Indian Journal of Pharmacology 1999; 31: 388-403

EDUCATIONAL FORUM
NEUROCHEMICAL BASIS OF OBESITY

OBESITY: AN INSIGHT INTO ITS NEUROCHEMICAL BASIS AND TREATMENT

S.K. KULKARNI, GURPREET KAUR
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh.
Manuscript Received: 1.7.99

Revised: 20.8.99

Accepted: 19.9.99

SUMMARY

Obesity threatens to become the 21st centurys leading health problem. Its prevalence is on the rise in all
age groups and in all developed countries of the world. The exact aetiology of obesity still remains
obscure. It is mainly caused by a combination of genetic factors, inappropriate eating and reduced
activity. Besides, dysregulation of various hypothalamic mechanisms controlling energy intake and energy
expenditure have also been implicated in its development and progression. In the last few years, steady
advances made in the understanding of the bodys weight regulating mechanisms has helped to define
novel sites for targeting and intervention in order to reduce intake and enhance expenditure. Based on
this, many new antiobesity drugs have been developed. Some of them are in the early stages of
development and some of compounds acting on these sites are already available.

KEY WORDS

Obesity
energy intake
treatment strategies

energy expenditure

INTRODUCTION
Obesity is nowadays a common and challenging
health problem. It is not only a problem in itself but
also a predisposing factor for many other adverse
health outcomes like non-insulin dependent diabetes mellitus (NIDDM), insulin resistance, atherosclerosis, dyslipidemias, cardiovascular and all-cause
mortality1. The World Health Organisation has described it as an escalating epidemic and one of the
greatest neglected public health problems of our time
with an impact on health which may well prove to be
as great as smoking2. Obesity results from a positive energy balance i.e., when caloric intake chronically exceeds energy expenditure. This inturn causes
excess of adipose tissue mass with body mass index (BMI) > 30 kg/m 2 (Table 1)3.
EPIDEMIOLOGY
The epidemic of obesity is on the rise and this is
probably due to increasingly sedentary lifestyles combined with easy availability of palatable, high fat foods.
Its prevalence has shown a startling increase in all
age groups and in all the countries of the world during past 19 years. In 1980, a Department of health
Survey in U.K. showed that 6% of men and 8% of
women were obese, as defined by a BMI >30 kg/m2.
Correspondence: S.K. Kulkarni

neurotransmitters

neuropeptides

In 1995, 15% of men and 16.5% of women were

obese and more than half of the adult population is
now either overweight or obese. It has been predicted
that if this trend continues to the year 2005, the prevalence of obesity among men and women would by
then be 18 and 24% - exactly three times the target
figure4,5. There has also been an increase in comorbid
risk factors like coronary heart disease, hypertension, various cancers (e.g., endometrium, ovaries,
breast, colon), gall bladder disease, NIDDM,
arthritis, respiratory disease, pregnancy complications, menstrual difficulties, varicose veins, psychological problems (poor self-esteem, depression, poor
employment prospects).
ETIOLOGY
The exact etiology of obesity is unclear. The multiple
causative factors like genetic, environmental, nutritional, physiological, psychological, social and cultural factors have been linked to its development and
progression6.
Genetic factors
Early evidence of genetic component underlying
obesity came from a variety of animal models produced by genetic alterations in single gene (ob/ob,
db/db, fa/fa, Cpefat, tub/tub, Ay/a, KK), multiple genes

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S.K. KULKARNI AND GURPREET KAUR

(BSB, NZO, AKR mice, and OM rats) and transgenic

techniques (knockouts : BAT, WAT, 3 adrenoceptor ;
antisense:type II glucocorticoid receptor; overexpression:Glut 4, CRF)7,8. Thus, the genetic basis of obesity is complex with the probability of a number of interacting genes being involved (polygenic inheritance). Each of the main components of energy balance relationship (energy intake, BMR, the thermic
effect of food and physical activity) and even body
fat distribution has a distinct genetic basis. The genetic predisposition to obesity accounts for 20-40%
of cases9.

Figure 1. The pathogenesis and pathophysiology of visceral fat

syndrome (TG = triglycerides, FFA = free fatty acids).

Environmental factors
The current environmental risk factors include overconsumption of energy (increase in fat to carbohydrate ratio) and decrease in physical activity. These
factors offer more reasonable explanation for the recent dramatic surge in the prevalence of obesity.
Nutritional factors
Numerous metabolic studies have shown that high
fat diets may lead to a high energy intake and hyperphagia. The reason may be that fat has a weaker
effect on the satiety centre and on heat production
(diet-induced thermogenesis) and it possesses a
higher energy density compared to carbohydrates.
Also fats are highly palatable and heighten the flavour of food stuffs which leads to their passive overconsumption. This ultimately increases fat deposits
and causes obesity and related problems10.
Physiological factors
These involve the impairment of the central mechanism regulating appetite and food intake which is
thought to be regulated by a complex interplay of
neurotransmitters in the hypothalamic region of the
brain. Approximately 1 - 2% of obesity can be ascribed to lesions in hypothalamic regulatory centres.
Such lesions may be due to trauma, tumours, inflammatory processes, or carotid artery aneurysms11.
Psychological factors
The psychogenic theory of obesity long held that
obesity resulted from an emotional disorder in which
food intake, relieved the anxiety and depression to
which obese persons are usually susceptible. Stress
associated with traumatic emotional events has been
held responsible for certain cases of obesity and has

been implicated in the pathogenesis of eating disorders such as night-eating syndrome and bulimia12.
TYPES OF OBESITY
The concept of fat distribution (android and gynoid)
was first introduced in obese subjects with diabetes
mellitus or cardiovascular disease by Vague13. Later,
Kiessebah et al., proposed a classification of obesity - upper body segment and lower body segment
using waist-to-hip circumference ratio14. There are
two types of obesity- the central adiposity (upper
body segment, android obesity), and the peripheral
adiposity (lower body segment, gynoid obesity).
Central adiposity
Apple-shaped people have excess fat in subcutaneous abdominal and visceral depots. This condition is associated with an increased morbidity and
risk of a number of metabolic complications such as
coronary heart disease, NIDDM, hormone-related
cancers and several abnormalities in endocrine secretions including increased activity of CRF-ACTHadrenal axis, an elevated cortisol secretion as well
as hyperandrogenicity in women, and a relative hypogonadism in men. There is also pronounced insulin resistance. Upper body obesity resembles Cushings disease in fat distribution. Such individuals have

NEUROCHEMICAL BASIS OF OBESITY

Table 1. Classification of overweight and obesity in adults
Classification

BMI (kg/m2)*

Underweight

<18.5

Normal range
Overweight
Obese
class I
class II
class III

18.5-24.9
25.0-29.9
> 30.0
30.0-34.9
35.0-39.9
> 40.0

Table 2.

