Ml. Klebig et al., ECTOPIC EXPRESSION OF THE AGOUTI GENE IN TRANSGENIC MICE CAUSES OBESITY, FEATURES OF TYPE-II DIABETES, AND YELLOW FUR, Proceedings of the National Academy of Sciences of the United Statesof America, 92(11), 1995, pp. 4728-4732
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
.