Genetics of obesity: towards the understanding of a complex syndrome

Obesity is a multifactorial disease combining the effects of genetic predisposition with very powerful environmental risk factors. Recent genetic studies have demonstrated that there is a continuum between different forms of human obesity. SINGLE GENE FACTORS: In certain cases, mainly cases of very severe obesity with childhood onset, a single gene would play a permissive role allowing environmental factors to have major impact. Rare mutations of the leptin gene and its receptor, proopiomelanocortin, or more frequently, melanocortin receptor 4 mutations, are evidence of the existence of an obesity gene. Inactivity of this gene would be sufficient to produce early onset anomalous eating habits. COMMON OBESITY: The more common forms of obesity are however polygenic. The strong environmental pressure exceeds the capacity for homeostatic adaptation of genetically predisposed persons, leading to an energy imbalance favoring fat storage. WHICH GENES? Certain candidate genes, such as decoupling genes, beta-3 adrenergic receptor genes, or regulator regions of the leptin gene, play a minor role in the constitution or aggravation of overweight. Recently, "whole genome" explorations in obese families have localized major obesity genes on chromosomes 2, 5, 10, 11, and 20. Identification of these genes with positional cloning and functional genomic techniques will be helpful in better understanding the molecular determinants of obesity and better defining targets for new therapies.