390

Some differences between visceral and subcutaneous

fat tissue

Risk of co-morbidities
Low (but risk of other clinical
problems increased)
Average
Mildly increased
Moderate
Severe
Very severe

Action

Lipolysis induced
by
catecholamines
Antilipolytic
effect of insulin

* body mass index

increased cortisol production and also increased

expression of glucocorticoid receptors and PPAR-
gene in the visceral region.
Peripheral adiposity
Pear shaped people with peripheral adiposity have
excessive fat distributed subcutaneously around the
gluteofemoral region and in the lower abdomen (on
the hips and thighs). They are less prone to metabolic disorders but more prone to mechanical disorders such as varicose veins and disorders of joints.
With the availability of computer assisted tomography (CAT) accurate analysis (surface area and volume) of subcutaneous fat and intra-abdominal visceral fat could be done and a novel classification of
obesity was proposed - visceral fat obesity (VFO)
and subcutaneous fat obesity (SFO) based on the
ratio of visceral fat area and subcutaneous fat area
(V/S ratio) at the level of umbilicus. Significant positive correlations were demonstrated between V/S
ratio and plasma glucose area, serum TG level, and
total cholesterol level as well as systolic and diastolic
blood pressure15,16 (Table 2).
A new clinical entity called visceral fat syndrome has
been reported as a multiple risk factor syndrome in
which visceral fat accumulation, glucose intolerance,
hyperlipidemia and hypertension cluster to induce the
occurrence of atherosclerosis. This syndrome resembles syndrome X or the deadly quartet17 (Figure 1).
PATHOPHYSIOLOGICAL FACTORS UNDERLYING
OBESITY
In order to develop new treatments for obesity, it is very
important to understand the physiological pathways that
regulate the energy balance (both intake and expenditure) and to identify factors causing obesity.

Antilipolytic effect
of adenosine and
prostaglandins

Site with more

activity

Mechanism (visceral
Vs subcutaneous)

Increased function of -AR

and decreased function of
2-AR (antilipolytic) in visceral cells
Subcutaneous Decreased insulin receptor
affinity and signal transduction in visceral cells
Visceral

Subcutaneous Decreased agonist receptor

number in visceral cells

Glucocorticoidsteroid action

Visceral

Increased glucocor ticoid

receptor number in visceral
cells

Peroxisome
proliferator
activated
receptor- activity

Visceral

Gene expression (mRNA)

increased in visceral cells of
obese people

Leptin secretion

Subcutaneous Decreased leptin gene expression in visceral cells

ENERGY BALANCE EQUATION

ENERGY INTAKE = ENERGY EXPENDITURE+ ENERGY STORAGE

ADIPOSE TISSUE
(TRIACYLGLYCEROL)

As illustrated above energy intake and energy expenditure play a pivotal role in controlling body fat
stores18. The energy intake depends on appetite
which is mainly controlled by glucostatic and lipostatic
feedback systems. The energy expenditure depends
on heat production (diet induced thermogenesis, DIT,
10 - 12%), metabolism (basal metabolic rate, BMR
65%) and physical exercise (variable). Any imbalance
between these two is translated into a change in fat
stores and obesity. This balancing act also involves
various neural and endocrine signals acting peripherally as well as centrally which cause disturbance
and derangement of various other physiological functions as well8.

Energy intake regulation in obesity

The nerve centre for the regulation of energy balance is the hypothalamus, which integrates neural,
hormonal, nutrient messages from elsewhere in the

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S.K. KULKARNI AND GURPREET KAUR

Figure 2. Neuroendocrine hypothesis of metabolic complications

resulting from visceral obesity. CR, corticotropin-releasing factor; ACTH, adrenocorticotropic hormone, FFA.
Free fatty acid.
PERCIEVED STIMULUS

COPING REACTION
THREAT OF CONTROL
FIGHT - FLIGHT

LOSS OF CONTROL

'

DEPRESSION

DEFENSE REACTION

DEFEAT REACTION

CENTRAL
SYMPATHETIC AROUSAL
$
$
CONTROL
STRIVING

PITUITARY
ADRENAL AROUSAL
$
LOSS OF CONTROL

ADRENALINE h
NORADRENALINE

FFA h

CRF h
ACTH h

FFA h

GLYCOGENOLYSIS h GLUCOCORTICOIDS1 GLUCOCORTICOIDSh

TESTOSTERONE h

OVULATION i

TESTOSTERONE i

HYPERTENSION

METABOLIC ABBERATIONS
VISCERAL FAT ACCUMULATION

'

