ABSTRACT
Genetic studies in humans and experimental ndings from mice suggest that satiety, energy intake, expenditure, and deposition are regulated by the integration of central nervous system and peripheral organs, particularly the hypothalamus and through the hypothalamic actions of factors derived from metabolic organs such as the adipose tissue. The outcome of the studies on family-based linkage analyses of monogenic (Mendelian) disorders (with severe and early-onset obesity) and common forms of population-based obesity studies links excess body weight and adiposity to an extreme tilting of an “adipostatic set point” at which body fat stores are normally stabilized.1 For example, mutations associated with extreme and early-onset obesity were discovered in leptin (LEP), leptin receptor (LEPR), and melanocortin 4 receptor (MC4R) genes, all of which target the hypothalamic regulatory circuits.2-5 Genome-wide population genetic studies contributed to the identication of additional mutations in genes that also target the central nervous system or other endocrine pathways, although the effect size in general is rather small.6-10 While the majority of genetic studies support a strong genetic component, the target pathways remain to be established in obesity in concert with environmental inuences and interactions between peripheral endocrine signals. There is yet a lack of evidence of signicant associations between obesity and genetic variations related to intrinsic factors such as the basal metabolic rate, energy expenditure, or the drive to exercise.10,11 These are important areas of current research efforts in experimental systems as well as in humans, and they indicate the power of the homeostatic drive to establish equilibrium, which is resistant to most single assaults.
