for common variants
may be due to the fact that such a peak requires a strong effect and most of the
common variants have small effect sizes.
‘Genome Wide Association Approach’
A ‘hypothesis free’ approach is used to deduce associations between millions of

specific variants and a particular disease by screening the whole genomes at higher
resolution levels than that used in genome-wide linkage studies. This screening can
be narrowed down to identify a specific variant or locus associated with the disease
and has therefore replaced genome-wide linkage approach. The first gene found in
2007 to be associated with obesity was ‘Fat mass and Obesity associated (FTO)
gene’ and was identified in three independent GWA studies (Dina et al. 2007;
Frayling et al. 2007; Scuteri et al. 2007).
HapMap, the international project for the determination of complete range of
genetic variation in human genome is the basis for GWA studies as it gives SNPs’
information and their LD (Linkage Disequilibrium) patterns (‘‘The International
HapMap Consortium. A haplotype map of Human Genome.,’’ 2005; ‘‘The
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Biochem Genet (2016) 54:1–28 13
International HapMap Consortium. A second generation human haplotype map of

over 3.1 million SNPs.,’’ 2007). This information is then utilized by companies to
design arrays for the analysis of millions of SNPs in very large sample size, which is
the key feature for making GWA studies possible (Mccarthy et al. 2008).
The study design for GWA studies is typically case control, allowing to recruit
large numbers of study subjects that ultimately increase the study power (Walley
et al. 2009). However, there are some limitations of this approach, as the approach
investigates common variants in common diseases it may ignore rare variants
(Cirulli and Goldstein 2010). Despite the limitations, the role of GWA studies in
unraveling the role of DNA variants in complex diseases like obesity has been
remarkable.
Monogenic Obesity
The hypothesis that mutations in single genes can cause obesity was proved in late
1990’s after the identification of mutations in leptin gene, first in mice, and
afterward in humans (Zhang et al. 1994). Leptin deficiency was identified as the first
cause of monogenic obesity in humans (Montague et al., 1997b). Further studies
identified several downstream genes in the leptin-melanocortin pathway including
‘leptin receptor (LEPR),’ ‘proopiomelanocortin (POMC),’ ‘prohormone convertase
subtilisin/kexin type 1 (PCSK1)’ and ‘melanocortin 4 receptor (MC4R)’ (Clement
et al. 1998a; Krude et al. 1998; Yeo et al. 1998). Recently, three more genes with
role in neural development have been implicated in some rare monogenic forms of
obesity namely ‘single-minded homologue 1 (SIM1),’ ‘brain derived neurotrophic
factor (BDNF),’ and ‘tropomyosin related kinase B (TRKB, also called neurotropic
tyrosine kinase receptor type 2, NTRK2)’ (Holder et al. 2000; Yeo et al. 2004;
Friedel et al. 2005). It can be clearly observed that all of these genes involved in
monogenic obesity are related directly to hypothalamic function and any change in
these genes will result in hyperphagia and obesity due to distortion of body energy
and food intake regulation pathway (Walley et al. 2009). We shall now discuss each
of these genes, their normal function, mutations reported in them and the
consequences on body weight regulation.
Leptin Gene Mutations
Leptin gene encodes leptin, a hormone synthesized primarily by adipocytes;