DISEASE

body and sends signals to the higher centres leading to feeling of hunger or satiety. The hypothalamus
also controls energy expenditure via the autonomic
nervous system and pituitary hormones.
The neuroendocrine axis involved in energy balance
regulation may be the hypothalamic links with the
adrenals, gonads and the sympathetic nervous system. The hypothalamic arousal by physical and mental stressors result in fight or flight (defeat) reaction
which leads to changes in these links 19. The fight reaction occurs via the sympathetic pathways to help
gain control by increasing the readiness of circulatory factors and to mobilise substrates needed to
meet the challenges. When the individual loses control and ends up in a defeated, submissive, helpless
situation, there is hyperactivity of CRF-ACTH-cortisol axis, hypercortisolism, and decreased secretion

of sex-hormones. This type of reaction has been

shown to be followed by abdominal fat accumulation
and metabolic aberrations, including signs of insulin
resistance20. The reaction patterns may also shift from
one type to another due to perceived stimulus, varying between and among individuals. It has been
shown that long-term stress, in addition to being responsible for over-eating through neural mechanisms,
results in elevated plasma levels of glucocorticoids
(Figure 2). Glucocorticoid excess results in increased
hepatic gluconeogenesis and diminished arteial glucose transport and utilisation21.
A large number of hypothalamic neurotransmitters
have also been implicated in the control of energy
balance. Those that increase food intake generally
suppress sympathetic nervous system activity and
thus thermogenesis, whereas the reverse is true for
neurotransmitters that decrease the appetite 22
(Table 3).
Neuropeptide Y (NPY)
Of the few neurotransmitters that stimulate feeding,
neuropeptide Y has attracted the most interest. It is
a linear 36 amino acid peptide which was first isolated from the porcine brain. It is a member of the
pancreatic polypeptide (PP) family of regulatory
peptides that includes the endocrine peptides, peptide YY (PYY) and PP. It has been shown to have
powerful and complex effects on feeding, anxiety, circadian rhythms, reproduction, pituitary-adrenocortical axis function, memory retention, seizures, thermoregulation, and cardiovascular and gastro-intestinal functions. One of the most striking action of NPY
is the induction of feeding. Further, NPY activates a
heterogenous population of at least six receptor
subtypes, Y1-Y6, of which Y1 and Y5 receptors are
required for appetite regulation by NPY86.
It is the most abundant neuropeptide in the central
and peripheral nervous systems especially in the
hypothalamus of rodents and humans. Its cell bodies are sited in the arcuate nucleus (ARC) and project
to the paraventricular nucleus (PVN) and dorsomedial
nucleus (DMN) and there are binding sites (probably
the Y5 receptors) in the lateral hypothalamus. By acting on Y5-receptors, it increases the food intake, reduces thermogenesis in brown fat, increases insulin
levels (by stimulating vagal outflow to the pancreas)
and reduces muscle sensitivity to insulin.

NEUROCHEMICAL BASIS OF OBESITY

Table 3. Neurotransmitters affecting energy balance
Factors increasing food intake

Factors inhibiting food intake

* Noradrenaline
* GABA
* Growth hormone releasing
hormone
* Galanin
* Melanin-concentrating
hormone
* Neuropeptide - Y
* Opioids
* Orexin

* Serotonin
* Dopamine
* Cholecystokinin
* Corticotrophin-releasing factor
* Neurotensin
* Bombesin
* Calcitonin gene-related peptide
* Amylin
* Adrenomedullin
* Glucagon
* Glucagon - like peptide - 1
* -Melanocyte stimulating
hormone
* Anorectin
* CART
* Thyrotropin-releasing factor
* Cyclo - histidyl proline
diketopiperazine
* Pituitary adenylate cyclase
activating polypeptide
* Acidic fibroblast growth factor
* Oxytocin
* Interleukin 1

Neuropeptide Y is the most powerful appetite stimulant known in the rodents. It has been reported to
increase the triglyceride content in white fat and after 5 days of intracerebral administration it doubled
the fat stores in both lean and ob/ob mice. Its expression is also reported to be increased in ARC,
PVN and DMN in the ob/ob mouse and Zucker rat.
But the genetic studies have not shown any association with the genes for neuropeptide Y1 or Y5 receptors in human obesity.
The NPY neurons in the ARN possess glucocorticoid, insulin and leptin receptors and leptin has an
inhibitory effect on the NPY neurons via the Rb receptors and reduces NPY mRNA, NPY protein and
NPY release. The prototype NPY5 antagonists have
been shown to inhibit feeding in genetically obese
rats and in food deprivation8,12. But their effects in
rodents with diet-induced obesity (the nearest model
to human obesity) have not yet been reported. It is
speculated that NPY5 antagonists could be effective
antiobesity drugs.
Melanin concentrating hormone (MCH)
MCH is a cyclic 19 amino-acid neuropeptide identi-

392

fied initially in the intermediate lobe of the teleost

fish pituitary from which it is released into circulation
and causes aggregation of melanophores. MCH receptors are found exclusively in the zona incerta and
the lateral hypothalamus. It is reported to stimulate
food intake after central administration and expression of gene encoding MCH is upregulated in ob/ob
mice and through fasting in wild type of mice23. Leptin
decreases expression of this gene in the hypothalamus via co-existing leptin receptors. The exact
mechanism of action of MCH in the hypothalamus is
not known. MCH has been reported to both mimic25
and antagonise the actions of -MSH26.
Serotonin
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has an established role in decreasing
appetite. The widely prescribed anorectic drugs like
dexfenfluramine, fenfluramine, fluoxetine also cause
hypophagia by increasing brain extracellular 5-HT
levels27. The main antagonistic system for this is
noradrenergic. Besides regulating appetite serotonin
is also responsible for the selection of foods of major
constituents. The high local levels of serotonin result
in preference for proteins and low levels the opposite. The high carbohydrate and low protein diet promotes uptake of serum tryptophan in the brain and
promote its conversion to serotonin which decreases
feeding. This forms a self regulatory mechanism for
serotonergic system. But in patients with decreased
insulin sensitivity, this system may be disturbed causing over-consumption of carbohydrates resulting in
clinical picture of 'carbohydrate craving obesity' 28.
Cholecystokinin (CCK)
Cholecystokinin is released from the gut after ingestion of lipids and other nutrients and may be one of
many peripheral satiety signals29. Interestingly, it also
acts as a central inhibitor of appetite and its peripheral release may mediate its release in the CNS. CCK
levels are normal in obese persons but infusion of
CCK-8 peptide has been shown to decrease the meal
size in humans30.
Two pathways have been suggested for inhibitory
effect of CCK on food intake : the action of CCK at
peripheral sites, mediated by CCKA-type receptors,
and the action at central sites mediated by CCKBtype receptors. The pretreatment of rats or pigs with

393

S.K. KULKARNI AND GURPREET KAUR

Figure 3. The genetic model of obesity characterised by excess of agouti protein.

