THE EFFECTS OF CALCIUM-CHANNEL BLOCKADE ON AGOUTI-INDUCED OBESITY

We have previously observed that obese viable yellow (A(vy)/a) mice ex hibit 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 effect of Ca2+ channel block ade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expres sing the agouti gene in a ubiquitous manner, The transgenic mice initi ally were significantly heavier (30.5+/-0.6 vs, 27.3+/-0.3 g; P<0.001) and exhibited a 0.81 degrees C lower initial core temperature (B<0,00 05), an approximately twofold increase in fat pad weights (P=0,002), a sevenfold increase in adipose FAS activity (P=0,009), and a twofold i ncrease in plasma insulin level (P<0,05) compared to control mice. Nif edipine treatment resulted in an 18% decrease in fat pad weights (P<0. 007) and a 74% decrease in adipose FAS activity (P=0.03), normalized c irculating insulin levels and insulin sensitivity (P<0,05), and transi ently elevated core temperature in the transgenic mice, but was withou t 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 p artially attenuate agouti-induced obesity.