The effects of calcium channel blockade on agouti-induced obesity

We have previously observed that obese viable yellow (A(vy)/a) mice exhibit increased intracellular Ca²⁺ ([Ca²⁺](i)) and fatty acid synthase (FAS) gene expression; further, recombinant agouti protein increases in cultured adipocytes and these effects are inhibited by Ca²⁺ channel blockade. Accordingly, we determined the affect of Ca²⁺ channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the agouti gene in a ubiquitous manner. The trasgenic mice initially were significantly heavier (30.5 ± 0.6 vs. 27.3 ± 0.3 g; P < 0.001) and exhibited a 0.81°C lower initial core temperature (P < 0.0005), an approximately twofold increase in fat pad weights (P = 0.002), a sevenfold increase in adipose FAS activity (P = 0.009), and a twofold increase in plasma insulin level (P < 0.005)compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P < 0.0007) and a 74% decrease in adipose FAS activity (P = 0.03), normalized circulating insulin levels and insulin sensitivity (P < 0.005), and transiently elevated core temperature in the transgenic mice, but was without effect in the control mice. These data suggest that agouti regulates FAS, fat storage, and possibly thermogenesis, at least partially, via a [Ca²⁺](i)-dependent mechanism, and that Ca²⁺ channel blockade may partially attenuate agouti- induced obesity.