Genes and the hypothalamic control of metabolism in humans

Heritability of obesity and body weight variation is high. Molecular genetic studies have led to the identification of mutations in a few genes, with a major effect on obesity (major genes and monogenic forms). Analyses of these genes have helped to unravel important pathways and have created a more profound understanding of body weight regulation. For most individuals, a polygenic basis is relevant for the genetic predisposition to obesity. Small effect sizes are conveyed by the polygenic variants. Hence, only if a number of these variants is harboured, a sizeable phenotypic effect is detectable. Most, if not all, of the genes relevant to weight regulation are expressed in the hypothalamus. This underscores the major role of this region of the brain in body weight regulation.