Genes Implicated in Obesity and Overweight: Potential Biomarkers of Early Diagnosis
María Luz Gunturiz Albarracín1*,
Ana Yibby Forero2, Pablo Enrique Chaparro3
1Project Bank Team,
Public Health Research Division, National Institute of
Health, Colombia
2Nutrition Group, Public Health
Research Division, National Institute of Health, Colombia
3National Health Observatory
Division, National Institute of Health, Colombia
*Corresponding author: María Luz
Gunturiz Albarracín, BsC, PhD.
Project Bank Team, Public Health Research Division,
National Institute of Health, Avenue Street 26 No 51-20 CAN, Bogotá, D.C.,
Colombia. Tel: +5712207700; +573123600581; Email: mgunturiz@ins.gov.co
Received Date: 10 October, 2018; Accepted
Date: 23 October, 2018; Published Date: 30 October, 2018
Citation: Gunturiz ML, Forero AY, Chaparro PE (2018) Genes Implicated in Obesity and Overweight: Potential Biomarkers of Early Diagnosis. Curr Res Clin Diab Obes: CRCDO-101. DOI: 10.29011/CRCDO-101/100001
1. Abstract
Obesity is a chronic, complex and multifactorial disease, characterized by excess body fat, positive imbalance between energy intake and energy expenditure. The adverse metabolic effects caused by obesity can increase the risk of type 2 diabetes, many forms of cancer, fatty liver disease, hormonal disorders, hypertension, cardiovascular disease, metabolic syndrome and increased mortality, among others. In children, childhood obesity increases the chances of an earlier adolescence, gynecomastia in children and polycystic ovary syndrome, among other diseases; In addition, obese children and adolescents are more likely to remain obese in adulthood and develop various cardiovascular and metabolic diseases that decrease their quality of life. Several studies of the human genome have led to the identification and characterization of multiple genes that contribute to obesity; however, relatively few studies have allowed the identification of genes or biomarkers involved in obesity and overweight, especially in low and middle income countries. They are used routinely in early diagnosis and as a tool for the management of this condition. In this article, we review different genes that can serve as early diagnostic markers in children and adolescents in countries like Colombia, where there is a high prevalence of overweight and predisposition to obesity from these ages.
2. Keywords: Biomarkers; Genes; Genetic; Obesity; Overweight
3.
Abbreviations
ACTH : Adrenocorticotropin
ACP1 : Acid Phosphatase 1
ADIPOR1 : Adiponectin receptor 1
BMI : Body Mass Index
CARTPT : Cocaine- and
Amphetamine-Regulated Transcript Prepropeptide Gene
DM2 : Diabetes Mellitus type 2
ENPP1 : Ectonucleotide Pyrophosphatase/Phosphodiesterase
1
FTO : Fat Mass and Obesity-Associated
Gene
GHR : Ghrelin and Obestatin
Prepropeptide
GRPR : Gastrin Receptor
LEP : Leptin
LEPR : Leptin Receptor
MACP : Anion Transport Proteins
Mitochondrial
MC4R : Melanocortin 4 Receptor
MC-R : The Melanocortin Receptor Ligand
MSH : Melanocyte Stimulating Hormones
MYT1L : Myelin Transcription Factor 1
NR0B2 : Nuclear Receptor Subfamily 0 Group
B Member 2
PCGR : Protein-Coupled G-Receptors
POMC : Proopiomelanocortina
PPAR : Peroxisome Proliferator-Activated
Receptor
PPARGC1β : Peroxisome Proliferative
Activated Receptor, Gamma, Coactivator 1 beta
PXDN : Peroxidasin
SDC3 : Syndecan-3
SIM1 : Single-Minded 1
SNPs : Single Nucleotide Polymorphisms
TMEM18 : Transmembrane Protein 18
UCPs : Uncoupling Proteins
4. Introduction
Overweight and obesity prevalence has dramatically
increased during the last decade and reached epidemic dimensions. By 2030 it is
expected that there will be 2.16 billion overweight individuals with 1.12
billion adults predicted to be clinically obese. With current trends, by 2030,
some researchers project that 86.3% of American adults will be overweight (25
< body mass index (BMI) ≤ 30) or obese (BMI > 30) and that overall 51.1%
will be obese [1-6].
