Obesity as a pleiotropic effect of gene action.

Obesity, an easily detected and quantifiable phenotypic endpoint, is often considered, colloquially, as a disease. However, the study of obesity in rodents suggests that it is merely a convenient indicator of diverse underlying metabolic and physiologic dysregulations, rather than a disease entity in itself. To illustrate this concept, the differences between the murine Lepob/Lepob and Avy/- "obesity" syndromes are delineated. In both syndromes, pleiotropic effects of single mutations play a major role in altering the homeostatic regulation of energy metabolism and a myriad of extra- and intracellular processes in a diversity of tissues and cell types. The Lepob/Lepob syndrome mimics juvenile-onset obesity, whereas the Avy/- syndrome resembles maturity-onset obesity. The Avy/- syndrome has its basis in overabundance of agouti protein, whereas the Lepob/Lepob syndrome results from a lack of active leptin hormone. Lepob/Lepob mice have a smaller lean body mass, whereas Avy/- mice have a larger lean body mass than their respective lean siblings. Lepob/Lepob mice have fewer lung and mammary tumors than their lean Lep/- littermates, and Avy/- develop more mammary and lung tumors than their lean A/- or a/a siblings. Lepob/Lepob mice are infertile or sterile, whereas Avy/- mice are fertile. Thus, although adult Lepob/Lepob and Avy/- mice are both obese, many of the other morphologic and physiologic attributes of one mutant are diametrically opposite to those of the other.