Date of Award
Doctor of Philosophy
Michael B. Zemel
Jay Whelan, Naima Moustaid, Richard P. Woychik
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 (Avy), 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 Avy 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.
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.