Indian Journal of Experimental Biology

Vol. 45, November 2007, pp. 929-936

Review Article

Pathophysiology and genetics of obesity

Neena Srivastava1, Ram Lakhan2 & Balraj Mittal2
1
Department of Physiology, K G Medical University, Lucknow 226 003, India
2
Department of Medical Genetics, SGPGIMS, Lucknow 226 014, India

Obesity, a global problem, is a multifactorial disorder. The factors are environmental, metabolic and genetic and their
interaction with each other regulates the body weight. Imbalance in either of the factors may be responsible for weight gain.
With advancement of research techniques in the last decade, genetic studies have been undertaken for several different
causative mutations involving obesity loci on different chromosomes. Monogenic and polygenic obesity has been observed
however, polygenic forms are more common. So far more than 200 genes in mouse and more than 100 genes in humans
have been identified which result in phenotypes that affect body weight regulation. In spite of this knowledge, the field of
obesity has still not been explored extensively. There remain a lot of lacuna regarding causes and treatment of obesity.
Challenges are still there to identify the exact cause of weight gain and the use of current knowledge for development of
anti-obesity drugs targeted for body weight regulation. In this review, we have explained neuropathophysiologic regulation
of feeding behaviour and some aspects of obesity-genetics especially with single nucleotide polymorphism of selected
candidate genes and their functional aspects mainly in monogenic obesity.

Keywords: Body mass index, Genetics, Obesity, Polymorphism, Single nucleotide polymorphism

Obesity, a chronic, relapsing, stigmatized,
neurochemical disease that is more prevalent in
developing/developed countries and leading to much
comorbidity. Multiple factors are involved that
contribute to the development of obesity. These may
be social, behavioural, environmental and genetic. It
is a global health problem in the present era. During
the early 20th century, the prevalence of obesity rose
slowly, but it began to rise more rapidly in 1980. A
continuously rising trend in the prevalence of obesity
in childhood and adolescence has been noted in
several studies, associated with this rise in obesity
rates presage a dire future for these children as
complications of blindness, heart disease, renal
failure, amputation and compromised quality of life1,2.
Understanding of the pathophysiology of obesity has
increased markedly over the last decade, but this
knowledge is insufficient for the management of
obesity. A better understanding of molecular
mechanism of pathogenesis and role of environmental
and genetic factors will provide hope for planning the
treatment strategies of weight reduction.
The regulation of appetite relies on complex
hypothalamic neurocircuitry in which the arcuate
nucleus and the hormone leptin, ghrelin play
___________
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E-mail:drneenasrivstava@hotmail.com
important roles. Excess body fat is stored in adipose
tissue which forms over 10% of total body weight, but
it is now clear that adipocytes have functions other
than simple storage cells. The most significant of
these appears to be the secretory3. The control of
appetite and body composition has been explained by
the occurrence of physiological set point for body
weight 4.
The commonly used clinical methods of fat
assessment and classification are body mass index
(BMI; weight in kg/height in m2) and waist to hip ratio
(WHR), respectively. The range of BMI varies
significantly according to the stage of economic
transition and associated industrialization of a country,
the shift from dietary deficit to one of dietary excess.
Obesity, defined as a BMI of more than 30, is a
common condition in Europe and the United States. A
BMI cut-off of >23 has been suggested by WHO as
indicative of overweight for Asia-Pacific inhabitants
due to their greater fat deposits5. BMI may not be
necessarily best measure for obesity and BMI data
should be taken with bit of caution as there is potential
misclassification bias. (Putting individuals in to wrong
category: such as muscled athlete in the overweight
category). Evidences show that individuals with a body
mass index (BMI; within the normal range) of 23 to
25 are at increased risk of diabetes, compared with
individuals with a lower BMI.
930 INDIAN J EXP BIOL, NOVEMBER 2007
Prevalence of obesity
Prevalence of obesity is increasing rapidly in
developed and developing countries. There is a
growing body of evidence that prevalence of
overweight and obesity increases in areas where
tremendous socioeconomic changes have taken place
such as in East Germany. Prevalence of obesity in
Indian population is 20% in adults and 10% in
children. In Punjab state of India6, frequency of
overweight and obesity has found to be more among
urban females than in their rural female counterparts.