SKIN

HYPOTHALAMUS

-Melanocyte

melanocyte

stimulating hormone

stimulating hormone

inhibits

Agouti protein

Melanocortin 2 receptor

inhibits

Melanocortin 4 receptor

Pigmentation

Reduced food intake

Excess agouti protein results in fat, yellow mouse

selective CCKA antagonists - devazepide, lorglumide

prior to administration of fats decreases the satiating
potency of specific fats31,32. But pretreatment with
CCKB antagonists did not alter fat-induced satiety in
the rat33,34. Thus, CCKA agonists could be useful in
the treatment of obesity. But no CCKA agonist with
acceptable bioavailability is available and therefore,
compound which prevented the breakdown of CCK8 could prove useful. Butabindide is a new drug in
the pipeline that acts by inhibiting the action of CCK8 inactivating peptidase. The studies have shown
butabindide to potentiate the delay of gastric emptying by CCK-8 at a dose of 10mg/kg and reduce food
intake35.
- Melanocyte stimulating hormone (
-MSH) and
melanocortin (MC) receptors
-MSH is produced from proopiomelanocortin
(POMC) neurons which exist in the ARC and nucleus
stria terminalis of hypothalamus. It acts on MC4 receptors to reduce feeding. In mice, -MSH is a centrally acting appetite suppressant. The physiological
significance of this is indicated by up-regulation of
MC4 receptors in food deprivation, presumably resulting from inhibition of -MSH release. Also targeted disruption of MC4 receptors results in mice that
develop maturity onset obesity syndrome associated
with hyperphagia, hyperinsulinaemia and hyperglycaemia36. This resembles agouti mouse model (yel-

low obese mouse) which overexpresses agouti protein, a pigmentation factor normally expressed in the
skin. This protein is antagonist at MC2 receptors expressed in skin (failure to produce melanin, yellow
coat colour) and MC4 receptors expressed in hypothalamus (obese mouse).
(TNF-
Tumour necrosis factor-
)
TNF-
has been recognised as an inflammatory
cytokine produced not only by the classic inflammatory cells but also by adipocytes. Within adipocytes,
has been postulated to be a mediator of insuTNF-
lin resistance via alterations in the phosphorylation
status of insulin receptor substrate -1 (IRS-1)38 and
to alter insulin receptor activity39. Because of the over mRNA and protein in the adiexpression of TNF-
pose tissue of obese animals 40 and humans41,
is a potential mediator of insulin - resistance
TNF-
associated with obesity. It is also expressed at higher
levels in muscle cells of insulin resistant subjects and
may also inhibit lipoprotein lipase (LPL) expression42.
Thus, it is a candidate gene product for the genetic
is normally
predisposition to obesity. Since TNF-
present at very low concentration in the circulation,
it must act as an autocrine or paracrine factor43.
Lipoprotein lipase (LPL)
Human fat cells do not synthesise lipids but derives
most of its lipids for the storage from circulating

NEUROCHEMICAL BASIS OF OBESITY

Leptin
Leptin (in greek leptos means thin) is a 16 KD plasma
protein exclusively produced in white adipose tissue.
It is the product of ob gene that is defective in ob/ob
mice46. It plays an important role in control of body
weight, energy expenditure, reproduction and neuroendocrine signalling47. It is secreted into circulation
and then transported to brain through a modified area
of blood brain barrier near the arcuate nucleus or via
choroid plexus, where short-form leptin receptors are
sited which transfer leptin to hypothalamus. Once
within CNS leptin acts on long-term receptors to
stimulate satiety. It also mediates a negative feedback control on white adipose tissue. Through action
in the hypothalamus, possibly mediated by inhibiton
of neuropeptide Y(NPY) secretion and stimulation of
corticotropin releasing hormone (CRH) secretion,
leptin decreases food intake, stimulates sympathetically (SNS)-mediated brown adipose tissue (BAT)
thermogenesis, and reduces the parasympathetically
(PNS)-mediated insulin secretion. The increased thermogenesis and decreased energy intake leads to the
energy deficit that is satisfied by mobilisation of fat
stores. In addition, leptin may enhance the glucose
uptake into nonadipose tissue, such as muscle, to

Figure 4. Poential sites of action of leptin to modulate energy

balance and peripheral metabolism. Leptin synthesis
and secretion is increased by body fat, insulin, and
glucocorticoids (GC). + = stimulation, - = inhibition.

Ventromedial nucleus of
hypothalamus (NPY)
BRAIN

NPY

CRH

+
m SNS

GC

+
l
LEPTIN

FOOD
INTAKE

-m
+

INSULIN

expression of

PNS

3 AR, UCP, leptin

OTHER
TISSUES

Mitochondria with UCP

Nucleus

trigylcerides (TGs). LPL provides these lipids by

hydrolyzing TGs and acts as metabolic gate-keeper.
Lipoprotein lipase is synthesized in heart, skeletal
muscle, adipose tissue, and several other extrahepatic tissues. After secretion, the enzyme is transported to its functional site which is at vascular endothelium bound to heparin sulfate. Fatty acids are
liberated through the hydrolytic action of LPL on TG
in circulating very low density lipoproteins (VLDL) &
chylomicrons. The changes in LPL have been reported in metabolic disorders associated with ageing like insulin resistance, obesity and impaired hormonal balance44. Adipose LPL is also reported to be
elevated in obesity. When obese subject loses weight,
LPL is elevated further, suggesting attempts to maintain lipid stores during fasting and to replenish lipid
stores during refeeding. But the muscle LPL is regulated in response to feeding and fasting; feeding results in an increase in adipose enzyme and a decrease in muscle LPL. Thus, an increased adipose/
muscle LPL ratio would partition dietary lipid into
adipose tissue and explains some of the variability in
weight gain when humans are exposed to excess
calories45.