Obesity is the excessive deposition of adipose tissue
resulting of energy imbalance. The changes in food availability and
characteristics, as well as the decrease in physical activity during the last
decades have favored the energy imbalance causing that energy intake exceeds
energy expenditure. This trend has been observed in all age groups across
different countries. The response to environmental changes affecting diet and
physical activity is widely diverse and certain subjects and populations seem
to be more prone to develop obesity and its related comorbidities. In early
onset obesity it is important to differentiate between obesity due to rare
genetic abnormalities from the common forms. Numerous genetic abnormalities are
characterized by obesity. In some cases, single gene mutations can have a very
important effect on Body Mass Index (BMI) [7].
Obesity is a multifactorial disease that occurs from the
interaction between a genetic predisposition and the presence of certain
external factors (caused by both genetic and non-genetic factors) [8,9]. It is
characterized by an increase in body weight beyond the needs of the skeletal
physical structure, as a result of the excessive accumulation of body fat [9-12].
Usually is defined in adults as a BMI greater than 30 kg/m2, obesity
has become a leading public health concern for both genders, all ages, and all
ethnic groups [1].
The relationship between the increase in the obesity
index, and the consequent risk of morbidity and mortality associated with it,
such as dyslipidemia, hepatic steatosis, ovarian syndrome and hypogonadism, musculoskeletal
problems, cholecystitis, cardiovascular diseases, diabetes, pseudotumor
cerebri, and certain types of cancers, make obesity an important health problem
[13].
Obesity is currently one of the main public health
problems in Western countries, so it is important, in addition to promoting
good habits, to study and understand its genetic bases, molecular mechanisms
and the susceptibility of each person. that will contribute to improve the
strategies of prevention and treatment and to diminish the negative impact that
this disease exerts on society [14]. Childhood
obesity is a serious public health problem associated with the development of
several chronic diseases, such as type 2 Diabetes Mellitus (DM2), dyslipidemia,
and hypertension (HTA) and the elevated prevalence of this condition is mostly
due to inadequate diet and lifestyle, but it is also influenced by genetic
factors [15].
5. Causes
of Obesity
Obesity has become a serious health
problem worldwide due to its close link with the main causes of morbidity and
mortality in countries industrialized and developing [16]. This disease is a
complex disorder metabolism that is frequently associated in addition to with
DM2 and HTA with coronary heart disease, thrombosis, dyslipidemias, gallstones,
hepatic steatosis, sleep apnea, dysfunctions endometrial cancer and cancer,
among others [17,18].
The vast majority of cases of obesity are the result
of a complex interaction of genetic, hormonal, nutritional, physical activity,
environmental, physical and social factors, a condition that increases the risk
of various cardiometabolic, pulmonary and psychosocial complications in
children, that often continue until adulthood. In addition to those mentioned,
the causes of obesity can be the increase in caloric intake, genetic
predisposition, sedentary lifestyle and, exceptionally, neurological diseases.On
the other hand, pathological obesity represents only a small percentage of
these cases, therefore, prevention strategies and early intervention are key to
reversing the obesity epidemic [19,20].
6. Monogenic,
Polygenic and Syndromic Obesity
Obesity tends to aggregate in
families, its form of inheritance does not correspond to known patterns, and is
highly dependent on environmental factors [21-23]. Numerous studies have shown
that predisposition to obesity, and their associated conditions are more
similar among genetically related individuals than in those not related. The
phenotypes associated with obesity have an additive heritability (h2)
significant, this parameter being the proportion of the variability of a trait
that is attributable to genetic factors. In the case of the Body Mass Index (BMI)
the h2 has values from 40 to 70% in different studies in human groups [7,22-24].
The heritability of many other
phenotypes associated with adiposity, such as body weight, percentage of body
fat, or free mass of fat, circulating concentrations of adipocytokines, and
other markers of inflammation, has been estimated in different populations and
different age groups, with consistent observations of the contribution of
genetic factors to the variation of these traits. Obesity is phenotypically
expressed in a very heterogeneous way, with mechanisms very diverse molecular.
The Scientific evidence indicates that genetic factors are involved in the
development of obesity in approximately 30% to 40% of cases, not just in the
forms monogenic, but also in common obesity [18,25,26].
Although in recent years has
increased the study of genetic factors, there is still ignorance of the genetic
control of common forms of obesity [18,25,26]. Currently, the contribution of
genetic factors to this pathology can be summarized in:
·
Monogenic obesity is caused by a
single dysfunctional gene (simple mutations) and represents a small number of
severe cases that appear in childhood and are accompanied by different
neuroendocrine disorders, development and behavior. It is severe and rao
character and is presented from the beginning of childhood. Monogenic obesity
can be syndromic or non-syndromic. This ultim is produced by alterations of
simple genes, but unlike the syndromic it does not produce characteristic
phenotypes (are included mutations in genes of the leptin-melanocortin pathway
which plays a key role in the hypothalamic control of food intake).
