The effects of calcium channel blockade on agouti-induced obesity.
We have previously observed that obese viable yellow (Avy/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 effect of Ca2+ channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the agouti gene in a ubiquitous manner. The transgenic mice initially 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 (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<0.05) compared to control mice. Nifedipine 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 circulating insulin levels and insulin sensitivity (P<0.05), 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.
Kim
J H
JH
Department of Nutrition, University of Tennessee, Knoxville 37996, USA.
Mynatt
R L
RL
Moore
J W
JW
Woychik
R P
RP
Moustaid
N
N
Zemel
M B
MB
D000273:Adipose Tissue; D054366:Agouti Signaling Protein; D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009543:Nifedipine / Q000008:administration & dosage*; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D054366:Agouti Signaling Protein; D002121:Calcium Channel Blockers; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C515183:a protein, mouse; D064429:Fatty Acid Synthases; D009543:Nifedipine