COMBINED EFFECTS OF INSULIN-TREATMENT AND ADIPOSE TISSUE-SPECIFIC AGOUTI EXPRESSION ON THE DEVELOPMENT OF OBESITY

The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals, Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression o f agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus, The human agouti protein is 8 5% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue, To address wheth er expression of agouti in human adipose tissue is physiologically rel evant, transgenic mice were generated that express agouti in adipose t issue. Similar to most humans, these mice do not become obese or diabe tic, However, we found that daily insulin injections significantly inc reased weight gain in the transgenic lines expressing agouti in adipos e tissue, but not in nontransgenic mice, These results suggest that in sulin triggers the onset of obesity and that agouti expression in adip ose tissue potentiates this effect, Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus i n mice holds significant promise for understanding the pathophysiology of human obesity.