·
Some genetic variants of high risk in
common obesity; that is, polygenic obesity, in which, each susceptibility gene
would only have a small effect on body weight and its contribution would be
more significant when predisposing environmental factors are present for its
phenotypic expression, as excessive feeding and reduction of physical activity.
·
There are approximately 30 syndromes
(syndromic obesity) that present obesity as part of the representation clinical
and that are generally accompanied by mental retardation, dysmorphisms and
other characteristics. Among the best characterized forms, are: Prader Willi
syndromes, Bardet-Biedl, Albrigt bereditary osteodystrophy, Adler, Fragile X
syndrome, Borjeson-Eorssman-Lebman, Coben, among others. Some of these
syndromes are associated with chromosomal abnormalities, and others are
monogenic forms with pleiotropic effects. Determine the origin of obesity in
children with these syndromes, it is difficult because it is not possible to
control all the factors surrounding them [7,27-29]. However, at least four of
these syndromes are accompanied by severe hyperphagia and other signs of
hypothalamic dysfunction, suggesting an origin at the level of the central
nervous system, making it easier to diagnose [7,27-29].
Specifically, Prader-Willi syndrome
is a complex genetic condition that affects many parts of the body. In infancy,
this disease is characterized by weak muscle tone (hypotonia), feeding
difficulties, poor growth, and delayed development. Beginning in childhood,
affected individuals develop an insatiable appetite, which leads to chronic
overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome,
particularly those with obesity, also develop type 2 diabetes [30].
Bardet-Biedl syndrome is considered a
rare form of obesity and has a prevalence of less than 1/100.000. It is an
autosomal recessive form that is frequently associated with central obesity,
mental retardation, limb dysmorphia and other abnormalities. This is a heterogeneous
syndrome that has been associated with 8 loci and seven of them have been
located at the molecular level 18. The genes associated with this syndrome are
BBS1 on chromosome Ilql3 and BBS2 on 16q2. In most cases the function of the
proteins encoded by these genes is not known [31].
On the other hand, the Cohen syndrome is one of the
rare autosomal recessive disorders characterized by nonprogressive mild to
severe psychomotor retardation, motor clumsiness, microcephaly, characteristic
facial features, childhood hypotonia and joint laxity, progressive
retinochoroidal dystrophy, myopia, intermittent isolated neutropenia, and a
cheerful disposition. Specific facial features include high-arched or
wave-shaped eyelids; long, thick eyelashes; thick eyebrows; prominent root of
nose; short philtrum (which is unable to cover the prominent upper central
incisors); small or absent lobuli of the ears; thick hair and low hairline;
narrow hands and feet; and mild syndactylies (in 50% to 60%) [32,33].
Obesity at an early age is a
phenotype common to several monogenic forms of human obesity, and to syndromes
caused by chromosomal abnormalities. Of course, these genetic alterations do
not explain proliferation of obesity in recent years, however, the study of
these forms of obesity has given valuable information on relevant metabolic
pathways in the development of this condition [33-35].
Some studies have compared homogenous population
groups of different ages and obese and thin. These groups have studied, among
others, the energy consumption, the intestinal microbiome, the number of
adipocytes, and several genetic markers and it has been shown that the energy
consumption is lower in children who become overweight compared to other
children. thin children; that the microbiome of the obese contains less
Bacteriodes than the thin ones, which suggests that obesity would also have a
microbial component, in which case the obese microbiome would have greater
capacity to save energy from the diet. Additionally, it has been observed that
the number of existing adipocytes of adults is acquired in childhood and
adolescence, while in children it remains constant, both in obese and thin,
even when they lose weight, changing in childhood and adolescence, and staying
constant in adulthood. In this stage of life, neither destroy nor increase [15].
Numerous studies reported that single gene variants
cause Mendelian forms of obesity, determined by mutations of major effect in
single genes. Rare, non-syndromic forms of obesity are a result of
loss-of-function mutations in genes that act on the development and function of
the hypothalamus or the leptin-melanocortin pathway. These variants disrupt
enzymes and receptors that play a role in energy homeostasis, resulting in
severe early-onset obesity and endocrine dysfunctions.
Among the genes involved in the etiology of obesity
are they find metabolic genes, genes that code for peptides that control the
signals of hunger and satiety, regulatory genes of energy expenditure and genes
that regulate the growth and differentiation of adipocytes There are many loci
and several genes that have been associated with the predisposition for obesity
and thinness, obesity development and classified according to their expression
in different stages of this condition, such as in early onset, predisposition
to obesity, late onset, severe obesity (morbid). Table 1 shows some of the
genes associated with obesity in their different stages of presentation.
