Everyone wishes to attain and maintain healthy body weight. However, the weight that one gains is influenced by three main factors which are: genetics, diet, and aerobic physical exercises (Singh, Kumar, & Mahalingam, 2017). A healthy weight is defined as body weight that doesn’t increase one’s probability of developing comorbid weight-related problems such as type II diabetes mellitus, hypertension, and stroke. Instead of a single number, the ideal body weight (IBW) is a range of bodyweight that’s optimal for one’s sex, muscle mass, and height (Ravussin & Bogardus, 2000). The body mass index provides a simple and straightforward way of assessing body weight.
In the last four decades,’ obesity has become a ‘pandemic’ since it affects individuals regardless of their social-economic status (Singh, Kumar, & Mahalingam, 2017). Initially, scientists thought it would only affect the industrialized countries, but it’s still a major health concern in the third world nations. From 2000 – 2016, the cases of obesity in the world have quadrupled (Singh, Kumar, & Mahalingam, 2017). Obesity occurs when one’s BMI is greater than 30 kg/m3. When the energy equilibrium in the body is chronically distorted, then an increase in adiposity occurs. The energy equilibrium theory assumes that the body’s energy stores mirror the variation between energy utilization and energy intake. If the energy intake increases relative to energy utilization for prolonged periods, obesity is bound to occur. Studies on obesity are important because obesity is associated with a myriad of serious health complications. Some of these complications include; hypertension, Type II DM, cancer e.g. endometrial cancer, osteoarthritis, late onset Alzheimer’s disease, lower back pain that doesn’t resolve after use of anti-inflammatory drugs e.t.c .
In this paper, we will explore how genetics partially affects the bodyweight of an individual. Although scientists have not fully comprehended the pathogenesis of obesity, in most scenarios, an increase in adiposity is due to complex interactions between environmental and genetic factors (Silventoinen et al., 2007). Most obesity cases are not a result of gluttony, but due to inborn metabolic errors, which when combined with unsuitable ecological triggers such as fast foods and decreased aerobic exercises due to simple machines’ mechanization, obesity develops (Silventoinen et al., 2007). In first-world countries, technological advancements create an ‘obesogenic environment,’ resulting in reduced energy expenditures favoring weight gain.
There is a strong correlation between BMI in childhood and adulthood. The probability of being obese in adulthood can be predicted from the adiposity levels one has when he/she is below eighteen (Hinney, Vogel, & Hebebrand, 2010). Following these observations, scientists are trying to analyze how genetic and environmental factors influence relative weight gain from childhood to adolescence. Studies on how genes influence longitudinal weight gain in adulthood indicate diminished dopamine signaling reduces responsiveness to food reward in adulthood (Kvaløy, Holmen, Hveem, & Holmen, 2015). Genes linked to obesity are associated with metabolic syndrome. Metabolic syndrome is characterized by abdominal obesity, suboptimal activation of glut-4 receptors by insulin, hypertension, and increased LDL (low-density lipoprotein) levels.
Genome-wide association studies ‘GWAS’ have revealed 127 locations on the human genome linked with obesity development (Singh, Kumar, & Mahalingam, 2017). Since 2006 GWAS has paved the way for advancement in the knowledge currently available for the genetic determinants of metabolic syndrome (obesity). Studies on nonsynonymous SNPs (single nucleotide polymorphisms) on animal models are being used to pinpoint common genetic variations that cause obesity. SNPs are biomarkers are used to single out how genetic alterations have adverse consequences on the functioning of proteins. The FTO (fat mass obesity associated) gene was identified as a locus that increases obesity susceptibility. This gene(FTO) has the greatest influence on obesity phenotype risks. Alleles of the FTO gene are linked with at least a two-kilogram increase in body weight and a 35% increase in obesity (Singh, Kumar, & Mahalingam, 2017).
Epigenetics studies changes in the functioning of genes without alterations in the nucleotide sequence. Epigenetic modifications like methylation of guanine residues and histone modification may contribute to gene-environment interactions which result in metabolic syndromes and an increase in adiposity (Kvaløy, Holmen, Hveem, & Holmen, 2015).
Genetics affect weight maintenance by influencing how the body will utilize calories by regulating the rate at which body cells produce heat. Individuals with a high percentage of non-exercise-associated-thermogenesis (NEAT) have a high probability of maintaining a constant weight. In contrast, individuals with low NEAT levels are more likely to become obese despite being exposed to identical environmental factors. I will be expounding on how molecular genetics affects adiposity and energy homeostasis in the upcoming section.
