The Journal of Nutrition Vol. 127 No. 9 September 1997, pp. 1897S-1901S
Copyright ©1997 by the American Society for Nutritional Sciences

Obesity as a Pleiotropic Effect of Gene Action

George L. Wolff

National Center for Toxicological Research, Food and Drug Administration, U.S. Department of Health and Human Services, Jefferson, AR 72079 and Departments of Biochemistry/Molecular Biology and Pharmacology/Interdisciplinary Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205

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 Lep^ob/Lep^ob and A^vy/- "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 Lep^ob/Lep^ob syndrome mimics juvenile-onset obesity, whereas the A^vy/- syndrome resembles maturity-onset obesity. The A^vy/- syndrome has its basis in overabundance of agouti protein, whereas the Lep^ob/Lep^ob syndrome results from a lack of active leptin hormone. Lep^ob/Lep^ob mice have a smaller lean body mass, whereas A^vy/- mice have a larger lean body mass than their respective lean siblings. Lep^ob/Lep^ob mice have fewer lung and mammary tumors than their lean Lep/- littermates, and A^vy/- develop more mammary and lung tumors than their lean A/- or a/a siblings. Lep^ob/Lep^ob mice are infertile or sterile, whereas A^vy/- mice are fertile. Thus, although adult Lep^ob/Lep^ob and A^vy/- mice are both obese, many of the other morphologic and physiologic attributes of one mutant are diametrically opposite to those of the other.

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