7. Genes Associated
with Early Onset and Predisposition to Obesity
7.1. Proopiomelanocortina (POMC) Gene
Also known as LPH; MSH; NPP; POC; ACTH; CLIP; OBAIRH
is located on the short arm of chromosome 2 (2p23.3) encodes the precursor of
the adrenocorticotropin sérica, ACTH in the pituitary gland. POMC is regulated
by leptin and is cleaved by prohormone-convertases to produce ACTH, the Melanocortin
Receptor ligand (MC-R) and alpha, beta and gamma Melanocyte Stimulating
Hormones (MSH). The reddish pigmentation of the hair, adrenal insufficiency and
obesity are caused by deficiencies in the ligands and the subsequent lack of
activation of the MC1 MC2 and MC4 receptors, respectively. In addition to the
total deficiency of POMC, some cases of isolated deficiency of beta-MSH, the
ligand for MC4-R derived from POMC, have also been described. These individuals
have a distinct POMC mutation in the region that codes for beta-MSH. This
isolated deficiency of beta-MSH results in a clinical phenotype similar to that
observed in MC4-R deficiency (childhood obesity, hyperphagia and increased
linear growth) but is not associated with red hair or adrenal insufficiency [36-39].
POMC deficiency is a form of monogenic obesity that causes severe early onset
obesity, adrenal insufficiency, red hair and pale skin.
7.2. Nuclear Receptor Subfamily 0
Group B Member 2, NR0B2 Gene
Also
known as SHP; SHP1 is located on the short arm of chromosome 1 (1p36.1), it
codes for a protein that interacts with the retinoid and thyroid receptor
hormones, inhibiting its ligand-dependent transcriptional activation. In
addition, when it interacts with estrogen receptors its function is inhibited.
It has been suggested that the protein represses transactivation mediated by
the nuclear hormone receptor through two separate stages, competition with
coactivators and the direct effects of its transcriptional repressor function.
18 variations have been identified from this gene [40].
7.3. Ghrelin and Obestatin
Prepropeptide (GHRL) Gene
Also known as MTLRP is located on the short side of
chromosome 3 (3p26-p25), codes for ghrelin-obestatin preproprotein that is
cleaved to produce two peptides, ghrelin and obestatin. Ghrelin is a powerful
appetite stimulant and plays an important role in energy homeostasis and
regulating multiple activities, including hunger, reward perception through the
mesolimbic pathway, gastric acid secretion, gastrointestinal motility and
secretion of the insulin stimulated by glucose. On the other hand, obestatin
regulates the function of adipocytes and the metabolism of glucose. Four
mutations, 3 of them without meaning, have been identified in the GHRL gene
that increase the predisposition to obesity [10,41-47].
7.4. Uncoupling Proteins (UCP1 And
3) Gene
UCP1 is located
on the long arm of chromosome 4 (4q28-q31), and encode mitochondrial uncoupling
proteins, a member of the family of anion transport proteins mitochondrial
(MACP). In general, UCPs are mitochondrial transport proteins that create
proton leakage through the inner mitochondrial membrane, therefore decompose
the oxidative phosphorylation of ATP synthesis, so that the energy is
dissipated as heat [48,49].
On the other hand the UCP3 gene is located on the long arm of chromosome 11 (11q13.4), it codes for
mitochondrial uncoupling proteins, from the family of mitochondrial anion
transport proteins (MACP). These proteins create proton leakage through the
inner mitochondrial membrane, causing the uncoupling of oxidative
phosphorylation of ATP synthesis, so that energy dissipates as heat. 9
mutations in the UCP3 gene have been described [50].
Seven mutations in the UCP1 gene and 9 mutations in
the UCP3 gene have been described, changes that have been associated with an
increased susceptibility to obesity, generally of early onset [48,49].
7.5. Cocaine- and
Amphetamine-Regulated Transcript Prepropeptide Gene (CARTPT)
Located on the long arm of chromosome 5 (5q13.2),
codes for a satiety factor closely associated with the actions of leptin and
neuropeptide Y. This anorectic peptide inhibits induced hunger and completely
blocks the response of Feeding induced by neuropeptide Y, regulated by leptin
in the hypothalamus. In addition, it promotes neuronal development and in vitro
survival. Two mutations have been identified in the CARTPT gene, which have
been associated with a greater predisposition to obesity, usually of early
onset [51].
