Obesity: Genetics

Abstract

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.
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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.

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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]