How leptin genetics influence weight gain and maintenance
The leptin gene (LEP) produces the leptin peptide that is composed of 167 amino acids. The adipose tissue secretes the leptin peptide which acts in the hypothalamus to induce satiety, thus reducing food intake (Friedman & Halaas, 1998). The amount of fat in the adipose tissue is the principal determinant of the serum levels of leptin. It generates the AMP protein kinase, thus augmenting its fatty acid oxidation, which ultimately increases the energy expenditure. Therefore, a reduction in leptin levels will be associated with obesity. Leptin receptor gene (LEPR) and the peroxisome proliferator-activated receptor-gamma gene (PPARG) are polymorphic genes that play a role in leptin regulation. Mutation in either of the genes is linked with weight gain. The mutation of the LEP gene stops leptin generation. This alteration in the genetic code results in obesity, polyphagia, and insulin resistance, which can only be corrected by subcutaneous leptin administration from an exogenous source. Mouse and human leptin peptides share 83% sequence homology. Two teenagers whose LEP gene mutated due to guanine residue’s deletion based on the 133 codon developed early-onset obesity and polyphagia (Singh, Kumar, & Mahalingam, 2017).
The LEPR gene is located on the 1p31 chromosome and has several isoforms. The short and long variants share similar extracellular and intracellular domains. The long isoform of the LEPR gene is located in the hypothalamic arcuate nuclei. It reduces appetite by inhibiting the NPY neurons. Mutations of this receptor are associated with obesity, and obesity due to modification of LEPR cannot be corrected from exogenous leptin sources (Singh, Kumar, & Mahalingam, 2017). When proline is substituted for alanine amino acid at residue 12 of PPARG protein, it increases incidences of obesity, metabolic syndrome, and type II DM.
Not long ago, multiple nucleotide polymorphisms of the LEPR gene (Lys109Arg) & (Gln223Arg) were discovered among the Indonesian population in Yogyakarta. One hundred ten individuals were included in the study, which had 55 healthy adults and 55 obese people. The serum leptin levels and BMI levels were measured for both groups, and the obese group leptin levels were significantly higher than the control group (healthy adults). Obese individuals had a genetic variation whereby (Arg103Arg) gene occurred more frequently than the control group, whereas the (Gln223Gln) homozygote was higher in the control group than the obese group (Hastuti, Zukhrufia, Padwaswari, Nuraini, & Sadewa, 2016). These alterations in amino-acid sequences altered leptin levels, which influenced adiposity. Therefore, it is evident that polymorphisms of (Lys109Arg gene) and (Gln223Arg gene) are linked to an increase in adiposity by altering the leptin concentrations from the normal physiologic range (Hastuti, Zukhrufia, Padwaswari, Nuraini, & Sadewa, 2016).
How variants of the neuropeptide Y gene influence weight gain
Neuropeptide Y(NPY) is a peptide composed of 36 amino acids; physiologically, it plays a crucial role in regulating food intake obesity. NPY is the most potent endogenous molecule that stimulates appetite by acting on the hypothalamic paraventricular nucleus. Mutations of the NPY gene cause abnormal body weight increase by promoting increased food appetite and reducing utilization energy (Singh, Kumar, & Mahalingam, 2017). Variants of the NPY gene have been associated with obesity by various studies. According to (Bray, Boerwinkle, & Hanis, 2000) study, variation in the NPY nucleotide sequence is linked with increased adiposity among the Mexican-Americans subgroup living in Texas. Multiple studies have also confirmed that Single nucleotide polymorphisms (SNP) of the NPY are strongly correlated to increased BMI, dyslipidemia and coronary artery disease (Masoudi-Kazemabad et al., 2012).
Mutation of the melanocortin-3-receptor gene
Melanocortin 3 receptor (MC3R) maintains an ideal balance between energy utilization and consumption of foods. The MC3R located in the melanocortin pathway ensures energy balance is maintained by either stimulating or inhibiting leptin and its receptor. Once the adipose tissue secretes leptin, leptin can either increase or reduce appetite. It increases appetite by binding to the NPY receptors or reduces appetite by binding to the proopiomelanocortin receptors; this indicates the critical role played by the MC3R in influencing weight gain or loss.