Another similar study reported that the prevalence of
overweight (BMI 25) was high among urban
southern Indian children. (17.8% in boys, 15.8% in
girls) obesity (BMI 30 kg/m2 in this study) was seen
in 3.6% of boys and 2.9% of girls7. Level of overall
and central adiposity, as well as body fat, was found
to be high among Marwaris, as compared with other
ethnic populations of India8. The prevalence of
overweight and obesity among the affluent children in
Amritsar was as high or higher as in some
industrialized countries due to life style changes and
change in eating behaviour9. The prevalence of
overweight among affluent Bengali children in
Kolkata was higher than those reported from other
Asian countries10.
Pathophysiology of obesity
Modulation of the amount of energy that we take in
as food involves several mechanisms and networks
that connect the brain with the gut, this process being
key to the regulation of body weight over time, as
well as to the modification of long-term eating
behaviours. Obesity is characterized by an increase in
subcutaneous adipose tissue. Its metabolic
consequences, such as insulin resistance, are primarily
attributable to increased fat deposition at sites such as
the omentum, liver, and skeletal muscles. Recently, a
virus has also been found to be associated with
obesity. Human adenovirus Ad-36 causes adiposity in
animal models and enhances differentiation and lipid
accumulation in human and 3T3-L1 pre-adipocytes,
which may, in part, explain the adipogenic effect of
Ad-3611.
Body weight regulation is at both, short term
(day to day) and long term basis. Obesity occurs as a
result of imbalance in energy input and expenditure.
For weight regulation there is a set point in every
individual. A lot of information is available regarding
genes, peptides, neurotransmitters, and receptors in
the hypothalamus and neighbouring areas which
regulate appetite and body weight12. Neuropeptide
which increases appetite is neuropeptide Y.
Other appetite increasing neuropeptides are orexin
A and B, agouti related peptides (AGRP) and melanin
concentrating hormones (MCH). Neuropeptides
which decrease food intake are pro-opiomelanocortin
(POMC) derivatives which act on MC4 receptor,
cocaine and amphetamine related transcripts (CART),
corticotropin Releasing hormone (CRH), prolactin
releasing peptide (PrRP), -melanocyte stimulating
hormone (- MSH), 5- hydroxy triptamine (5HT),
serotonin and leptin receptor (LEPR).
There are four hypotheses regarding afferent
mechanisms involved in appetite regulation. (Fig. 1)
According to lipostatic hypothesis adipose tissue
produces a hormonal signal that is proportionate to the
amount of fat. Obesity is also said to be an
inflammatory condition of the body. A growing list of
adipocytokines involved in inflammation (IL-1beta, IL-
6, IL-8, IL-10, IL-1813 TNF-alpha, TGF-beta,) and the
acute-phase response (serum amyeloid A, PAI-1) have
been found to be increased in the metabolic syndrome.
From white adipose tissue, there is release of leptin
and resistin which decrease appetite. There is also
release of adiponectin and adipocytokines like tumor
necrosis factor- and interleukin-6 (IL-6) which
increase appetite. Brown adipose tissue also releases
PPAR- and uncoupling protein (UCP-1) which are
responsible for high metabolic rate and thus, for
weight reduction.
Gut peptide hypothesis determines release of
peptides like GRP from the stomach. Glucagon and
somatostatin from pancreas which decrease appetite
and control weight. Some more peptides like CCK
and PYY released from intestine and colon also are
responsible for appetite and body weight regulation.
Polypeptide ghrelin is released from stomach. It
exerts orexogenic effect through NPY/AGRP pathway
in the arcuate nucleus14,15.
Glucostatic hypothesis holds that reduced blood
glucose level increases appetite, frequent fasts lead to
reduction in basal metabolic rate and increase in
adiposity.
Thermostatic hypothesis postulates that fall in body
temperature below set point stimulates appetite and
above set point inhibits.
