Role of Intracellular Free Calcium in the Obesity and Insulin Resistance Associated with Dominant Agouti Mutations

Author

Jung Han Kim, University of Tennessee, Knoxville

Date of Award

8-1996

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Human Ecology

Major Professor

Michael B. Zemel

Committee Members

Jay Whelan, Naima Moustaid, Richard P. Woychik

Abstract

Several dominant mutations at the agouti locus in the mouse cause a syndrome of adult-onset obesity, hyperinsulinemia, and insulin resistance. Although ectopic overexpression of the agouti gene is directly responsible for the disease in these mutations, the precise mechanism is unclear. Intracellular Ca²⁺ ([Ca²⁺]i) appears to have a role in mediating insulin signal transduction, and altered handling of [Ca²⁺]i homeostasis and flux is observed in obese and insulin resistant animals and humans. Data reported here demonstrate that mice carrying the dominant agouti mutation, viable yellow (A^vy), exhibit an elevation of [Ca²⁺]i and Ca²⁺ influx rate in insulin-sensitive type I skeletal muscle. The degree of elevation in [Ca²⁺]i is highly correlated with the degree of expression of agouti gene and the elevation of body weight. Moreover, recombinant agouti protein directly induced a sustained increase in [Ca²⁺]i in cultured myocytes and adipocytes; this effect is substantially inhibited by Ca²⁺ channel blockade. Ca²⁺channel blockade was also effective in reducing fat pad mass and fatty acid synthase (FAS) mRNA levels and activity in adipocytes of transgenic mice expressing the agouti gene in a ubiquitous manner. These results are consistent with previous reports in which recombinant agouti protein directly stimulates FAS mRNA levels and activity and triglyceride content in cultured adipocytes in a Ca²⁺ dependent manner. Accordingly, altered [Ca²⁺]i metabolism appears to be involved in development of obesity syndrome in A^vy mice, and this defect in Ca²⁺ signaling may cause activation of FAS either directly or indirectly and subsequent de novo lipogenesis, contributing accumulation of fat depot in these mice.

Recommended Citation

Kim, Jung Han, "Role of Intracellular Free Calcium in the Obesity and Insulin Resistance Associated with Dominant Agouti Mutations. " PhD diss., University of Tennessee, 1996.
https://trace.tennessee.edu/utk_graddiss/3796