The MC3R gene is located on the 20th chromosome. Mutation of the MC3R gene, a G-protein coupled receptor, negatively influences energy homeostasis and adiposity levels. As per the database that contains information on mutations of human genes, around 5/6 of the total 18 missense mutation occur on this gene. In the year 2002 (Lee, Poh, & Loke, 2002) identified the first MC3R mutation that was linked to an increase in adiposity. According to (Lee, 2002) alteration of the Ile183Asn amino acid sequence in the gene resulted in obesity in a thirteen-year-old girl whereby she had (49% fat levels) while the father had (30%) fat levels (Lee, Poh, & Loke, 2002). In this specific research Lee analyzed and screened the entire MC3R gene coding zone of 41 obese teenagers who weren’t related and 121 samples of DNA from individuals who weren’t obese. The DNA samples were analyzed via the polymerase chain reaction (PCR) for new sequence variations (Ile183Asn). A study conducted by (Zegers et al., 2011) found these new alterations in the genetic codes of obese children (Leu299val, Asn128ser and Val211Ile).
Variations in the (ILE335Ser) were found in extremely obese subjects in the United States of America and Italy, causing obesity by affecting the MC3R (Mencarelli et al., 2008). Some MC3R mutations occur naturally. For example, () has pointed out nine naturally occurring mutations in Singaporean obese patients: (Ser69Cys, Ala260Val, Thr280Ser, Met275Thr, Leu297Val, Leu249Val, Ala70Thr, Ile87Thr and Met134Ile). These mutations cause downregulation of expression of cell surface receptors, alter the extracellular ligand-binding domains and intracellular cAMP generation from enzymes, hence causing obesity by altering intracellular energetics (Yang, Huang, & Tao, 2015).
How mutations of the MC4R gene are linked to obesity
Melanocortin 4 receptor(MC4R) is a GPCR located in the hypothalamic nuclei, adipocytes, and muscles regulating energy balance in the body and feeding behaviors (Tatro). Mutations in the MC4R genes trigger obesity. The first MC4R gene mutation was pointed out as a frame-shift mutation. The human gene mutation database(HGMD) discovered that there were one-hundred and eighteen missense mutations for the MC4R receptor of the 139 mutations already identified for these genes. GWAS researches indicate that SNPs close to the MC4R gene are associated with childhood-onset of obesity. The SNP (rs1778231) is linked with increased adiposity and BMI for the European population, whereas the SNP (rs129070134) causes obesity in the Indian Race. Homozygous MC4R mutations cause more severe obesity than the Heterozygous Mutations MC4R gene containing a Var103Ile variation causes abdominal obesity (Rosmond, Chagnon, Bouchard, & Björntorp, 2001). A research study conducted by (Lv et al., 2015) indicated that SNP variants (rs17782131) were associated with obesity and metabolic syndrome.
FTO gene and obesity
GWAS findings indicate that the FTO (fat mass obesity) gene was the initial obesity-prone locus to be detected. To date, this gene (FTO gene) has the largest influence on obesity phenotype risk. Every allele of FTO has been linked to at least 1 kg spike in body weight and at least 20% rise in the obesity risk. The FTO gene is distributed in many adult and fetal tissues. The hypothalamic nuclei contain the highest expression of this gene, regulating energy utilization and food intake. GWAS investigations indicate that the FTO gene is the most crucial gene linked to increased adiposity in adolescents, adults, and children. This gene is also linked to type II DM. According to a study carried out by (Laber & Cox, 2015), the rs(1421085 T-C) variation of the FTO gene increases the risk of obesity because it prevents ARID5B repressor from binding, which depresses IRX3 and IRX5 during the initial differentiation of adipocytes. This mutation generally depresses thermogenesis, further increases the lipid stores and thus weight gain. Analysis of 306 obese women’s genome in a study conducted by () indicated they had the rs9939609 FTO gene variation. This variation results in weight gain indicating the FTO gene plays a crucial role in weight regulation by affecting fat cells’ lipolysis rate. Based on the various studies, the (rs9939609) variant of the FTO gene elevates causes hyperglycemia and insulin resistance, which increases the obesity risk in Pakistan women. Four nonsynonymous SNPs of the FTO gene have been discovered: (rs139000284, rs139577103, rs368490949 and rs373076420) which play a crucial role in the development of obesity. Lately () has proved that the FTO gene variant (rs9939609) is linked to obesity-associated with type II DM among Indian study participants. In this study, there were 1036 study participants, whereby 518 participants had type II DM, and the remaining 518 were healthy and used as controls. Type II DM patients were classified based on their obesity levels, whereby their BMI levels were used in stratification. This study found out that the association between type II DM to be meaningful only in the obese study participants as compared to the control group.