Role of genetics in obesity
Genetics has shown tremendous effect on the
process of weight gain. Overall, data from twin and
adoption studies are consistent with a genetic
 SRIVASTAVA et al.: PATHOPHYSIOLOGY & GENETICS OF OBESITY
Fig. 1 Neurophysiologic regulation of eating behaviour
contribution for body mass index (BMI) of between
40 and 70 %. Comprehensive profiling technologies
coupled with creative statistical analyses have
revealed that interactions between genetic and
environmental factors are responsible for the common
obesity which is currently challenging many
developed and developing countries 16.
Recent obesity related genetic studies have
produced a large repertoire of predisposing alleles of
diverse importance. Current obesity appears to be an
interaction of paramount genetic factors with an
abundance of calorically dense food and decline in
physical activity17. In the genetic perspectives
identification and characterization of monogenic and
polygenic obesity syndromes have led to an improved
understanding of the precise nature of inherited
component of severe obesity. Genome wide scans in
different ethnic populations have identified major
obesity loci on chromosomes 2, 5, 10, 11 and 20.
Recent genetic studies have identified several
different causative mutations underlying such
syndromes. There are a large number of genes in
humans which are believed to affect body weight and
adiposity. The obesity gene map shows putative loci
on all chromosomes except Y. Around 176 human
obesity cases due to single-gene mutations in 11
different genes have been reported, 50 loci related to
mendelian syndromes relevant to human obesity have
been mapped to a genomic region, and causal genes
931
or strong candidates have been identified for most of
these syndromes.
Inherited forms of obesity are syndromic and are
result of abnormal functioning of single genes leading
to weight gain i.e., obesity as salient clinical feature.
About 30 mendelian disorders with obesity as a
prominent clinical feature, often are in association
with mental retardation, dysmorphic features and
organ-specific developmental abnormalities
(i.e. pleiotropic syndromes) have been identified
which include mainly Prader-willi, BardetBiedl
syndrome, Albrights hereditary osteodystrophy,
Fragile X syndrome, BorjesonForssmanLehmann
syndrome, Binge eating syndrome, Cohen syndrome,
WAGR syndrome (Wilms tumour, anorexia,
ambiguous genitalia and mental retardation) and
Alstrm syndrome etc 16.
The more common forms of obesity are however
polygenic. For most overweight people, obesity is a
product of gene environment interaction. The
assimilation, storage, and utilization of nutrient
energy include a number of metabolic pathways that
control body weight and body fat content by a set-
point mechanism. This system involves a pool of
genes, several of which have been recently identified
on the basis of their known roles in energy
homeostasis in animals combined with the finding of
gene mutations that appear to be associated with
obesity phenotypes in humans; mainly leptin,
932 INDIAN J EXP BIOL, NOVEMBER 2007
leptin receptor pro-opiomelanocortin, pro-hormone
convertase -1, insulin gene, peroxisome proliferator-
activator receptor-, uncoupling protein,
melanocortin-3 and melanocortin-4 receptor genes.
Mutations in mitochondrial genome also have been
associated with severe forms of obesity.
Selected candidate genes associated with obesity
Role of POMC geneIn cases of very severe
obesity that starts in infancy, a single gene might be
playing a permissive role allowing environmental
factors to have major impact. Mutations in leptin gene
and its receptor, pro-opiomelanocortin (POMC), or
more frequently, melanocortin receptor 4 mutations,
are evidence of the existence of an obesity gene. It has
been observed that inactivity of either of these genes
would be sufficient to produce early onset anomalous
eating habits. Adipocytokine, leptin released from
adipocytes acts on hypothalamic neurons to release
pro-opiomelanocortin (POMC), leading to a cascade
of neuronal and hormonal events that inhibit feeding
behaviour18. Some null mutations of the pro-
opiomelanocortin gene (POMC) have been found to
cause obesity in humans and rodents.
Genetic findings have proven that the loss of only
one copy of the POMC gene is sufficient to render
mice susceptible to the effects of high fat feeding to
emphasize the potential importance of this locus as a
site for gene-environment interactions predisposing to
obesity 19. Rare mutations in POMC gene cause severe
early-onset childhood obesity. A recent study has
demonstrated that central nervous system POMC
peptides play a critical role in energy homeostasis that
is not substituted by peripheral POMC20.
