ECTOPIC EXPRESSION OF THE AGOUTI GENE IN TRANSGENIC MICE CAUSES OBESITY, FEATURES OF TYPE-II DIABETES, AND YELLOW FUR

Mice that carry the lethal yellow (A(y)) or viable yellow (A(vy)) muta tion, two dominant mutations of the agouti (a) gene in mouse chromosom e 2, exhibit a phenotype that includes yellow fur, marked obesity, a f orm of type II diabetes associated with insulin resistance, and an inc reased susceptibility to tumor development, Molecular analyses of thes e and several other dominant ''obese yellow'' a-locus mutations sugges ted that ectopic expression of the normal agouti protein gives rise to this complex pleiotropic phenotype, We have now tested this hypothesi s directly by generating transgenic mice that ectopically express an a gouti cDNA clone encoding the normal agouti protein in all tissues exa mined. Transgenic mice of both sexes have yellow fur, become obese, an d develop hyperinsulinemia. In addition, male transgenic mice develop hyperglycemia by 12-20 weeks of age, These results demonstrate conclus ively that the ectopic agouti expression is responsible for most, if n ot all, of the phenotypic traits of the dominant, obese yellow mutants .