7.6. Beta-2-Adrenergic Receptor (ADRB2)
Gene
Located on the long arm of chromosome 5 (5q31-q32),
codes for the beta-2-adrenergic receptor that is a member of the superfamily of
G-protein coupled receptors and is directly associated with one of its final
effectors, class C calcium channel Ca type L (V) 1.2. This receptor-channel
complex also contains a G protein, an adenylate cyclase, cAMP-dependent cAMP,
and the PP2A phosphatase. The assembly of the signaling complex provides a
mechanism that ensures specific and rapid signaling by this receptor coupled to
protein G. Six mutations have been described in the ADRB2 gene, which have been
associated with an increased susceptibility to obesity, generally from the
beginning early [43,52].
7.7. Beta-3-Adrenergic Receptor (ADRB3)
Gene
Located on the short arm of chromosome 8 (8p12), it
codes for a protein that belongs to the family of beta adrenergic receptors, which
mediate the activation induced by catecholamines of adenylate cyclase through
the action of proteins G. This receptor is located mainly in adipose tissue and
is involved in the regulation of lipolysis and thermogenesis. Two nonsense
mutations have been described in the ADRB3 gene, changes associated with a
greater predisposition to obesity, generally of early onset [43,52,53].
7.8. Ectonucleotide Pyrophosphatase/Phosphodiesterase
1 (ENPP1) Gene
Located on the long arm of chromosome 6 (6q22-q23),
codes for a protein called ectonucleotide pyrophosphatase/phosphodiesterase 1
(ENPP1). This protein helps break down adenosine triphosphate (ATP), especially
when it is outside the cell. The ENPP1 protein also plays a role in the control
of cell signaling in response to the hormone insulin, through the interaction
between a part of the ENPP1 protein, called the SMB2 domain, and the insulin
receptor. They have been identified 54 variations in the ENPP1 gene, associated
with a greater predisposition to obesity, generally of early onset [54-56].
7.9. Genes Implicated in Late-Onset
Obesity
7.9.1.
Melanocortin-3 and Melanocortin-4 Receptor Antagonist (AGRP) Gene
Located on the long arm of chromosome 16 (16q22), it
encodes a melanocortin-3 and melanocortin-4 receptor antagonist that seems to
regulate the hypothalamic control of feeding behavior through the melanocortin
receptor and / or the regulation of the intracellular calcium, and therefore,
plays a role in the homeostasis of body weight. Five mutations in the AGRP gene
have been described, associated with late-onset obesity [39,57].
7.9.2.
Genes Involved in Severe (Morbid) Obesity: Leptin (LEP) Gene
Located on chromosome 7 (7q31.3), it codes for the
protein leptin, a hormone secreted primarily in white adipose tissue, which
circulates in the blood in proportion to the fat content to regulate the amount
of adipose tissue and the body mass by interacting with certain neuronal
receptors that affect appetite and energy homeostasis. To this end, leptin
receptors are highly expressed in neurons of the hypothalamus, which act as
primary sensors for alterations in energy reserves, controlling food intake and
energy expenditure. In this way, leptin regulates these two neuronal
populations reciprocally, contributing to the regulation of appetite and energy
homeostasis. In addition, leptin is expressed in the male and female
reproductive organs, in the mammary glands and in the immune system. Mutations
homozygous in it can generate a truncated protein with undetectable
concentrations in serum, leading to severe obesity of early onset. The symptoms are heterogeneous, although it is common
to observe severe obesity of early onset and hyperphagia and, frequently, also
hyperinsulinemia. In this gene, 6 nonsense mutations, 1 splicing mutation, 2
regulatory mutations and 3 small deletions have been described [58-61].
7.10.
Leptin Receptor (LEPR) Gene
Located on chromosome 1 (1p31), it encodes for the
leptin receptor, a membrane protein homologous to the receptor of the family of
class 1 cytokines. 3% of those affected by obesity have homozygous mutations in
this gene, which cause the loss of all isoforms of the leptin receptor. In
addition, heterozygous mutations are also associated with an increase in
weight, but for the development of morbid obesity the loss of the two alleles
is required, either as a result of a homozygous mutation or compound
heterozygous mutations. Certain mutations that affect regions near the
transmembrane domain of the leptin receptor can result in a truncated
extracellular domain that it could act as a spurious binding protein, resulting
in elevated levels of leptin. However, genetic alterations located in other
areas of the LEPR gene do not usually generate large accumulations of leptin.
In this gene, 11 nonsense mutations, 1 cut / splice mutation, 1 small insert, 1
major insert / duplication, and 1 repetition variation have been described [58-61].