394

GLUCOSE
DISPOSAL

BROWN ADIPOSE TISSUE

THERMOGENESIS

m
m

3 AR

NE

AXONAL
TERMINAL

REDUCED ADIPOSE
TISSUE MASS
IMPROVED INSULIN
SENSITIVITY

improve glucose disposal and insulin sensitivity.

Leptin levels show diurnal rhythm in both sexes, with
highest leptin levels between midnight and early
morning hours48. Its production in white adipose tissue (WAT) is enhanced by body fat, feeding, fever,
insulin, glucocorticoids, cytokines and its production
is decreased by fasting, cold, exercise, sympathetic
activity acting on 3 adrenoceptors, testosterone, thyroid hormone, thiazolidinediones8 (Figure 4).
The ob/ob mice with a mutation in the ob gene dont
secrete leptin and exhibit obesity, hyperphagia, hyperglycaemia, insulin resistance and increased expression of NPY in hypothalamus. Injection of small
quantities of leptin into ob/ob mice reverses
hyperinsulinemia, decreases NPY level and normalises food intake and energy expenditure49. Two other
rodent models of obesity, the db/db mouse and the
fa/fa rat, have defects in the leptin receptor; exogenous leptin is ineffective in these animals.

395

S.K. KULKARNI AND GURPREET KAUR

The plasma leptin levels are closely correlated with

body fat; they are decreased in states of severe malnutrition such as anorexia nervosa and elevated in
obese humans suggesting resistance to the central
effects of leptin in obesity. The importance of leptin
in humans was recently established with the description of two cousins with morbid obesity of early onset who had a mutation in the leptin gene50. Leptin
receptor polymorphism has also been linked to obesity in three sisters51. Although low leptin production
or mutations of the leptin gene may not be a direct or
common cause of human obesity, yet understanding
of its action and regulation may help in the development of new therapeutic strategies52.
Peroxisome proliferator activated receptor
(PPAR)- gene
PPAR- is a member of the PPAR subfamily of nuclear hormone receptors. PPAR- exists as two
isoforms ( 1 and 2) formed by alternative splicing
and differing in their N-termini. PPAR-2 is expressed
at high levels in adipose tissue, while low levels of
PPAR- 1 can be found in many other tissues. This
receptor is induced very early in adipose cell differentiation, and is present at higher levels in
preadipocytes. PPAR- appears to function as both
a direct regulator of many fat-specific genes and also
as a master regulator' that can trigger the entire program of adipogenesis53. It is also implicated in the
control of adipocyte differentiation. Recently, the gene
expression (mRNA) of PPAR- was found to be higher
in subcutaneous than in visceral adipocytes of nonobese people. However, the mRNA concentrations were
similar in subcutaneous and visceral depots in obese
people, mainly because of an obesity-linked increase
in the expression of the gene in visceral region16.
Galanin
It is a 29-amino acid peptide that stimulates feeding
behaviours, especially fat intake, when injected into
the paraventricular nucleus. Administration of galanin
receptor antagonists and antisense oligonucleotides
reduces fat intake which suggests a physiological role
for the peptide in fat digestion. A recent study showed
that a high-fat diet can enhance galanin production
in an anterior parvocellular region of the paraventricular nucleus and that the increased galanin expression is closely linked to circulating glucose levels and body adiposity54.

Neurotensin
It is a 13 amino acid peptide that produces behaviourally specific reductions in food intake after central administration. Leptin decreases galanin gene
expression and increases neurotensin gene expression in the hypothalamus. Increased galanin gene
expression or hypothalamic content of galanin protein and decreased neurotensin mRNA levels are
associated with the development of obesity in fa/fa
rats or ob/ob mice 54.
CART (Cocaine and amphetamine-regulated transcript) peptides
CART peptides are members of a new neuropeptide
family with neurotransmitter-like actions within the
brain. The possible physiological functions of CART
peptides are many and as yet little understood. However, the available research findings strongly support a role for CART peptides in the complex controls of addiction and nutrient intake. These peptides
have a broad heterogenous distribution in the brain.
The CART peptide immunoreactivity is also found in
hypothalamic nuclei containing NPY suggesting interactions between CART peptides and the NPY system87. Also, the recombinant CART peptide is a potent inhibitor of feeding and completely blocks the
feeding response induced by NPY. Besides, the expression of CART mRNA in the arcuate nucleus is
decreased in food-deprived animals and is almost
absent in ob/ob mice, although in the latter it is restored by leptin treatment suggesting that CART
peptides are newly discovered leptin-dependent
anorectic peptides that are closely associated with
the actions of NPY54. These peptides may thus,offer
novel treatment for obesity.
Corticotropin-releasing factor (CRF)
It is a 41 amino acid peptide produced in the
paraventricular nucleus (PVN) and other brain regions. It is a major catabolic peptide in the hypothalamus whose synthesis and release are sensitive to leptin and opposes actions of NPY. Besides
acting as a controller of the hypothalamic-pituitaryadrenal (HPA) axis, it inhibits food intake, increases
energy expenditure and produces sustained weight
loss. Calorific restriction and glucocorticoid administration lower expression of the gene encoding CRF
in the PVN whereas involuntary overfeeding and
adrenalectomy cause anorexia and stimulate CRF
expression54.

NEUROCHEMICAL BASIS OF OBESITY

Glucagon-like peptide 1 amide (GLP-1)

It is produced by tissue-specific post-translational
processing of preproglucagon in the brain as well as
in the gut. In rodents, acute intracerebroventricular
injection of GLP-1 reduces food intake and chronic
administration reduces body weight. Administration
of exendin, a specific GLP-1 receptor antagonist, increases food intake in several animal models, which
indicates that endogenous GLP-1 is an inhibitor of
feeding54.