however, some other tissues have been shown to express leptin as well, e.g.,
placenta, ovaries, skeletal muscles, and stomach. It is encoded by leptin gene
located in chromosome 7q31.3 in humans. Leptin is synthesized as a 167 amino acid
peptide with a 21 amino acid signal sequences that direct it to microsomes where
signal peptide is cleaved, and fully functional leptin is therefore 146 amino acid
(16KDa) peptide. The concentration of circulating leptin depends on the amount of
adipose tissue as well as the size of adipocytes. It is an anorexigenic hormone that
acts on its receptor in hypothalamus and conveys the feeling of satiety (Cummings
and Schwartz 2003).
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Mutations in leptin gene or the promoter region result in the low levels of
circulating hormone that results in failure of hypothalamus to sense the energy need
resulting in more and more energy consumption and weight gain. It has been
reported that leptin administration in individuals with leptin deficiency restores the
energy regulation (Farooqi et al. 2002; Rosenbaum et al. 2002). Two cousins with
severe early onset obesity from a highly consanguineous Pakistani family had very
low levels of leptin in serum. Both were found to be homozygous for a frameshift
mutation in the ‘Ob gene’ (mG133), resulting in a truncated protein that could not
be secreted from cell (Montague et al. 1997a). Six more individuals from Pakistan
have also been reported to be homozygous for the same mutation in the leptin
gene.(Farooqi et al. 2001) Another study describes a missense mutation (C105T) in
a Turkish family resulting in severe early onset obesity and intense hyperphagia
(Strobel et al. 1998). Leptin deficiency in children results in developmental
abnormalities in immune system due to altered T cell number and function.(Farooqi
et al. 2002) Due to such an important role, consequences of its deficiency and effect
of administration of recombinant form, leptin received much attention and the field
of interest was whether a large proportion of human obesity is due to mutations in
leptin. To test this, leptin gene from hundreds of individuals was sequenced, but no
mutation was found in the coding or regulatory region in large number of
individuals indicating that proportion of individuals carrying leptin mutations may
not be very high (Maffei et al. 1996; White and Tartaglia 1996; Mantzoros et al.
1997). It was also observed that the levels of circulating leptin are not severely low
in majority of subjects suggesting that there must be some form of leptin resistance
(Clement et al. 1996). This led to the identification of leptin receptor and mutations
in receptor gene that results in leptin resistance due to deficiency of receptor.
Leptin Receptor Gene Mutations
Tartaglia et al. identified leptin receptor (LEPR also known as Ob-R) to which leptin
binds in the hypothalamus in 1995. LEPR is a single membrane spanning receptor
encoded by LEPR gene and is functionally related to gp130 IL-6 receptor family
(Tartaglia et al. 1995). Sequencing of cDNA and protein structure identification
revealed that receptor has membrane spanning, extracellular and cytoplasmic
domains. Signaling form of leptin receptor is highly expressed in hypothalamic
arcuate nucleus.(Schwartz et al. 2000).
Another leptin receptor mutation in three obese subjects from a Kabilian
consanguineous family has been reported. These individuals carried a mutation in
homozygous form that resulted in receptor truncation before the synthesis of
transmembrane domain. The phenotypic expression of leptin receptor deficiency is
similar to that of leptin deficient individuals; however, it does not result in
completely ‘null’ phenotype. These subjects gained weight rapidly in infancy, but a
normal birth weight, severe hyperphagia, and manifested aggressive behavior if
refused for food (Clement et al. 1998b).
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Biochem Genet (2016) 54:1–28 15
Pro-opiomelanocortin (POMC) Gene Mutations
Leptin has a dual function in hypothalamus, in the hypothalamic arcuate nucleus it

acts on ‘anorectic’ (reducing food intake) ‘POMC’ and ‘orexigenic’ (increasing
food intake) ‘neuropeptide-Y/agouti-related protein (NPY/AgRP)’ neurons. Pro-
opiomelanocortin (POMC) deficiency is another cause of obesity. Forty percent of
these neurons express long form of leptin receptor regulated positively by leptin.
Two German children with POMC mutations have been identified and had
hyperphagia, early onset obesity, impaired melanocortin signaling in hypothalamus,
faced adrenal problems due to ‘adrenocorticotropic hormone (ACTH)’ deficiency
(ACTH is synthesized from POMC), had yellowish skin and blonde hair because of
malfunctioning of MC1R in skin with melanocyte stimulating hormone. (Krude
et al. 1998) A heterozygous missense mutation (Arg236Gly) in POMC gene results
in disruption of dibasic amino acid processing site between b-MSH and b-endorphin
which results in an aberrant b-MSH/b-endorphin fusion protein which binds to
MC4R with affinity identical to a and b-MSH but has a reduced ability to activate
the receptor. (Challis et al. 2002).
Proconvertase 1 (PC1) Mutations
Deficiency of proconvertase 1, caused by PC1 mutations, has been reported as

another important cause behind obesity. PCs cleave prohormones where pairs of
basic amino acids occur, producing C-terminal residues which are then excised by
carboxypeptidase E. (Jackson et al. 1997) A number of neuropeptides are cleaved by
PC1 in hypothalamus including POMC, glucagons like peptide 1. A woman (47
year) with PC1 mutations resulting in severe obesity, abnormal glucose homeosta-
sis, and very low plasma insulin has been described. (O’rahilly et al. 1995) A loss of
function mutation in PC1 gene has been identified in a child with severe early onset
obesity. The child showed a number of phenotypes including hypocorticosolaemia,
impaired prohormone processing, and severe small intestine absorptive dysfunc-
tion.(Jackson et al. 2003).
Melanocortin Gene Mutations
Obesity caused by melanocortins is perhaps most frequent among all causes.