In a different research, the (rs9939609) variation of the FTO gene was linked to excessive adiposity and weight gain in Brazil. Another study conducted by (Illangasereka, Kumarasiri, & Dalton, 2016) has further proven that (rs9939606) FTO gene variant increases adiposity for both the metropolitan and non-urban populations in Sri Lanka.
Weight gain due to Ghrelin receptor mutation
The ghrelin receptor is a GPCR that signals the presence of hormone Ghrelin. Natural alterations of the Ghrelin receptor’s amino acid sequence result in suboptimal activation of the ghrelin receptor after binding of the natural ligand (ghrelin). Ghrelin modulates several physiologic functions like food appetite, energy utilization, HCl’s secretion by parietal cells, energy utilization, immune function modulation, glucose breakdown, and cardiovascular function (Singh, Kumar, & Mahalingam, 2017). Ghrelin’s effect on energy utilization antagonizes leptins’s action. Studies conducted on single nucleotide polymorphisms of the ghrelin gene indicate that ghrelin mutations can be linked to obesity-associated with short stature. Gene mutations of ghrelin cause obesity during the adolescent period. The two SNPs associated with an increase in adiposity and short stature are (Ala204Glu and Phe279Leu). These mutations are not common and have only been identified in East Asia and Southern American populations (Holst & Schwartz, 2006).
How gene mutations of the Beta-adrenoceptors can be linked to obesity
Beta-adrenergic fall in the GPCRs superfamily of receptors. Adrenaline and Nor-adrenaline are the endogenous ligands for this receptor. These receptors play a critical role in regulating physical fitness in individuals with increased adiposity by modulating inflammatory cytokine levels. To understand how Beta receptors, modulate energy homeostasis, we must first grasp how they act. Once Epinephrine binds to this receptor, it activates the Gs protein, which binds to adenylyl cyclase enzyme, increasing the intracellular cAMP concentrations. C AMP activates a kinase enzyme that adds phosphate moieties to serine and threonine residues. Activation of the B-arrestin protein ends the cascade of enzymatic reactions. This cascade of enzymatic reactions modulates the utilization of energy and lipolysis. Beta-adrenoceptor mutations can affect the rates of fat breakdown and thus cause obesity.
Mutations of the (ADRB1, ADRB2 and ADRB3) genes of the beta-adrenoceptor can cause obesity. ADRB1 receptor gene mutations are the principal causes of obesity by influencing how catecholamine regulate energy balance. Activation of the ADRB1 receptor on the adipocytes stimulates lysis of lipids, which reduces the risk of developing obesity. The (Arg389Gly) variation of the ADRB1 gene has been postulated to cause obesity from infancy to post-puberty. A study carried out by (Large et al., 2013) has pointed out two nonsynonymous SNPs (Ser49Gly & Gly389Arg) form the foundation for prolonged weight gain and the post-puberty onset of obesity females. Polymorphism of the ADRB2 gene has been shown to increase adiposity in females and lipid metabolism. The 27Glu allele increases the BMI, leptin and triglyceride levels in men, whereas, in women, it increases the hip to waist ratio and subcutaneous fat levels.
The (Trp64Arg) is the most common polymorphism that affects the ADRB3 gene. The ADBR3 gene plays a crucial role in influencing the adipocytes’ metabolic profiles and delaying the onset of type II DM. The (Trp64Arg) polymorphism decreases the lipo-lytic effect of adipocytes, resulting in increased lipid accumulation in adipocytes hence causing obesity. Obesity due to (Trp64Arg) begins early during adolescence.
The SLC6A14 gene is the newest gene to be identified that affects weight gain. This gene expresses aromatic amino acid transporters that modulate tryptophan’s availability for serotonin biosynthesis. Serotonin controls one’s food appetite and energy homeostasis. In the hypothalamus, this gene is widely expressed; it will alter one’s food seeking behaviour by influencing the amount of tryptophan available for 5-hydroxytryptamine (serotonin) synthesis. SLC6A14 gene mutations that contain the (rs2071877) are cause polygenic obesity (Ovesjö, Gamstedt, Collin, & Meister, 2001). This has been observed in the Finnish population.
The adipose tissue contains various uncoupling proteins, which are UCP1, UCP2 and UCP3. The uncoupling proteins usually regulate thermogenesis. Ala55val is a UCP gene variant whose mutation is associated with obesity.