[Genomic approach to obesity: understanding a complex syndrome]

Obesity is a multifactoral condition. Environmental risk factors related to sedentary lifestyle and unlimited access to food apply constant pressure in subjects with a genetic make-up predisposing to gaining weight. Recent genetic studies have demonstrated a continuum among the different forms of human obesity: certain cases, mainly very severe forms beginning in childhood, are monogenic conditions transmitted by recessive inheritance, the environment simply playing a permissive role. Other more frequent mutations, such as mutation of the melanocortin receptor 4 gene, have variable expression, but inactivity is sufficient to lead to early eating disorders. The common forms of obesity are however polygenic. The extreme pressure of the modern environment over-runs the capacity of homeostatic adaptation in individuals genetically predisposed to obesity, leading to an energy imbalance favoring energy storage in the form of fat; Certain candidate genes such as decoupling proteins, adrenergic beta-3 receptor, or regions regulating the leptin gene play a minor role in the development or aggravation of obesity. Recently, "whole genome" screening in families of obese subjects has localized major obesity genes on chromosomes 2, 5, 10, 11 and 20. Their identification using techniques of positional cloning and functional genomics will help better understand the molecules determining obesity and define targets for future therapy.