Genetic basis of obesity: a review

Obesity is a state of “positive” energy balance when energy intake in is much greater than energy expenditure. The familial aggregation of body size was first published by Sir Francis Galton in 1889, which become a well-established risk factor for childhood obesity. Obesity is often allied with insulin resistance, dyslipidemia and cardiovascular disease. Monogenic obesity includes the involvements of Leptin (LEP) gene, leptin receptor(LEPR), Proopiomelanocortin (POMC), Melanocortin-4 receptor (MC4R), single-minded gene 1 (SIM 1), Proprotein convertase subtilisin/ kexin type 1 (PCSK1), Neuropeptide Y (NPY). Polygenic obesity is due to Adrenoceptor beta 1 (ADRB1), ADRB2, ADRB3, Uncoupling protein 1(UCP1), UCP2, UCP3. Monogenic and polygenic obesity; pleiotropic syndromes, chromosomal rearrangement are different types of obesity with genetic cause. Surprisingly all “obesity genes” carriers do not become overweight, and exercise, maintaining healthy routine is a significant contributing factor to nullify genetic prediposition. Journal of Biomedical Sciences , Vol. 3, No.2, 2016, Page: 24-28


ABSTRACT
Obesity is a state of "positive" energy balance when energy intake in is much greater than energy expenditure.The familial aggregation of body size was first published by Sir Francis Galton in 1889, which become a well-established risk factor for childhood obesity.Obesity is often allied with insulin resistance, dyslipidemia and cardiovascular disease.Monogenic obesity includes the involvements of Leptin (LEP) gene, leptin receptor(LEPR), Proopiomelanocortin (POMC), Melanocortin-4 receptor (MC4R), single-minded gene 1 (SIM 1), Proprotein convertase subtilisin/ kexin type 1 (PCSK1), Neuropeptide Y (NPY).Polygenic obesity is due to Adrenoceptor beta 1 (ADRB1), ADRB2, ADRB3, Uncoupling protein 1(UCP1), UCP2, UCP3.Monogenic and polygenic obesity; pleiotropic syndromes, chromosomal rearrangement are different types of obesity with genetic cause.Surprisingly all "obesity genes" carriers do not become overweight, and exercise, maintaining healthy routine is a significant contributing factor to nullify genetic prediposition.

Background:
Obesity is a state of "positive" energy balance when energy intake in is much greater than energy expenditure.Obesity occurs when excess body fat accumulates.It is a well known fact that obesity is associated with cardiovascular disorder (CVD), type 2 diabetes, and cancer.Although environment contributes for the development of obesity, but genetics also plays a crucial role (40% -70%).The familial aggregation of body size was first published by Sir Francis Galton in 1889, which become a well-established risk factor for childhood obesity.The search for human obesity genes started long back.The search was intensified by the advances in the molecular biology techniques.Genetics influence the normal physiology, embryonic development, adaptation, and obesity.Still the research in "genetic environment interactions" is in the early stage [1,2].

Role of Leptin
The LEP gene produce hormone leptin from adipocytes, regulates body weight.Leptin binds to leptin receptor, found in many organs including hypothalamus, which controls hunger and thirst.Leptin binds with receptor and acts via Janus Kinases-start activators of transcription (JAK-STAT) signaling pathways.

Figure -2 Chromosome location: Leptin gene
It is downstream signaling pathways, inhibit feeding & promote energy expenditure i.e. producing a feeling of fullness (satiety) [5].The chromosome for leptin is located in 7q32.1, long (q) arm of chromosome 7 at the position 32.1 [6].leptin gene and regulatory regions mutation cause severe morbid obesity associated with Hypo gonadism [7].Subcutaneous injection of leptin is clinically recommended in LEP deficient children and adults.It decreases food intake and slower rate of eating which leads to weight loss and decrease in fat mass.

Obesity and Melanocortin 4 receptor (MC4R)
MC4R gene encodes MC4R protein, controls feeding behaviour, metabolism, sexual behaviour, and erectile function in males [9,10].In 2009, two very large genomewide association studies of BMI confirmed the association of variants with insulin resistance, obesity. 2 -3% of adult and child obesity is associated with MC4R [11][12][13].Normally α melanocyte-stimulating hormone plays a vital role on MC4R, which reduces food intake [14].It is well documented that mutations or failure in the function of proopiomelanocortin gene causes obesity in experimental models like mice and humans.Carriers of MC4R gene variant (22% of the general population) have both appetite & satiety.Remarkable behavioural changes include eating larger amounts of food, frequent intake of snacks, and more attractions towards fatty foods are common.Research evidences suggests each copy of the variant is responsible for a BMI (Body Mass Index) 0.22 which risks obesity by 8% [15][16][17].

Polygenic obesity "common obesity" mutations in multiple genes
Majority (>95% of cases) of the obesity is polygenic obesity, in clinical situations.Each susceptibility gene, contributes a little on weight gain.'obesogenic lifestyle' increases the risk for cumulative effect from these genes.Obesogenic lifestyle factors includes overfeeding, Sedentariness and stress [8].Ample evidence available from animal models, human linkage studies, monozygotic and dizygotic twins, and association research works of large populations shows significant contributions in common obesity.Twin studies unfolded the genetics of common obesity.Data obtained from 25,000 twin pairs and 50,000 biological and adoptive family members, showed that mean correlations for BMI (estimated) were 0.74 for monozygotic twins, where as 0.32 was for dizygotic twins [13].Researchs showed that genes played a significant contribution for BMI of monozygotic twins but in shared genes the effect is relatively less.However, the study assumed that both twins grown up same degree of sahred environment.

Syndromic obesity
Genetic syndromes also contributes obesity.Significantly impaired intellectual and adaptive functioning, dysmorphic features, anomalies in the development is most commonly observed in severe obesity.

"Fat mass and obesity-associated" (FTO) gene
It is located in chromosome 16.This gene is associated with appetite in humans."High-risk" FTO variants are the most susceptible with an increase in age.There is an 20-30% increase obesity risk for the varients.A specific highrisk variant is rs1421085.Fat mass and obesity-associated protein is an enzyme (encoded by the FTO gene), identified in 2007 [12,13 ].It has been observed that highfat food is a preferable choice for its carriers.They become obese with advance in age [19].

Figure -3 Proposed mechanism of action of FTO in controlling obesity
Although human genes have not changed more but rising obesity cases may be a result of changed environmental factors -physical, social, political, economic surroundings.These factors determines our physical activity, food habbit and eating behavior causes the recent surge of overweight and obesity [18].Research showed physically active individuals can counterbalance the effects of one obesitypromoting gene (FTO varient) [20,21].