Melanocortins’ effect is manifested by interaction with G protein-coupled receptors.
Among these, MC3R and MC4R are abundantly expressed in the brain, while
MC4R is more closely linked to energy homeostasis as compared to MC3R. Loss of
MC4R in mice leads to obesity due to increased food intake, and severe early
hyperinsulinemia. Heterozygous mutations of MC4R cause dominantly inherited
obesity syndromes in different ethnic groups. In case of MC4R mutations, obesity is
manifested in heterozygous state as these mutations do not have detrimental effect
on reproduction, therefore, a reasonably high frequency of disease is maintained but
heterozygotes’ phenotype is intermediate between homozygotes and thus represent
codominant mode of inheritance (Farooqi et al. 2003).
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16 Biochem Genet (2016) 54:1–28
Obesity caused by MC4R mutations is identified by an increase in lean body

mass and bone mineral density, increased linear growth throughout childhood,
hyperphagia and severe hyperinsulinemia (Farooqi et al. 2003). Signaling properties
of mutant receptors may help to advance understanding of structure–function
relationship and provide in vitro support for the use of MC4R agonist in these
patients (Yeo et al. 1998).
Polygenic Obesity
Recent explosion of obesity could not be explained on the basis of rare monogenic
mutations worldwide. First genome-wide association study (GWAS) in 2007 opened
the way to explore the reason for such high numbers of overweight and obese
individuals. ‘FTO (Fat mass and obesity associated)’ gene was identified in the same
year in three independent GWA studies, to be strongly associated with obesity.
Since then a number of non-candidate genes have been reported to be associated
with common forms of obesity (Heber 2010; Fukuda et al. 2012; Gorkin and Ren
2014).
FTO—The ‘First Gene’ Contributing Toward ‘Common Forms of Obesity’
Genome-wide association scan has shown that polymorphisms in FTO gene are
associated with obesity phenotype, e.g., BMI, waist/hip circumference, WHR, and
weight (Dina et al. 2007; Frayling et al. 2007; Scuteri et al. 2007). Strong
correlation between BMI and polymorphisms in ‘FTO’ gene has been confirmed in
various independent genome-wide association studies that have been identified by
Fischer-Posovszky et al. (2010). The ‘FTO (Fat mass and obesity associated)’ gene
was originally identified when a 1.6-Mb deletion in chromosome 8 in mice resulted
in a fused toes phenotype and severe developmental defects (Peeters et al. 2008).
The mechanism by which FTO gene variants influence obesity and lead to type
2-diabetes is still unknown. The expression of the gene is high in hypothalamic–
pituitary–adrenal axis which may be a reason for role in body weight regulation
(Dina et al. 2007). Its expression is increased by approximately 60 % in the
hypothalamus of mice in the fed state as compared to the mice in the fasting state
(Gerken et al. 2007). Human FTO gene is located on chromosome 16, is over
400 Kb long, and spans nine exons. Predisposition to obesity is mostly conferred by
risk alleles concentrated in the first intron. These variations have been observed to
be associated with risk of overweight and obesity, leptin levels, subcutaneous fat
mass, fat mass, waist, and hip circumference (Scuteri et al. 2007). These variants
affect and persist in childhood. The homozygotes are on average 3 kg heavier than
heterozygotes for that allele (Dina et al. 2007; Frayling et al. 2007). Although
influence of FTO on weight is modest but consistent among Caucasians as
demonstrated by various studies. The presence of one risk allele increases the BMI
by 0.10–0.13 Z-score units, meaning that 1.3–2.1 kg of body weight will be added
in a person with a risk allele. The association of FTO with obesity, particularly class
III obesity (BMI [40 kg/m2), has been confirmed in French Caucasians and with
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Biochem Genet (2016) 54:1–28 17
BMI, hip circumference, and weight in Sardinians, European Americans, and