Energy expenditure regulation in obesity

The energy expenditure has three components - resting metabolic rate, physical activity and thermogenesis. Among these, thermogenesis plays an important role in regulating bodys fat stores. By definition,
thermogenesis is a process which is used to generate heat from food energy and also in response to
stress. It represents about 10% of energy expenditure. It mainly occurs in the brown adipose tissue.
Catecholamines (adrenaline and noradrenaline)
stimulate thermogenesis in BAT, as well as lipolysis
in white adipose tissue (WAT) .Any drug which could
increase thermogenesis might, therefore, be useful
for the treatment of obesity4.
3 Adrenoceptors (
3 AR)
3 - adrenergic receptor (formerly known as an atypical adrenoceptor) is mainly expressed in adipocytes.
It is the principal mediator of catecholamine - mediated thermogenesis and fatty acid -oxidation in BAT
and an important stimulator of lipolysis in WAT. In
contrast to other adrenoceptors, it is activated by high
concentrations of catecholamines found in
noradrenergic synapses (e.g., after a meal or during
cold exposure) but not by lower levels present in the
3 AR)
blood stream. Also, the 3 adrenoceptors (
subtype is refractory to desensitisation by exposure
to its ligands55.
Considerable evidence is available for their physiological role. Studies on rodents has established that
3 AR is the predominant receptor type expressed in
BAT and WAT and that 3 agonists considerably reduce diet-induced obesity56. There is modest increase
of body fat in the 3 AR - deficient mice and reduction of 3 AR mRNA levels in genetically obese ob/
ob mice57 and fa/fa Zucker rats58. Treatment of dogs
3 agonist) reduced
for two months with ICID7114 (
weight and induced the reappearance of BAT, which

396

is the tissue most responsible for thermogenesis and

is undetectable in adult mammals (except rodents)59.
In humans, functional expression of the 3 AR has
now been well documented in isolated mammary
white and immor talised differentiated brown
adipocytes where it regulates lipolysis60.
Some studies have reported a polymorphism in the
3 AR gene to be associated with increased prevalence of obesity. Over 50% of Pima Indians from Arizona who display hereditary obesity express mutation in 3 AR gene in which tryptophan at position 64
is replaced by arginine. This mutation is also found
in 25% of African-Americans and in 8-10 % of the
general population of the U.S. and Europe61,62.
The development of various selective 3 agonists like
BRL-37344, CL-316243, CGP-12177A, LY-10419,
SB-200464, bucindolol, carazolol, oxprenolol,
pindolol, cyano-pindolol, alprenolol, nadolol have
opened new doors for the treatment of obesity63. The
selective 3 agonist with mild 1 or 2 antagonistic
activity will be especially beneficial in obese patients
with stressed cardiovascular system. Many of these
compounds are excellent lipolytic agents in rodents
but perform poorly in humans which may be due to
1) differences in rodents and human 3 adrenoceptors, 2) differences in metabolism and
pharmacokinetics in the rodent and humans, 3) because the human has fewer 3-adrenoceptors, or 4)
because these receptors are less well coupled to
thermogenesis.
Mitochondrial uncoupling proteins (UCP)
The uncoupling proteins play an important role in
generating heat and burning calories64. They uncouple oxidative phosphorylation process in mitochondria and oxidise the fatty acids released by lipolysis
without forming ATP. These uncoupling proteins thus,
form an important link between 3-adrenoceptor and
thermogenesis. They play an important role in regulating the body temperature, body composition and
glucose metabolism65. There are 3 forms of UCP.
UCP1 expressed mainly in BAT and is induced by
cold and 3 agonists. This form of UCP is likely to be
involved in weight regulation in adult large-size animals and humans living in thermoneutral environment
as there is little BAT present66. The studies in UCP1
knock out mice has shown them to be extremely sensitive to cold, unresponsive to 3 agonists and not

397

S.K. KULKARNI AND GURPREET KAUR

Figure 5. A simplified model for the interaction of leptin with hypothalamic neuropeptides within a regulatory feedback loop. + =
stimulatory input, - = inhibitory input, CART, cocaine- and amphetamine-regulated transcript, CCK, cholecystokinin, MCH,
melanin concentrating hormone. Large arrows indicate main pathway in the feedback loop.

hyperphagic or obese. They also overexpress UCP2

in BAT which compensates for absence of UCP167.

INTERPLAY BETWEEN VARIOUS NEUROCHEMICAL FACTORS

UCP2 is widely expressed in adult human tissues

including the WAT and is upregulated in response to
fat feeding. It is also expressed highly in spleen,
macrophage, thymus and bone marrow which suggests that this gene may underlie thermogenic responses to inflammatory stimuli68. In addition, UCP2
maps to region of human chromosome 11 and mouse
chromosome 7 that has been linked to hyperinsulinemia and obesity.

NeuropeptideY is the key component of feeding drive

systems. Galanin, MCH, opioid peptides, desacetylMSH are the other molecules increasing food intake
and decreasing sympathetic activity. The secretion
and actions of NPY are further regulated by GLP-1,
CRF, CART which are feeding-inhibitory, catabolic in
nature, stimulators of sympathetic activity and the
targets of leptin. The regulators of leptin are insulin
and glucocorticoids and favour leptin secretion in a
process that is independent of the amount of adipose tissue present. Both of these also influence
NPY and other neuropeptide like effector molecules.
Other suggested interplays include between GLP-1
g CRF, and also those in the opposite directions such
as NPYgCRF, and NPYg melanocortin. These might
have implications for the regulation of feeding and
body weight or the activation of the hypothalamicpituitary-adrenal axis or both. Further research
efforts are required to elucidate the functional and
anatomical connections in each component of the

UCP3 is mostly expressed in skeletal muscle and in

rodents in BAT69. Other as yet undiscovered UCPs
may exist. Agents that activate them or increase their
expression offer a new therapeutic approach.
In some people, age-associated increase in body fat
has been related to UCP polymorphisms and in mice
UCP 2 has been found to be up-regulated in response
to high-fat diet. These findings suggest that uncoupled mitochondrial respiration may help dissipate excess energy in people70.