In general, the results of leptin deficiency and those
of leptin receptor deficiency are similar, observing that affected individuals
experience a rapid increase in weight during the first months of life, with
excessive accumulations of subcutaneous fat deposited on the trunk. and in the
extremities. In line with the severity of obesity, hyperinsulinemia is observed
and, in some adults, type 2 diabetes mellitus develops during the third or
fourth decade of life. All cases are characterized by intense hyperphagia and
may be associated with hypogonadotropic hypogonadism.
7.11.
Peroxisome Proliferator-Activated Receptor (PPARG) Gene
Located on the short arm of chromosome 3 (3p25), it
encodes the PPARgamma protein, a regulator of adipocyte differentiation and
glucose homeostasis that acts as a critical regulator of bowel homeostasis by
suppressing proinflammatory-kappa-β responses mediated by NF. Likewise, it
plays a role in the regulation of cardiovascular circadian rhythms by
regulating the transcription of Arntl / BMAL1 in blood vessels. 20 mutations
have been described, 2 deletions and 1 insertion / deletion in the PPARG gene,
variations related to severe obesity [62,63].
7.12.
Peroxisome Proliferative Activated Receptor, Gamma, Coactivator 1 Beta (PPARGC1β)
Gene
Also known as PERC; ERRL1; PGC1B; PGC-1(beta), is located
on the long arm of chromosome 5 (5q32), it codes for a protein that stimulates
the activity of several transcription factors and nuclear receptors, including
alpha estrogen receptors, the nuclear respiratory factor 1, and the receptor
glucocorticoids. The encoded protein may be involved in the oxidation of fats,
the non-oxidative metabolism of glucose, and the regulation of energy
expenditure. Three mutations in this gene related to important obesity have
been identified [62,63].
7.13.
Fat Mass and Obesity-Associated (FTO) Gene
Polymorphisms in this gene are related to individual
differences in food intake and energy balance and can also influence skeletal
muscle phenotype [64,65]. Multiple Single Nucleotide Polymorphisms (SNPs) occur
on the FTO gene that may influence adipogenesis and obesity [66-68]. Since the
obesity-associated SNPs are on the intron 1 region of the FTO gene, the
mechanisms through which they influence body mass are uncertain. However, it
has recently been shown in humans that a T-C SNP at position 53,767,042 on the
FTO gene (rs1421085) causes an increase in IRX3 and IRX5 protein expression
during early adipocyte differentiation in favor of energy-storing/white
adipocytes over energy-dissipating/beige adipocytes. The critical downstream
effect of this is increased energy conservation in the form of augmented fat
storage [10,64,68,69].
In FTO a great number of additional susceptibility
variants have been identified altogether still accounting for a small
percentage of the overall risk for obesity [9,55,65,70-72].
7.14.
Single-Minded 1 (SIM1) Gene
Is a basic helix-loop-helix transcription factor
involved in the development and function of the paraventricular nucleus of the
hypothalamus, is located on the long arm of chromosome 6 (6q16.3), it encodes a
transcription factor that can have pleiotropic effects during embryogenesis and
in adults. A deletion and complex rearrangement in the SIM1 gene associated
with severe obesity has been identified [73,74].
7.15.
Other Genes Involved in Obesity
7.15.1
Melanocortin 4 Receptor, MC4R Gene
Located on the long arm of chromosome 18 (18q22),
belongs to the superfamily of Protein-Coupled G-Receptors (PCGR). The
neuropeptides that act as ligands bind to its central cavity causing a
conformational change that induces its activation. Genetic abnormalities in the
MC4R gene are the most common genetic alterations in obese individuals.
Mutations in this gene give rise to obesity as an isolated trait. 137
variations have been described that cause disturbances in the binding of the
ligand and alter the affinity of the receptor agonists against their
antagonists, hindering ligand coupling and subsequent signal transduction, so
this gene has been implicated in the dominant autonomic obesity [55,58,75].
7.15.2
Solute Carrier Organic Anion Transporter Family Member 4C1 (SLCO4C1) Gene
Also known as OATPX; OATP-H; OATP-M1; OATP4C1;
PRO2176; SLC21A20 is located on the long arm of chromosome 5 (5q21), belongs to
the organic anion transporter (OATP) family that are involved in the membrane
transport of bile acids, conjugated steroids, thyroid hormone, eicosanoids,
peptides, and numerous drugs in many tissues [76]. Specifically, SLCO4C1 is
involved, among other functions, in the transport of thyroid hormones that have
been linked in numerous occasions with weight variations, being hypothyroidism
a frequent cause of overweight [77,78].