Hispanic Americans but not in African Americans (Fredriksson et al. 2008).
The FTO gene has not been previously implicated in obesity but it maps to a
region where BMI linkage has been confirmed in two genome-wide linkage scans
with LOD scores of 3.2 and 2.2 in ‘Framingham Heart study’ and ‘Family Blood
Pressure Program study,’ respectively (Wu et al. 2002). A syndrome that includes
obesity as one of its features has also been mapped to a region near FTO on
chromosome 16. A cluster of multiple SNPs associated with body weight, waist, and
hip circumference has been found to overlap with FTO but these do not point toward
multiple independently associated SNPs, so they may be in linkage disequilibrium
with the same causal variants (Scuteri et al. 2007).
Some studies have proposed a central role of FTO by affecting cerebrocortical
insulin sensitivity because in individuals who were homozygous for risk allele,
reduced insulin response in brain was observed. FTO mRNA levels in healthy
women increase with BMI, while risk allele carriers had reduced lipolytic activity
independent of BMI (Bouchard 1997).
When FTO gene is inactivated it results in less physical activity and reduced
weight in mice. Human FTO gene has been identified as a candidate gene
predisposing to obesity correlating to variants in intron 1 to BMI. Human FTO gene
variants might lead to up or dysregulation of FTO expression predisposing to
obesity. Human FTO risk allele carriers develop obesity as a consequence of
hyperphagia in the absence of altered energy expenditure. Molecular basis of the
regulation of sympathetic system and substrate cycling by FTO may be studied in
future leading to the identification of new therapeutic targets in the treatment of
obesity (Fischer-Posovszky et al. 2010). Association of FTO variants with obesity
varies across geographical regions in White Europeans; the association is
established but is inconsistent in Asians. The association difference may be due
to varying study designs, inadequate sample sizes, and ethnic differences. This
association in Whites with obesity and type 2 diabetes seems to be mediated through
BMI, but a north Indian Sikhs studies showed strong association with type 2
diabetes and FTO variants which was independent of BMI. Indians develop diabetes
at a much lower BMI than do the Europeans (Yajnik et al. 2009).
The study of this gene is still in initial stages of investigation, and it has not been
studied in detail in experimental models so no recognizable functional domains and
putative functions have been currently imputed to it but the fact that it is associated
with BMI, waist and hip circumference is consistent in all analyses of heritability
(Wardle et al. 2008). Need of the hour is to develop new methods that can tackle
these problems. Knowledge about human genome, availability of new bioinfor-
matics tools and new analysis strategies taking into account hundreds of items of
genetic and environmental information will facilitate future analyses (Clement et al.
1996).
In addition to FTO and the SNPs identified in this gene, there is a list of genes
and their variants found in different GWA studies to be associated with the
polygenic obesity (Albuquerque et al. 2015). Table 2 summarizes these genes and
their SNPs.
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Table 2 An overview of the loci recently identified to be associated with obesity

Gene symbol Gene name SNP ID OR (95 % CI)*
FTO Fat mass and obesity associated rs9939609 1.31 (1.23–1.39)

