Single gene obesities in rodents: possible relevance to human obesity.

Obesity is a complex phenotype which "resolves" the influences of genes, development and environment. In any individual - and in the same individual at different times of life - the relative influence of these factors may vary. In this sense, obesity is a prototype of many of the diseases now confronting medical science. Among the most important concepts regarding such phenotypes is the idea that relevant genes mediate susceptibility to disease in a specific environmental context, not the inevitable occurrence of the phenotype regardless of the environment. Individuals with otherwise potent genetic predisposition to obesity will be lean in an environment of food deprivation/high demand for physical activity, and individuals not genetically predisposed to obesity may become so in an environment that includes tasty, calorically dense foods and/or few inducements to physical activity. Thus, in any effort to elucidate the genetic bases for susceptibility to obesity, the "environment" in which the obesity is occurring remains a critical factor regarding what sorts of genes will be identified. Because the genes that mediate susceptibility to obesity may affect energy intake, energy expenditure and/or the partitioning of calories between lean tissues and fat, the ability to define the gross metabolic basis for the obesity is very important in determining which genes are relevant to the phenotype. Because it is so difficult to experimentally define/control the environment of humans, and because the attainment of an obese state may actually rectify the metabolic differences predisposing to obesity, animal models of obesity have been looked at intensively for clues to the relevant genes in humans. Over the past 40 years, a series of autosomal dominant (Yellow) and recessive (obese, diabetes, tubby, fat, fatty) obesity mutations have been described in mice and rats. The molecular cloning of all of these genes has been accomplished within the past 4 years, providing an exciting array of new reagents for the molecular analysis of obesity. These genes encode molecules that appear to interact in physiologic systems that influence body fat stores. The genes and their apparent functions are summarized in the Table . The locations of these genes in the genomes of rodents and human are known, as are their genetic structure/sequence. Thus, their role(s) in human obesity can now be assessed directly.