7.15.3
Syndecan 3, SDC3 Gene
Also known as SDCN; SYND3 is located on the short arm
of chromosome 1 (1p35.2), it codes for a protein that belongs to the
proteoglycan family "sindican" that could play a role in the
organization of the cell form by affecting the actin cytoskeleton, possibly by
transferring signals from the surface of the cell in a carbohydrate-dependent
mechanism. Two nonsense mutations in the SDC3 gene that have been associated with
obesity have been described [79-82].
7.15.4
Adiponectin Receptor 1 (ADIPOR1) Gene
Located on chromosome 1 (1q32.1), it receptor
regulates several physiological aspects, including lipid metabolism and is overexpressed
in peripheral white cells of obese children. Has also been reported that higher
levels of receptor expression are associated with insulin resistance, which
could be a compensatory mechanism to mitigate the effects of decreased
adiponectin levels [10,83-85].
7.15.5
Acid Phosphatase 1, (ACP1) Gene
Also known as HAAP, LMW-PTP, LMWPTP
is located on chromosome 2 (2p25.3) and expressed in
adipocytes. Polymorphisms in this gene have been associated with severe obesity
and with total cholesterol and triglyceride levels [86,87]. There is an overall
positive association between obesity and low activity of ACP1 suggesting that
the heterozygous loss of this gene could contribute to the obesity observed in
your patients [55,87-90].
7.16.
Transmembrane Protein 18 (TMEM18) Gene or lncND Gene
Located on chromosome 2 (2p25.3)
and expressed in all brain sites, including the hypothalamus.
Genome-wide association studies by the GIANT consortium have shown a direct and
significant association between an single-nucleotide polymorphism, SNP near the
TMEM18 gene and obesity (BMI and weight) [88,91]. Almen et al. [92] reported
the involvement of TMEM18 in adult and childhood obesity and DM2, nevertheless,
the role of haploinsufficiency for TMEM18 is still debated [93].
Furthermore, peroxidasin (PXDN) and MYT1L genes are
located in the smallest region of overlap when looking at the common deleted
genes in obese patients with distal or interstitial deletion. PXDN also known
as PXN; VPO; MG50; PRG2; ASGD7; COPOA; D2S448; D2S448E is located on the short
arm of chromosome 2 (2p25.3) encodes for a heme-containing peroxidase enzyme, that is secreted into the extracellular matrix and is involved in
extracellular matrix formation and may function
in the physiological and pathological fibrogenic response in fibrotic kidney
[94]. The function of the PXDN gene is not clearly defined in humans, but
mutations in this gene cause corneal
opacification and other ocular anomalies, and also microphthalmia and anterior
segment dysgenesis.
On the other hand, Myelin transcription factor 1, MYT1L also known as NZF1; MRD39; myT1-L; ZC2H2C2; ZC2HC4B is located on the short arm of chromosome 2 (2p25.3), has not yet been described as candidate gene in obesity but in sixsome patients are deleted for MYT1L and show hyperphagia [95]. This gene encodes a member of the zinc finger superfamily of transcription factors whose expression, thus far, has been found only in neuronal tissues; the encoded protein belongs to a novel class of cystein-cystein-histidine-cystein zinc finger proteins that function in the developing mammalian central nervous system. Forced expression of this gene in combination with the basic helix-loop-helix transcription factor NeuroD1 and the transcription factors POU class 3 homeobox 2 and achaete-scute family basic helix-loop-helix transcription factor 1 can convert fetal and postnatal human fibroblasts into induced neuronal cells, which are able to generate action potentials. Mutations in this gene have been associated with an autosomal dominant form of cognitive disability and with autism spectrum disorder, in addition to those mentioned above [93,96,97].
Finally, several of the genes studied have
interrelated functions with the regulation of appetite, the sensation of
satiety and hormonal processes, among them the Glutamate receptors are the
predominant excitatory neurotransmitter receptors in the mammalian brain and
are activated in a variety of normal neurophysiologic processes. The GRIK1 and
GRM7 genes are members of this family, which have various roles in the
physiology of the central nervous system, one of them the regulation of energy
balance and intake. GRIK1 also known as EAA3; EEA3; GLR5; GLUR5; GluK1; gluR-5,
located on the long arm of chromosome 21 (21q21.3), his gene product belongs to
the kainate family of glutamate receptors, which are composed of four subunits
and function as ligand-activated ion channels and a mutation in this gene has
been associated with reduction of body mass index in heavy drinkers [14,98].
In studies with mice, it has been seen that the
absence of another glutamate receptor of the same family (mGLUR5) leads to a
considerable decrease in weight. On the other hand, GRPR is the gene that gives
rise to the gastrin-releasing peptide receptor, a hormone responsible for
facilitating digestion in the stomach and promote the sensation of fullness and
whose malfunction can cause difficulties to feel satiated and, consequently,
cause a greater eating of food [14,62,63,99].
