Agouti regulation of intracellular calcium: Role in the insulin resistance of viable yellow mice
- Univ. of Tennessee, Knoxville, TN (United States)
- Oak Ridge National Laboratory, Oak Ridge, TN (United States)
- Research Institute, Research Triangle Park, NC (United States)
Several dominant mutations at the agouti locus in the mouse cause a syndrome of marked obesity, hyperinsulinemia, and insulin resistance. Although it is known that the agouti gene is expressed in an ectopic manner in these mutants, the precise mechanism by which the agouti gene product mediates these effects is unclear. Since intracellular Ca{sup 2+} is believed to play a role in mediating insulin action and dysregulation of Ca{sup 2+} flux is observed in diabetic animals and humans, we examined the status of intracellular Ca{sup 2+} in mice carrying the dominant agouti allele, viable yellow (A{sup vy}). We show here that in mice carrying this mutation, the intracellular free calcium concentration ([Ca{sup 2+}]{sub i}) is elevated in skeletal muscle, and the degree of elevation is closely correlated with the degree to which the mutant traits are expressed in individual animals. Moreover, we demonstrate that the agouti gene product is capable of inducing increased [Ca{sup 2+}]{sub 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 polypeptide promotes insulin resistance in mutant animals through its ability to increase [Ca{sup 2+}]{sub i}. 36 refs., 3 figs., 2 tabs.
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-84OR21400
- OSTI ID:
- 75384
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, Issue 11; Other Information: PBD: 23 May 1995
- Country of Publication:
- United States
- Language:
- English
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