Melanocortin-4-receptorIncreasing number of
human disorders resulting from genetic disruption of
the leptin-melanocortin pathways have been
identified21. However, effects of mutations in
melanocortin-4 receptor (MC4R) gene, for which the
obese phenotype varies in the degree of severity
among individuals, are also thought to be influenced
by environmental surroundings16.
Polymorphisms of the human melanocortin-4-
receptor have been found in severely obese
individuals, suggesting that melanocortin-4 receptor
malfunction might be involved in human obesity and
obesity-associated diabetes. It has been seen that
deletion of MC4-R and POMC gene increases feeding
and weight in mouse models. A recent meta-analysis
of 29563 individuals confirms that the V103I
polymorphism protects against human obesity at a
population level. It suggests that genetic variants, at
least in part, explain susceptibility and resistance to
common forms of human obesity22. Since it is known
that MC4-R activation generates intracellular cAMP,
knowledge of molecules that can affect cAMP
generation or otherwise mimic MC4-R-induced
signaling specifically in adipocytes, these cells could
provide targets for novel anti-obesity drugs.
Stimulation of cAMP production, the human
melanocortin type 4 (hMC-4) receptor recently has
been shown to mediate p44/42 MAPK activation.
Uncoupling proteins Uncoupling proteins are
considered as candidate genes for association with
energy metabolism and obesity, constitute a subgroup
of mitochondrial-transporter-super- family that
uncouples protein entry in mitochondrial matrix from
ATP synthesis. Four homologous UCP isoforms have
been identified. UCP-1, the first UCP to be described,
is found exclusively in brown adipose tissue, UCP-2
in several tissues, UCP-3 in human skeletal muscle
and rat brown adipose tissue and skeletal muscle,
whereas UCP-4 is expressed in the brain. The
promoter polymorphism of UCP-2, -866G/A, has
been associated with increased gene expression and
also contribute to the biological variation of insulin
secretion in humans23. A study has evaluated the
prevalence of -866G>A change of UCP-2 gene in
Spanish pediatric population to study its influence on
the phenotype of obese children and found that
subjects carrying the A nucleotide present higher
values of tricepital and sub-scapular skin-folds as
compared to non-mutant subjects, which may indicate
a relationship between the presence of A allele in
obese children and higher amounts of subcutaneous
fat. The homozygote of UCP-2 gene, Ala55Val
mutation, increases the risk of obesity in Chinese
population. UCP2 gene mutation or ADR beta gene
mutation alone is not associated with obesity, the
possible additive effects of these two micro-genes
increase the occurrence of obesity. Emerging data
indicate that primary physiological role of UCP3 may
be the mitochondrial handling of fatty acids rather
than the regulation of energy expenditure through
thermo-genesis. Increased expression of UCP-2 and
UCP-3 under conditions of increased fatty acid
metabolism implies as yet undefined role in lipid
metabolism24 and body weight regulation. Various
studies to-date suggest that uncoupling proteins do not
cause obesity but can act as modifier genes.
 SRIVASTAVA et al.: PATHOPHYSIOLOGY & GENETICS OF OBESITY
Insulin and insulin receptor gene Insulin
substrate-1 gene occupies key position in insulin
signalling pathway. After insulin binding to alpha
subunit of insulin receptor, the beta subunit undergoes
auto-phosphorylation and in turn phosphorylates other
endogenous substrates in the cascade insulin action.
Several polymorphisms have been identified in IRS-I
gene, but Gly > Arg substitution at codon 972 is quite
prevalent in patients in Type II diabetes than in
healthy controls25. The polymorphism has also been
associated with impaired glucose tolerance, this
association has been more marked in obese subjects
(BMI > 25 kg /m2).
2-adrenergic and glucocorticoid receptor
Catecholamines stimulate lipolysis in fat cells through
AR (Adrenergic receptor) and inhibited through - the control of body weight in human, but also in
ARs. An association between codon 27 (Gln > Glu) of
2-AR has been associated with obesity. It has been
found that in the regulatory region of 2-AR, there is
polymorphism, which is in linkage disequilibrium
with codon 27 polymorphism26. The 5 leader region
of 2-AR mRNAs includes a short open reading
frame encoding a 19 amino acid leader peptide. A
short synthetic peptide corresponding to the peptide
encoded by 2-AR short open reading frame potently
inhibits translation in vitro, suggesting that leader
cistron may play a role in the regulation of 2_AR
expression. Therefore, there may be association of 5
leader polymorphism with obesity and obesity related
metabolic disorders. A polymorphism in the
glucocorticoid receptor gene at codon 363 results in
change of amino acid from aspargine to serine which
results in higher sensitivity to glucocorticoids and
leads to energy imbalance.
