Endocrine Abstracts (2010) 22 PL8

An update on the genetics of obesity

Stephen O’Rahilly

University of Cambridge, Cambridge, UK.

The recent and rapid increase in the prevalence of obesity in most developed and developing countries has correctly focused attention on environmental determinants of that secular trend. However, a fuller understanding of the factors determining any individual person’s adiposity requires appropriate consideration of inheritance. Studies of twins, adoptees and adopted twins provide incontrovertible evidence that heritable factors play a major, perhaps even the major factor, in determining a person’s fatness. Until recently, the precise mechanisms whereby such genes might influence fatness were obscure. However, in the past decade we have witnessed an explosion of information regarding the molecular mechanisms underlying the control of mammalian energy balance. That information, much of it originating from animal models, is beginning to demonstrate its clear relevance to human energy balance. Thus, defects in several individual genes have now been demonstrated to result in human obesity. One of these (MC4R deficiency) is not uncommon, being responsible for up to 5% of severe obesity in childhood, and one rare form (congenital leptin deficiency) is amenable to life-saving treatment. Importantly, the vast majority of single gene defects causing human obesity do so through the impairment of satiety. Evidence is accumulating that more subtle genetic variants affecting these pathways underlie susceptibility and resistance to common forms of obesity in the general population. Far from encouraging a mood of deterministic nihilism, the more precise knowledge of biological pathways that genetic information provides should assist the prevention and treatment of human obesity by allowing the design of better therapies and improving the focus and precision of behavioural strategies for treatment and prevention.

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