Obesity: Genetics


Obesity is a disorder of energy balance. In obese individuals, there is excess body fat accumulation, which can lead to myriad health problems. The dysregulation of energy intake (appetite) and energy expenditure (activity) in obesity remains incompletely understood, but studies in humans and in model systems clearly demonstrate a strong genetic component to this condition. Within the past decade, major progress has been made in characterising the genetic component of obesity, with genome‐wide association studies revealing the most loci, including identifying the strongest association signal harboured within the FTO gene. Such studies have thus provided greater insight into the aetiology of this complex trait and are aiding in making diagnostic and therapeutic inroads into this common health concern.

Key Concepts

  • Obesity is characterised by an accumulation of excess adipose tissue that has myriad adverse health effects in virtually every organ system.
  • The rising global prevalence of obesity, particularly in developing nations and in children, is worrisome and incompletely understood.
  • Despite clear environmental contributions to disease risk, obesity is highly heritable.
  • In so‐called ‘syndromic’ genetic forms of obesity, genetic changes lead to obesity along with involvement of other organ systems. In ‘non‐syndromic’ obesity, genetic changes lead to an obesity‐predominant phenotype. Animal models of these conditions have led to important insights on the hypothalamic control of appetite.
  • Technological advances have led to the ability to perform genome‐wide association studies and identify novel genes and pathways related to obesity.
  • The complex interaction between genetics/epigenetics and myriad factors including the microbiome, diet/environment, physical activity and circadian rhythm may hold clues as to what individualised therapeutics may improve prevention and treatment of this highly morbid condition.

Keywords: body mass index; polygenic; hypothalamus; genome‐wide association studies (GWAS); leptin

Figure 1. Homeostasis feedback loop. After a meal, the nutrients, carbohydrates and fat are absorbed by the digestive tract and are used by the cells of the body to maintain themselves and to support the activities of the organism. Excess nutrient energy is stored primarily as fat in the adipose tissue. Leptin is released into the bloodstream from the adipose cells in proportion to these fat stores. Blood leptin levels may also be modulated by insulin, whose levels rise after a meal. Leptin will bind to the leptin receptor in the hypothalamus. Certain hypothalamic cell clusters (nuclei) contain neurons that express several known orexigenic (appetite stimulating) and anorexigenic (appetite repressing) peptides. Leptin is able to turn on or activate anorexigenic peptides while also inactivating or downregulating orexigenic peptides. Upon leptin stimulation (through receptor binding), the anorexigenic peptide POMC is processed to a smaller peptide, α‐melanocyte stimulating hormone (α‐MSH). Binding of α‐MSH to the melanocortin 4 receptor (MC4R) in turn signals satiety.
Figure 2. Cartoon of known obesity pathways in the hypothalamic satiety centre. Shown here are neurons located in the hypothalamic nuclei around the third ventricle and some of their axonal projections. Key molecules and the steps disturbed in the mouse obesity mutations are indicated. ob, leptin mutation; db, diabetes mutation; fat, Cpefat mutation; Ay, lethal yellow mutation; ARC, arcuate nucleus; PVN, paraventricular nucleus; LH, lateral hypothalamus; VMH, ventromedial hypothalamus; LEPR, leptin receptor; INSR, insulin receptor; NPY, neuropeptide Y; AGRP, agouti‐related protein; POMC, proopiomelanocortin; CART, cocaine amphetamine‐regulated transcript; MSH, melanin‐stimulating hormone; MC4R, melanocortin 4 receptor; NPYR, neuropeptide Y receptor; DA, dopamine; MCH, melanin‐concentrating hormone; OX, orexin.


Ahima RS and Lazar MA (2013) Physiology. The health risk of obesity – better metrics imperative. Science 341 (6148): 856–858. Epub 2013/08/24. doi: 10.1126/science.1241244. PubMed PMID: 23970691.

Asai M, Ramachandrappa S, Joachim M, et al. (2013) Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341 (6143): 275–278. Epub 2013/07/23. doi: 10.1126/science.1233000. PubMed PMID: 23869016; PubMed Central PMCID: PMC3788688.

Bachmann‐Gagescu R, Mefford HC and Cowan C et al., (2010) Recurrent 200‐kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genetics in Medicine : Official Journal of the American College of Medical Genetics 12: 641–647

Bailey SM, Udoh US and Young ME (2014) Circadian regulation of metabolism. The Journal of Endocrinology 222 (2): R75–R96. Epub 2014/06/15. doi: 10.1530/JOE-14-0200. PubMed PMID: 24928941; PubMed Central PMCID: PMC4109003.

Cox LM, Yamanishi S, Sohn J, et al. (2014) Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158 (4): 705–721. Epub 2014/08/16. doi: 10.1016/j.cell.2014.05.052. PubMed PMID: 25126780; PubMed Central PMCID: PMC4134513.

Cupul‐Uicab LA, Klebanoff MA, Brock JW and Longnecker MP (2013) Prenatal exposure to persistent organochlorines and childhood obesity in the US collaborative perinatal project. Environmental Health Perspectives 121 (9): 1103–1109. Epub 2013/06/27. doi: 10.1289/ehp.1205901. PubMed PMID: 23799652; PubMed Central PMCID: PMC3764072.

Everett LJ and Lazar MA (2014) Nuclear receptor Rev‐erbalpha: up, down, and all around. Trends in Endocrinology and Metabolism: TEM. Epub 2014/07/30. doi: 10.1016/j.tem.2014.06.011. PubMed PMID: 25066191

Ferrannini E, Rosenbaum M and Leibel RL (2014) The threshold shift paradigm of obesity: evidence from surgically induced weight loss. The American Journal of Clinical Nutrition 100 (4): 996–1002. Epub 2014/08/08. doi: 10.3945/ajcn.114.090167. PubMed PMID: 25099551.