Near MC4R Melanocortin-4 receptor rs17782313 1.12 (1.08–1.16)
Near TMEM18 Transmembrane protein 18 rs7561317 1.2 (1.13–1.27)
rs6548238 1.19 (1.10–1.26)
FAIM2 Fas apoptotic inhibitory molecule 2 rs7138803 1.14 (1.09–1.19)
Near GNPDA2 Glucosamine-6-phosphate deaminase 2 rs10938397 1.12 (1.07–1.17)
SEC16B S. cerevisiae Sec16 rs10913469 1.11 (1.05–1.18)
BDNF Homolog of brain-derived neurotrophic factor rs925946 1.11 (1.05–1.16)
Near ETV5 Ets variant 5 rs7647305 1.11 (1.05–1.17)
SH2B1 SH2B adaptor protein 1 rs7498665 1.11 (1.06–1.17)
Near NEGR1 Neuronal growth regulator 1 rs2568958 1.07 (1.02–1.12)
Near KCTD15 Potassium channel tetramerization domain rs29941 1.10 (1.04–1.15)
containing 15 rs11084753 1.04 (0.98–1.10)
MTCH2 Mitochondrial carrier 2 rs10838738 1.03 (0.98–1.08)
Near PRKD1 Protein kinase D1 rs11847697 1.10 (1.03–1.17)
SLC39A8 Solute carrier family 39, member 8 rs13107325 1.1 (1.05–1.15)
TFAP2B Transcription factor AP-2 beta rs987237 1.09 (1.05–1.12)
QPCTL Glutaminyl-peptide cyclotransferase-like rs2287019 1.09 (1.05–1.12)
NRXN3 Neurexin 3 rs10150332 1.09 (1.05–1.12)
Near GPRC5B G protein-coupled receptor, family C, group 5, rs12444979 1.08 (1.04–1.11)
member B
Near RBJ- DNAJC27 DnaJ (Hsp40) homolog, subfamily C, rs713586 1.07 (1.05–1.09)
member 27
MAP2K5 Mitogen-activated protein kinase 5 rs2241423 1.07 (1.04–1.10)
Near Transmembrane protein 160 rs3810291 1.06 (1.03–1.08)
TMEM160
Near FANCL Fanconi anemia, complementation group L rs887912 1.06 (1.03–1.08)
Near Centriolar protein rs2112347 1.05 (1.03–1.08)
FLJ35779-
POC5
Near LRP1B Low density lipoprotein receptor-related rs2890652 1.05 (1.02–1.08)
protein 1B
MTIF3 Mitochondrial translational initiation factor 3 rs4771122 1.05 (1.01–1.08)
LRRN6C Leucine rich repeat neuronal 6C rs10968576 1.04 (1.02–1.06)
TNNI3 K Interacting kinase rs1514175 1.04 (1.02–1.07)
CADM2 Cell adhesion molecule 2 rs13078807 1.03 (1.00–1.06)
NUDT3 Nucleoside diphosphate linked moiety X type rs206936 1.03 (1.01–1.06)
motif 3
Near RPL27A Ribosomal protein L27a rs4929949 1.03 (1.01–1.05)
Near ZNF608 Zinc finger protein 608 rs4836133 1.03 (1.01–1.05)
Near PTBP2 Polypyrimidine tract binding protein 2 rs1555543 1.02 (0.99–1.04)
GNAT2 Guanine nucleotide binding protein (G protein) rs17024258 1.27 (p = 0.02)
alpha transducing activity
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Biochem Genet (2016) 54:1–28 19
Table 2 continued
Gene symbol Gene name SNP ID OR (95 % CI)*
HS6ST3 Heparin sufate 6-O-sulfotransferase 3 rs7989336 1.09 (p = 0.0001)

HNF4G Hepatocyte nuclear factor 4, gamma rs4735692 1.09
(p = 1.97 9 10-5)
RPTOR Regulatory associated protein of MTOR, rs7503807 1.08
complex 1 (p = 7.07 9 10-5)
MRPS33P4 Mitochondrial ribosomal protein S33 rs13041126 1.08 (p = 0.001)
pseudogene 4
ZZZ3 Zinc finger, ZZ-type containing 3 rs17381664 1.08 (p = 0.001)
ADCY9 Adenylate cyclase 9 rs2531995 1.06 (p = 0.01)
* Some studies did not report CI but the p-values

SNP ID single nucleotide polymorphism identity, OR odds ratio, CI confidence interval
Obesity Risk Scoring
GWA studies have made a large contribution in unraveling the genetic basis of
common and multifactorial complex diseases by determining the low effect size
variants in different candidate and non-candidate genes that not only bridged the
gap between research findings and implications in the health practice but also
helped find treatment options for various complex disorders (Janssens 2008; Khoury
et al. 2010). A big problem in using risk SNP data from GWAS research is the low
effect size of many common variants making it difficult to detect such variants that
may cause health effects when present together.
Genetic Risk Scores (GRS) represent the aggregate effect of risk SNPs across the
genome and pool the information of the individual SNPs.(Horne et al. 2005) When
the number of SNPs used for building a GRS is increased, the distribution curve
reaches normality indicating that the GRS method can be an effective approach to
assess the risk of an individual for weight gain. Obesity has become a well-suited
candidate for risk assessment by genetic risk scores analysis because of the
increased morbidity and mortality rates and health care costs due to obesity.
Role of Host Gut Microbiota in Obesity
Recently, many studies, both in rodents and humans, reported that the host gut
microbiota is a strong contributing factor to metabolic disorders especially obesity,
diabetes, and metabolic syndromes by affecting host energy regulation and
homeostasis (Kasai et al. 2015; Ussar et al. 2015). The human gut is colonized
by complex microbial communities which may be ten times greater in numbers than
the human’s own cells; however, 60–80 % of them are uncultivatable. However,
with the advancement in molecular methods, especially, next generation sequenc-
ing, some progress has been made in the detection of the unculturable fraction (Van
Citters and Lin 2005). It has been shown that obese humans and rodents have less
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diverse gut microbiota as compared to the lean controls. In addition, the