AdiponectinAn adipocytokine encoded by APMI
gene localized on chromosome 3q27 is one of the
adipocyte-expressed proteins which regulate the
homeostatic control of glucose, lipid, and energy
metabolism. Evidences suggest its role in the genetic
predisposition to metabolic X syndrome, such as
insulin resistance, obesity, type 2 diabetes, and
coronary artery disease27-29. Adiponectin also
enhances the transcription of other genes involved in
fatty acid metabolism, most notably peroxisome
proliferator-activated receptor- (PPAR-). It also
contains response elements for peroxisome
proliferator-activator receptor (PPAR ), a key
regulator of glucose and lipid metabolism. Mackevics
et al.30 have investigated the association of 2 SNPs of
ACDC (Adipocyte, C1q, and Collagen Domain
933
Containing) gene, 45T-G and 276G-T, and their
haplotypes with serum adiponectin concentrations.
Adiponectin downregulates its own production and
the expression of its AdipoR2 receptor in transgenic
mice. Evidences also suggest that adiponectin
secretion is modulated by interleukins such as IL-15
which indicates that interleukins may modulate fat,
lean body composition and insulin sensitivity31.
Combined deficiencies of IL-6 and IL-1 have been
shown to cause obesity in young mice32.
LeptinIt is a 16 kDa adipocyte derived hormone
that circulates in the serum in the free and bound
form. Serum levels of leptin reflect the amount of
energy stored in adipose tissue. Studies have
confirmed that leptin plays not only a crucial role in
several endocrine functions33. Leptin is the paradigm
of adipose tissue endocrine function. It is almost
exclusively produced by adipocyte and it has a central
role in energy storage regulation and fertility34. When
leptin signalling is defective, through a defect in
either receptor or in peptide itself (ob/ob mouse), the
NPY system is up-regulated (mRNA over-expression)
and leads to increased peptide release, whereas the
content and/or release of some inhibitory peptides
(neurotensin, cholecystokinin) are diminished33.
Genetic factors related to the leptin gene are
important in defining the set point of obese
individuals (i.e., the circulating leptin level for a given
degree of body fatness). Le Stunff et al.35 have shown
that girls of comparable adiposity have different
circulating leptin levels, depending on their genotype
at promoter region of the leptin gene. Girls with -/-
Lep-2549 genotype have 25% lower mean leptin
levels than the girls with other genotypes.
Peptide YY (PYY) It is secreted as a 36 amino
acid, straight chain polypeptide, and is found in
maximum concentration at the terminal ileum, colon
and rectum. PYY participates in regulation of appetite
and weight balance through hypothalamic-based
mechanisms. PYY (1-36) stimulates appetite and
weight gain through Y1 and Y5 receptors. Variations
in peptide YY and Y2 receptor genes are associated
with severe obesity in Pima Indian men36. Some
studies have suggested that peripheral administration
of peptide YY (3-36) and glucagon-like peptide-17-36
inhibit food intake additively. In a study, three rare
non-synonymous variants have been dentified, only
one of which, PYY Q62P, exhibited familial
segregation with body mass37. A common and
934 INDIAN J EXP BIOL, NOVEMBER 2007
conserved variant of PYY and NPY receptor Y2R
variant is also protective for obesity38.
Resistin It is a cysteine-rich 12.5 kDa
polypeptide, adipocytokine, with a controversial
history regarding its role in pathogenesis of obesity-
mediated insulin resistance and type 2 diabetes
mellitus. The serum resistin concentration
significantly correlates with the degree of obesity and
distribution of fat39. Variability in the serum resistin
levels might be related to polymorphic variants of the
promoter region of the gene. Chung et al.40 have
shown that stimulatory protein 1 (Sp1) interacts with
resistin, a common polymorphism of human resistin
promoter, 420C >G, is critical for binding of Sp1
and modulates the transcriptional activity of the
resistin gene by changing the binding ability of Sp1.
