THE POLYGENETICS OF DIABESITY IN MICE

This review describes major advances in our understanding of the molec ular bases for monogenic obesity mutations capable of producing obesit y-induced diabetes, or diabesity. In almost all of the mouse models of diabesity we review, males are more severely affected than females, H ypercorticism induced by mutations in either the leptin (Lep(ob)) or l eptin receptor (Lepr(db)) genes affects aberrant transregulation of ge nes encoding sex steroid metabolizing enzymes. These changes reduce th e ratio of hepatic estrogens to androgens by inducing an estrogen sulf otransferase that is not constitutively expressed in mouse liver, effe ctively virilizing hepatic metabolism, An insulin-responsive male diab esity syndrome elicited by a missense mutation in the carboxypeptidase E gene (Cpe(fat)) represents the first demonstration that a defect in prohormone processing in endocrine and neuroendocrine cells underlies development of both obesity and diabetes, Mouse models of polygenic o besity and male sex-dependent diabesity are also reviewed, A growing n umber of loci contributing to spontaneous and diet-induced polygenic o besity and identified by quantitative trait locus analysis are discuss ed, Inbred strains (e.g., NON, NZO) carrying separate genetic suscepti bility for impaired glucose tolerance and obesity are used to illustra te how multiple components of susceptibility inherited from each paren t mag underlie the ''garden variety'' NIDDM in humans, Techniques for identifying the genes contributing to this diabetogenic synergism in s egregating F-2 and backcross generations are discussed.