metagenomic studies have shown that the microbial gene repertoires of the obese
subjects are different than non-obese individuals (Turnbaugh et al. 2009; Ussar et al.
2015). Although research has shown differences in microbial composition of gut of
obese and lean subjects with the observation that the members of Bacteroidetes and
Firmicutes are significantly reduced in the obese subjects (Turnbaugh et al. 2006),
the results have been inconsistent in different studies (Duncan et al. 2008; Schwiertz
et al. 2010). Future studies are, therefore, needed to elucidate the exact role of gut
microbiota in the development of complex lifestyle associated disorders such as
diabetes and obesity.
Circadian Rhythms and Obesity
Mammalian physiology and behavior are coordinated by an intrinsic molecular

clock into rhythms that are synchronized with the 24 h solar day. This synchro-
nization allows anticipation of regular environmental changes to influence
molecular and behavioral decisions that impact fitness and survival, including food
intake and metabolism, predator/prey interactions, and the evasion of DNA damage
from environmental insults, among others (Lowrey and Takahashi 2004). Circadian
rhythms, therefore, allow an animal to achieve temporal homeostasis with its
environment at the molecular level by regulating gene expression to create a peak of
protein expression once every 24 h to control when a particular physiological
process is most active with respect to the solar day. Circadian rhythms are
genetically encoded by a molecular clock located in nearly every cell that generates
internal timing of approximately 24 h in the absence of external cues (Fig. 2).
Molecular clocks located throughout the body in peripheral tissues are organized
into a coherent, hierarchical system by a ‘master’ clock located in the supra-
chiasmatic nucleus (SCN) of the hypothalamus (Ko and Takahashi 2006). It has
been shown that the circadian clock undergoes nutritional programing, which may
contribute to the alternations in energy metabolism associated with the development
of metabolic disorders in early life and adulthood. Many genes have been identified
which disturb the body weight regulation by affecting the circadian clocks (Wang
et al. 2015).
Obesity Pandemic in Pakistan
Pakistan, as a low-income country, initially faced the problem of malnutrition and

under nutrition, but with the improvement in life standards and availability of a
variety of palatable foods at relatively low price resulted in an increase in overall
body weight which became more evident due to decrease in physical activity. Due
to illiteracy and psychological stigma, obesity has not been considered a disease
until recently that hindered research to understand what factors, biochemical as well
as genetic, are involved in the development of obesity in Pakistan. With a total
population of 184.35 millions in 2012–13, Pakistan is the 6th most populous
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Biochem Genet (2016) 54:1–28 21
Fig. 2 Temporal control of physiology via four integral clock proteins. The figure shows the molecular
control of circadian clock with two activators (CLOCK and BMAL1) and two repressors (PER and CRY)
(Partch et al. 2014). CLOCK circadian locomotor output cycles kaput, BMAL1 brain and muscle ARNT
(Aryl hydrocarbon receptor nuclear translocator) Like protein 1, CRY CRYptochrome, PER PERiod,
REV-ERB (alternate name for NR1D2 (nuclear receptor subfamily 1, group D, member 2) RORa RAR
(retinoic acid receptor) related orphan receptor alpha also known as NR1F1 (nuclear receptor subfamily 1,
group F, member 1), Ub Ubiquitin
country of the world (Tfr 2009). According to the Global Burden of Disease Study,
in terms of obesity, it ranked 9th out of 188 countries (Ng et al. 2014). Pakistan
faced a lot of health challenges during a decade long war on terror (Sherin 2014). In
Asian populations, multiple factors increase body fat percentage and resultantly
BMI (Tan 2004); therefore, lower BMI cutoff values have been proposed by
the international obesity task force to define overweight (23.0–24.9 kg/m2) and
obesity ([25.0 kg/m2) in Asians (Choo 2002; Alberti et al. 2009). According to this
criterion, in Pakistan, one fourth of the general population is either overweight or
obese. Various risk factors including female gender, old age, urbanization, and
high-life standards have been shown to influence body weight significantly (Jafar
et al. 2006). In addition to unhealthy dietary habits, changing life style and decrease
in physical activity are the main contributing factors for the increased prevalence of
obesity in Pakistan (Samir et al. 2011). In this context, it is needed to establish a
genetic panel representing common variants predisposing to common forms of
obesity in this region of the world. There has been limited research in the field of
obesity genetics in Pakistan and most of it focused on monogenic forms of obesity
but we have recently shown that common forms of obesity in Pakistan are polygenic
in nature whereby common low effect size variants in many genes act quantitatively
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to affect body weight (Shabana and Hasnain, 2015a, 2015b, 2015c; Shabana et al.
2015).
Conclusion
In the ever changing lifestyle trends and increasing knowledge becoming available
regarding the influence of genes and interaction of lifestyle, behavior and genetics, it
is needed to compile the past and present knowledge regarding the subject and
explore the future possibilities. Obesity has become a very important research
interest due to the alarming increase in the number of overweight and obese
individuals worldwide and the effects it has on public health and economy. The need
of the hour is to quantify the contribution of lifestyle and genetic factors in disturbing
the body weight regulation mechanisms and after that establish a genetic screening
program that involves common mutations and polymorphisms of large effect size
from all ethnic origins and combine the results with lifestyle and behavior
information in order to score the subjects and decision for medication and treatment
should be based on this risk score. Keeping this context in view, the current review
was written that clearly shows how the obesity epidemic is affecting developed as
well as developing countries and is posing a huge socioeconomic burden to them.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflict of interest.
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Biochem Genet (2016) 54:1–28