NEUROCHEMICAL BASIS OF OBESITY

cascade especially in relation to the 'escape' of the

positive modulators network from the inhibitory influences of leptin and anorectic signals (Figure 5).
TREATMENT STRATEGIES
These include drug treatment and nondrug treatment
strategies (behavioural, dietary and surgical).
Behavioral therapy
Behavioral modification is a method for systematically changing eating, exercise or other behaviours
that contribute to or maintain obesity71. These includeSelf-monitoring: This involves systematic observation and recording of target behaviours e.g.,
using food and activity diaries to record caloric
intake; how many fat grams and food groups are
eaten; conditions or situations when eating is
common and frequency, duration and/or intensity of exercise.
Stimulus control: Involves identifying and modifying environmental cues associated with
overeating and activity and thereby, changing an
individuals microenvironment e.g., eliminating
the availability of snack foods in the house or
restricting eating to particular rooms.
Cognitive restructuring: Many obese patients
hold unrealistic beliefs about themselves and
their weight. This strategy teaches the patients
to actively challenge and change aspects of their
internal dialogue.
Stress management: Stress is a primary predictor of relapse and over-eating. Various stress
management techniques like diaphragmatic
breathing, progressive muscle relaxation or
meditation helps to overcome various health related problems.
Social support: This gives patient greater self
acceptance, develop new norms for interpersonal relationships and manage stressful work
or family situations.
Physical activity: This helps to maintain the lost
weight and produces various psychological benefits like coping better with stressful situations,
reduces unhealthy reactions to stress such as
over-eating and the resultant negative emotions
and certain social situations such as travel or
parties to be associated with obesity.

398

Table 4. Various drugs for treatment of obesity

1.Appetite suppressants
(a) Centrally acting adrenergic agents
Benzphetamine, phentermine, diethylpropion,
mazindol, phendimetrazine, phenylpropanolamine
(b) Serotonergic agents
Dexfenfluramine, fenfluramine, fluoxetine
(c) Adrenergic/serotonergic agents
Sibutramine
2. Thermogenic agents
(a) Adrenergic agents
Ephedrine+caffeine
(b) 3 -Agonists
BRL 26830A, BRL 35135, RO 40-2148,
RO 16-8714, CL 316243
3. Digestion inhibitors
(a) Lipase inhibitors
Orlistat
(b) Carbohydrate-based fat substitutes
Guar gum, polydextrose, sugar beet fibre.
(c) Protein-based fat substitutes
Microparticulated egg white and milk protein.
(d) Fat-based fat substitutes
Olestra, caprenin
4. Hormonal manipulation
Leptin analogues and neuropeptide Y antagonists
5. Plant sources
INDIAN: Garcinia cambogia, Commiphora mukul, Teucrium
chamaedrys(germander), Paeonia suffruticosa (tree-peony),
hydrophilic mucilages, preparations from plantago seeds and
senna pods, noncarbohydrate sweeteners
CHINEESE: Qingshen No. 1, bofu-tsusho-san.

Dietary therapy
Dietary method remains the primary method for
obesity treatment. Dietary intervention along with
other treatment strategies remains a useful tool used
continuously overtime to accelerate weight loss or
to maintain a constant body weight. This involves
restricting total energy intake with healthful food
selections and exercising prudent control over eating habits. It can be implemented with the help of
encouragement of a dietitian along with a primary
health care physician72.

399

S.K. KULKARNI AND GURPREET KAUR

Drug therapy
Nowadays the replacement or supplementation of the
non-pharmacological treatments with hypophagic
drugs is receiving much more attention. This trend
has lead to a multi-million pound annual market for
these drugs. But still the pharmacological therapy
should be limited to specific cases in which associated clinical risks warrant more urgent intervention.
The main drugs used to treat obesity (Table 4) are
centrally acting anorectic agents. The potential sites
of these drugs are the control of energy intake, energy expenditure or both.
1. Targeting the energy intake: Food intake may
be reduced by decreasing appetite or by increasing
satiety. Drugs that affect appetite are commonly
known as anorectic medications. Their mechanism
of action may be limited to decreased appetite. These
anorexic agents affect neurotransmitter activity and
are of two main classes : those that affect the
catecholaminergic system (the amphetamines,
benzphetamine, phendimetrazine, phentermine,
mazindol, diethylpropion, and phenylpropanolamine)
and those that affect the serotonergic system
(fenfluramine, dexfenfluramine, fluoxetine,
sertraline)73. Amphetamines and closely related compounds are not recommended for the treatment of
obesity because of their high abuse potential74.
The monoamine appetite suppressants like
fenfluramine, dexfenfluramine, phentermine can induce 10-12% loss in body weight in 3 months and
often 5-10% loss is maintained for 12 months. However, inexplicably, this only occurs in 30% of patients,
the rest being nonresponders. There are also reports
of the association of fenfluramine, dexfenfluramine
and fentermine (fen-phen) therapy with increased
incidence of primary pulmonary hypertension and
neurotoxicity75. In August 97, US researchers first
reported cases of a rare vascular disease in 24
women treated with fen-phen combination who had
no history of heart disease76. Additional reports have
described valvulopathy with the fenfluramine/
dexfenfluramine alone also. Most cases involved
aortic regurgitation, some have documented mitral
regurgitation, with both occurring in small percentage of cases77. In 1997, the U.S. FDA reported overall incidence of cardiac valve abnormalities associated with these appetite suppressants drugs :79%