8.
Conclusion
The cases of obesity derived from chromosomal
alterations or monogenic conditions in humans represent a very small proportion
of the cases of obesity and overweight. On the other hand, to make an adequate
diagnosis and rule out genetic anomalies associated with obesity at early ages,
it is necessary to study other characteristics, such as developmental delay,
dysmorphisms, etc.
Common obesity and the phenotypes related to it have a
significant genetic component and there is ample evidence of the influence of
multiple genes on the development of this disease. The study of the genetics of
obesity has shown that some of the most likely mechanisms that predispose to
its development are found in the pathways that regulate appetite and energy
expenditure; however, there is no genetic variant that is consistently
associated with the common obesity risk.The
identification of the genes involved or associated with obesity and overweight
is relevant to the understanding of the pathophysiology of these conditions and
allows the establishment of early diagnosis biomarkers that in the future
contribute to improve the prevention and proper management of obesity in
children and adolescents.
9.
Acknowledgments
The authors wish to acknowledge the financial support
provided by the National Institute of Health of Colombia.
Gene |
Aliases |
Chromosome Location |
Stages/ Type of obesity |
Proopiomelanocortina |
POMC Gene Also known as LPH; MSH; NPP; POC; ACTH; CLIP; OBAIRH |
2p23.3 |
Early onset obesity |
Nuclear receptor subfamily 0 group B member 2 |
NR0B2 gene Also known as SHP; SHP1 |
1p36.1 |
|
Ghrelin and obestatin prepropeptide |
GHRL gene |
3p26-p25 |
Predisposition to obesity
|
Mitochondrial Uncoupling proteins |
UCP1 and UCP3 genes |
4q28-q31 and 11q13.4 respectively |
|
Cocaine- and Amphetamine-Regulated Transcript Prepropeptide |
CARTPT gene |
5q13.2 |
|
Beta-2-adrenergic receptor |
ADRB2 gene |
5q31-q32 |
|
Beta-3-adrenergic receptor |
ADRB3 gene |
8p12 |
|
Ectonucleotide pyrophosphatase/phosphodiesterase 1 |
ENPP1 gene |
6q22-q23 |
|
Melanocortin-3 and melanocortin-4 receptor antagonist |
AGRP gene |
16q22 |
Late-onset obesity |
Leptin |
LEP gene |
7q31.3 |
Severe (morbid) obesity
|
Leptin receptor |
LEPR gene |
1p31 |
|
Peroxisome proliferator-activated receptor |
PPARG gene |
3p25 |
|
Peroxisome proliferative activated receptor, gamma, coactivator 1 beta |
PPARGC1B gene Also known as PERC; ERRL1; PGC1B; PGC-1(beta) |
5q32 |
|
Fat mass and obesity-associated |
FTO gene
|
ND |
|
Single-minded 1 |
SIM1 gene |
6q16.3 |
|
Melanocortin 4 receptor |
MC4R gene |
18q22 |
Obesity |
Solute carrier organic anion transporter family member 4C1 |
SLCO4C1 gene Also known as OATPX; OATP-H; OATP-M1; OATP4C1; PRO2176; SLC21A20 |
5q21 |
|
SDC3 gene Also known as SDCN; SYND3 |
1p35.2 |
||
Adiponectin receptor 1 |
ADIPOR1 gene Also known as CGI45; PAQR1; ACDCR1; CGI-45; TESBP1A |
1q32.1 |
|
Acid phosphatase 1 |
ACP1 gene Also known as HAAP; LMWPTP; LMW-PTP |
2p25.3 |
|
Transmembrane protein 18 |
TMEM18 gene or lncND gene |
2p25.3 |
|
Peroxidasin |
PXDN gene Also known as PXN; VPO; MG50; PRG2; ASGD7; COPOA; D2S448; D2S448E |
2p25.3 |
|
Myelin transcription factor 1 |
MYT1L gene Also known as NZF1; MRD39; myT1-L; ZC2H2C2; ZC2HC4B |
2p25.3 |
|
Glutamate ionotropic receptor kainate type subunit 1 |
GRIK1 gene Also known as EAA3; EEA3; GLR5; GLUR5; GluK1; gluR-5 |
21q21.3 |
|
Gastrin-releasing peptide receptor |
GRPR gene Also known as BB2; BB2R |
Xp22.2 |
Table 1: Some of the genes associated with monogenic obesity in different stages of this pathology.