Obesity, More than a ‘Cosmetic’ Problem. Current

Shabana1 • Shahida Hasnain1,2

Abstract Obesity has been designated as a global epidemic by WHO as its

Keywords Obesity Epidemic Monogenic Polygenic

Body Mass Index as a Measure of Obesity

study groups that have been recruited for other reasons

Phenotypes Measurement methods Comments

Use of Waist to Hip Ratio (WHR) Rather than BMI?

Leptin is a hormone produced by adipocytes and acts as an anorexigenic signal to

Obesity—A Multifactorial Etiology

Understanding the complex interaction of human behavior, environment, and

as the body’s control of amount and frequency of ingestion, subsequent digestion,

Effect of Lifestyle on Obesity

The recent explosion of obesity is attributed to an abundance of calorie-rich food,

Effect of Behavior on Obesity

Considered as an eating disorder previously, obesity is now viewed as a

Do the Genes Contribute to Obesity?

Fig. 1 Physiological regulation of energy balance. The neuropeptide-Y (NPY)/agouti-related protein

Initial Studies to Explore Obesity Genetics

Although environmental factors play significant role in development of obese

Twin, Family and Adoption Studies

will definitely add information to ultimately settle the contribution of genetic

Approaches to Human Obesity Gene Identification

Candidate Gene Approach

Genome-Wide Linkage Approach

‘Genome Wide Association Approach’

A ‘hypothesis free’ approach is used to deduce associations between millions of

International HapMap Consortium. A second generation human haplotype map of

Leptin Gene Mutations

Leptin gene encodes leptin, a hormone synthesized primarily by adipocytes;

Leptin Receptor Gene Mutations

Pro-opiomelanocortin (POMC) Gene Mutations

Leptin has a dual function in hypothalamus, in the hypothalamic arcuate nucleus it

Proconvertase 1 (PC1) Mutations

Deficiency of proconvertase 1, caused by PC1 mutations, has been reported as

Melanocortin Gene Mutations

Obesity caused by melanocortins is perhaps most frequent among all causes.

Obesity caused by MC4R mutations is identified by an increase in lean body

FTO—The ‘First Gene’ Contributing Toward ‘Common Forms of Obesity’

BMI, hip circumference, and weight in Sardinians, European Americans, and

Table 2 An overview of the loci recently identified to be associated with obesity

FTO Fat mass and obesity associated rs9939609 1.31 (1.23–1.39)

Gene symbol Gene name SNP ID OR (95 % CI)*

HS6ST3 Heparin sufate 6-O-sulfotransferase 3 rs7989336 1.09 (p = 0.0001)

* Some studies did not report CI but the p-values

Obesity Risk Scoring

Role of Host Gut Microbiota in Obesity

diverse gut microbiota as compared to the lean controls. In addition, the

Circadian Rhythms and Obesity

Mammalian physiology and behavior are coordinated by an intrinsic molecular

Obesity Pandemic in Pakistan

Pakistan, as a low-income country, initially faced the problem of malnutrition and

Compliance with Ethical Standards

Conflict of Interest The authors declare no conflict of interest.

Bray GA (1992) Pathophysiology of obesity. Am J Clin Nutr 55(2):488S–494S

Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V, Ghoussaini M, Wachter C,

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