associated with fen-phen, 14% with dex, 7% with fen

and 5% with dex-phen, phen alone and dex-phenfen. In view of these findings fenfluramines were withdrawn from the international market by the manufacturer in September, 1997.
Sibutramine, a novel pharmacological agent, is a
mixed reuptake inhibitor for both serotonin and noradrenaline. It has recently been granted a license in
the U.S. The drug was originally being developed as
an antidepressant drug until the animal studies suggested the potential role for the drug in the management of obesity. It has been shown to enhance the
feeling of satiety, thereby reducing the food intake
and also increase the basal metabolic rate (BMR).
The drug has been demonstrated to produce a dosedependent decrease in weight in healthy subjects.
The associated side effects are constipation, dry
mouth, insomnia and modest increase in blood pressure and heart rate78,79.
2. Targeting the fat absorption: Orlistat is a new
drug in the pipeline which interferes with fat absorption by inhibiting pancreatic lipase responsible for converting triglycerides to free fatty acids and glycerol
which can then be absorbed. But it has only a partial
effect, inhibiting 30% of lipase activity and allowing
70% of fat intake to be absorbed while the rest passes
through the lumen and out in the feces. The recommended dose is 120 mg t.i.d. and higher doses has
no extra effect. It is aimed for use in combination with
other weight control methods (diet, exercise etc.) and
to produce a healthier lower body weight rather than
an ideal one.
The other beneficial effects of orlistat are a reduction in blood pressure in subjects with diastolic
pressure > 90 mm Hg and it also reduced LDL cholesterol. In diabetic patients, orlistat improves glucose tolerance and allows a reduction in dose of insulin or sulfonylurea.
The main adverse effect of orlistat is high fat content
in the stools causing oily spotting in 27% of patients
and faecal urgency or even incontinence. This occurs in first 2-3 weeks of treatment and can be controlled by reducing fat intake. Also there is reduced
absorption of fat soluble vitamins. The FDA is still
reviewing the use of orlistat as there is concern over
an increased incidence of breast cancer in orlistattreated versus the non-treated population80,88.

NEUROCHEMICAL BASIS OF OBESITY

Chitosan present in over-the-counter slimming products such as Fat-Magnets and Chito-Slimmer tablets is claimed to result in weight loss by absorbing
triglyceride molecules and increasing fecal fat excretion.
Targeting the energy expenditure: Energy expenditure may be increased by increasing physical activity or metabolic rate , for example, through changes
in the sympathetic nervous system tone or uncoupling of oxidative phosphorylation. Drugs that affect
thermogenesis-metabolism include ephedrine (including its combination with caffeine and/or aspirin) 81,82 and experimental agents such as BRL
26830A, a -adrenoceptor agonist. None of these
medications is currently approved by the FDA for
weight control.
Newer approaches include the development of CCKA
agonists, neuropeptide Y5 and Y1 (NY5, NY1) antagonists, agonists of melanocotin-4 receptors (MC4)
and glucagon-like-peptide 1, stimulators of uncoupling proteins, drugs that unbind corticotrophin-releasing factor from its binding protein and many other
potential targets waiting in the wings. Human trials
of recombinant leptin are also underway.

and the fact that obesity affects large and increasing

number of people, several risk factors have to be
considered. The British National Formulary recommends that drugs (for obesity) should only be considered for those with a BMI of 30 or greater if supervised diet, exercise and behaviour modification fail
to achieve a realistic reduction in weight. These
anorectic agents are not to be used for more than 3
months. But still long-term treatment is required as
there is regain of original weight after discontinuation of drugs. The long-term pharmacotherapy of
obesity is reported to result in significant reduction
in health risks, improvement in quality of life, and
amelioration of obesity-related risk factors like
dyslipidemias, insulin resistance, and blood pressure
etc. This long-term treatment with antiobesity drugs
involve several areas of concern84.
1.

Abuse potential of these drugs are high since

many people are desperate to lose weight. These
should be used with caution in patients with a
history of substance abuse.

2.

The weight reducing effect of some drugs plateau after 4 to 6 months even if the drug is continued and regain may occur despite long-term
drug treatment in some patients.

3.

Patients consider drug treatment as a magiccure and do not take the required precautions.

4.

Potential for causing adverse effects e.g., primary pulmonary hypertension and neurotoxic
effects caused by dexfenfluramine and fenfluramine.

5.

Cost of treatment.

Surgical therapy
This is indicated for morbid obesity in which there is
greater than 70% excess weight. Surgery can provide palliation for severe obesity when all medical
approaches have failed. It can result in decreased
food intake (gastric procedures - jaw wiring, vertical
banded gastroplasty, gastric stapling), affect calorie
absorption (intestinal shunting, biliopancreatic bypass), or remove excess fat (lipectomy, liposuction).
Gastric reduction operations are safe and effective
provided they are performed by experienced
surgeons in well-selected patients. They can be considered now as the best option for a minority of patients with morbid and refractory obesity. In very selected patients, mechanical means (such as waist
cord) may also help losing weight and/or avoiding
weight regain83.
POTENTIAL BENEFITS AND ADVERSE EFFECTS
OF LONG - TERM PHARMACOTHERAPY FOR
TREATMENT OF OBESITY
With increased awareness of risk factors associated
with obesity and increase in use of antiobesity drugs

400

CONCLUSION
Obesity is a major public-health issue world-wide. It
is a serious health problem associated with at least
one co-morbidity in most patients with BMI of 27 or
greater. Its treatment is difficult and challenging as
the exact etiology still remains obscure. Recent advances in the understanding of the molecular mechanisms underlying obesity provide great hope for the
development of treatments targeted to specific metabolic defects. Antiobesity agents with novel mechanisms of action will supplement and revolutionize the
current armamentarium for the treatment of obesity.
Ultimately, the treatment of obesity may prevent

401

S.K. KULKARNI AND GURPREET KAUR

co-morbidities of obesity such as diabetes, hypertension and hyperlipidemia and in some patients may
supplant the treatment of these disorders.

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ACKNOWLEDGEMENT

The Senior Research Fellowship (G.K.) of the Council of Scientific and Industrial Research (CSIR), New
Delhi, is gratefully acknowledged.
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