AGOUTI REGULATION OF INTRACELLULAR CALCIUM - ROLE IN THE INSULIN-RESISTANCE OF VIABLE YELLOW MICE

Several dominant mutations at the agouti locus in the mouse cause a sy ndrome of marked obesity, hyperinsulinemia, and insulin resistance, Al though it is known that the agouti gene is expressed in an ectopic man ner in these mutants, the precise mechanism by which the agouti gene p roduct mediates these effects is unclear, Since intracellular Ca2+ is believed to play a role in mediating insulin action and dysregulation of Ca2+ flux is observed in diabetic animals and humans, we examined t he status of intracellular Ca2+ in mice carrying the dominant agouti a llele, viable yellow (A(vy)). We show here that in mice carrying this mutation, the intracellular free calcium concentration ([Ca2+](i)) is elevated in skeletal muscle, and the degree of elevation is closely co rrelated with the degree to which the mutant traits are expressed in i ndividual animals, Moreover, we demonstrate that the agouti gene produ ct is capable of inducing increased [Ca2+](i) in cultured and freshly isolated skeletal muscle myocytes from wild-type mice, Based on these findings, we present a model in which we propose that the agouti polyp eptide promotes insulin resistance in mutant animals through its abili ty to increase [Ca2+](i).