A recent study concerning 123 middle-aged women
and 120 healthy young subjects has found that serum
resistin levels do not correlate with markers of
adiposity (including BMI, waist to-hip ratio, insulin
resistance, lipid profile, and serum leptin levels41
while increased serum resistin in adults with prader-
willi syndrome is related to obesity and not to insulin
resistance. Resistin expression is significantly
decreased in the white adipose tissue of several
different models of obesity including ob/ob, db/db,
tub/tub, and KKA(y) mice compared with their lean
counterparts.
Ghrelin Predominantly secreted from the
stomach, is the natural ligand for the growth hormone
secretagogue receptor in the pituitary gland thus,
fulfilling criteria of a brain-gut peptide. It has
profound orexigenic, adipogenic, and somatotrophic
properties, increasing food intake and body weight.
Ghrelin has ability to stimulate appetite by its
activation of neuropeptide Y neurons and inhibition of
pro-opiomelanocortin neurons. A negative feedback
regulation may exist between adipocytokines and
ghrelin production. Ukkola et al.42 have identified a
mutation at amino acid position 51 (Arg51Gln) of the
pre-proghrelin sequence in obese subjects, and found
that a mutation at codon 72 of pre-proghrelin gene
(Leu72Met) is associated with lower age of onset of
obesity. Circulating pre-prandial ghrelin to obestatin
ratio is increased in human obesity; obestatin is a
sibling of ghrelin derived from preproghrelin, opposes
the ghrelin's effects on food intake43.
Other candidate genes Genetic studies in
humans have shown that mutations in BDNF or TrkB
genes may account for certain types of obesity or
other forms of eating disorders. Neuromedin beta is
found to be very strong candidate gene of eating
behaviours and predisposition to obesity44. A novel
missense substitution (Val1483Ile) in the fatty acid
synthase gene (FAS) is associated with percentage of
body fat and substrate oxidation rates in non-
diabetics. A study performed on Pima Indians
indicated that Val1483Ile substitution in FAS is
protective against obesity. The SLC6A14 gene is an
interesting novel candidate for obesity. It encodes an
amino acid transporter, which potentially regulates
tryptophan availability for serotonin synthesis that
possibly affects appetite control45. In Zucker rats,
continuous stimulation of beta3-adrenoceptors by
KTO-7924 (a chemical compound) causes brown
adipose tissue-like adipocytes to appear in
retroperitoneal white adipose tissue, and improves
lipid metabolism46. Analysis of lineages of diabetic
individuals indicates that SHP [orphan nuclear
receptor small heterodimer partner (SHP, NR0B2)]
mutation is associated with obesity rather than with
diabetes47.
Deletion of CART gene in mice resulted in diet
induced obesity48. Mutational screening of CART
gene have shown that (Leu34Phe), mutation co-
segregates with the severe obesity phenotype over
three generations and has not been found in the
control population. While in other study49 no clear
association with obesity was found. A recently
identified adipocytokine visfatin, found to be highly
enriched in the visceral adipose tissue of both humans
and rodents. Interleukin-1 receptor antagonist gene
polymorphism has been found to be associated with
higher BMI in north Indian populaton50. Obese people
are more prone to gall stone diseases, but one study
has shown that LRPAP insertion deletion
polymorphism respective of BMI in gall stone
patients51.
Several studies have been conducted and reviewed
the interaction of environmental and behavioural
factors responsible for obesity. Overall existing
knowledge regarding contributing factors in
development of obesity suggests involvement of
environmental cognitive and genetic factors in the
progress of disease. A better understanding of their
interactions in the process of weight gain will provide
avenues for prevention and management.
The data in this review article is based on
MEDLINE and Pub Med searches using term
obesity and genetics in combination with other
 SRIVASTAVA et al.: PATHOPHYSIOLOGY & GENETICS OF OBESITY
key words prevalence, genes, mutation, 19 Challis B G, Coll A P, Yeo G S, Pinnock S B, Dickson S L,
Asian and India
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