Galassi A, Reynolds K and He J (2006) Metabolic syndrome and risk of cardiovascular disease: a meta‐analysis. The American Journal of Medicine 119 (10): 812–819. Epub 2006/09/27. doi: 10.1016/j.amjmed.2006.02.031. PubMed PMID: 17000207.

Gohir W, Ratcliffe EM and Sloboda DM (2014Epub 2014/10/15. doi: 10.1038/pr.2014.169. PubMed PMID: 25314580) Of the bugs that shape us: maternal obesity, the gut microbiome, and long‐term disease risk. Pediatric Research.

Hu FB, Li TY, Colditz GA, Willett WC and Manson JE (2003) Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA 289 (14): 1785–1791. Epub 2003/04/10. doi: 10.1001/jama.289.14.1785. PubMed PMID: 12684356.

Janesick AS, Shioda T and Blumberg B (2014) Transgenerational inheritance of prenatal obesogen exposure. Molecular and Cellular Endocrinology. Epub 2014/09/15. doi: 10.1016/j.mce.2014.09.002. PubMed PMID: 25218215

Johnson RJ, Nakagawa T, Sanchez‐Lozada LG, et al. (2013) Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62 (10): 3307–3315. Epub 2013/09/26. doi: 10.2337/db12-1814. PubMed PMID: 24065788; PubMed Central PMCID: PMC3781481.

Loos RJ and Yeo GS (2014) The bigger picture of FTO: the first GWAS‐identified obesity gene. Nature Reviews Endocrinology 10 (1): 51–61. Epub 2013/11/20. doi: 10.1038/nrendo.2013.227. PubMed PMID: 24247219; PubMed Central PMCID: PMC4188449.

Malik AN and Czajka A (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13 (5): 481–492. Epub 2012/10/23. doi: 10.1016/j.mito.2012.10.011. PubMed PMID: 23085537.

Nardelli C, Labruna G, Liguori R, et al. (2013) Haplogroup T is an obesity risk factor: mitochondrial DNA haplotyping in a morbid obese population from southern Italy. BioMed Research International. 2013: 631082 Epub 2013/08/13. doi: 10.1155/2013/631082. PubMed PMID: 23936828; PubMed Central PMCID: PMC3713591.

Ng M, Fleming T, Robinson M, et al. (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384 (9945): 766–781. Epub 2014/06/02. doi: 10.1016/S0140-6736(14)60460-8. PubMed PMID: 24880830.

Ogden CL, Carroll MD and Flegal KM (2014) Prevalence of obesity in the United States. JAMA: The Journal of the American Medical Association 312 (2): 189–190. Epub 2014/07/10. doi: 10.1001/jama.2014.6228. PubMed PMID: 25005661.

Polednak AP (2008) Estimating the number of U.S. incident cancers attributable to obesity and the impact on temporal trends in incidence rates for obesity‐related cancers. Cancer Detection and Prevention 32 (3): 190–199. Epub 2008/09/16. doi: 10.1016/j.cdp.2008.08.004. PubMed PMID: 18790577.

Romero‐Corral A, Caples SM, Lopez‐Jimenez F and Somers VK (2010) Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest 137 (3): 711–719. Epub 2010/03/06. doi: 10.1378/chest.09-0360. PubMed PMID: 20202954; PubMed Central PMCID: PMC3021364.

Schauer PR, Bhatt DL, Kirwan JP, et al. (2014) Bariatric surgery versus intensive medical therapy for diabetes – 3‐year outcomes. The New England Journal of Medicine 370 (21): 2002–2013. Epub 2014/04/01. doi: 10.1056/NEJMoa1401329. PubMed PMID: 24679060.

Smemo S, Tena JJ, Kim KH, et al. (2014) Obesity‐associated variants within FTO form long‐range functional connections with IRX3. Nature 507 (7492): 371–375. Epub 2014/03/22. doi: 10.1038/nature13138. PubMed PMID: 24646999; PubMed Central PMCID: PMC4113484.

Stunkard AJ, Harris JR, Pedersen NL and McClearn GE (1990) The body‐mass index of twins who have been reared apart. The New England Journal of Medicine 322 (21): 1483–1487. Epub 1990/05/24. doi: 10.1056/NEJM199005243222102. PubMed PMID: 2336075.

Tang‐Peronard JL, Heitmann BL, Andersen HR, et al. (2014) Association between prenatal polychlorinated biphenyl exposure and obesity development at ages 5 and 7 y: a prospective cohort study of 656 children from the Faroe Islands. The American Journal of Clinical Nutrition 99 (1): 5–13. Epub 2013/10/25. doi: 10.3945/ajcn.113.066720. PubMed PMID: 24153349; PubMed Central PMCID: PMC3862459.

Wadden TA, Webb VL, Moran CH and Bailer BA (2012) Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy. Circulation 125 (9): 1157–1170. Epub 2012/03/07. doi: 10.1161/CIRCULATIONAHA.111.039453. PubMed PMID: 22392863; PubMed Central PMCID: PMC3313649.

Further Reading

Beales PR, Sadaf Farooqi I and O'Rahilly S (eds) (2009) Genetics of Obesity Syndromes. Oxford Monographs on Medical Genetics. Vol. 56. Oxford: Oxford University Press.

Clément K and Sørensen TIA (2008) Obesity: Genomics and Postgenomics. New York: Informa Healthcare.

Grant SFA (ed) (2014) The Genetics of Obesity. New York, NY: Springer.

Taubes G (2011) Why We Get Fat: And What To Do About It. Anchor: New York, NY.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Grant, Struan FA, and McCormack, Shana E(Apr 2015) Obesity: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005567.pub2]