Obesity genes: Molecular and metabolic mechanisms

Within the past 3 years, all of the extant single-gene mutations resulting in obesity in rodents have been cloned. These mutations are Yellow, obese, diabetes, fat, and tubby. The rat fatty mutation, as predicted by earlier mapping experiments, is a molecular homologue of the mouse mutation diabetes. The fundamental principles of the physiology of energy metabolism, and the phenotypes of these animals in particular, suggested that their obesity must reflect alterations in any or all of the following processes: energy intake, energy expenditure, or the partitioning of energy between adipose tissue and lean tissues. Transgenic animals exemplifying discrete aberrations in each one of these processes confirm this conceptual framework. The early characterizations of the respective genes in the mutant rodents have elucidated novel, heretofore unknown, components of systems for the regulation and maintenance of body fat, in terms of both absolute fat mass as well as the relative amount of fat as a percentage of body mass. All of these newly identified genes have highly conserved human homologues that presumably play roles in comparable systems in humans. Genetic linkage and mutation studies are underway to test this possibility. Meanwhile, the further characterization of these mutations will undoubtedly lead to the discovery of new molecules as well as molecular links to known systems involved in mediating their effects on body fat content.