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The effects of calcium channel blockade on agouti-induced obesity
J H Kim1, R L Mynatt, J W Moore
1Department of Nutrition, University of Tennessee, Knoxville 37996, USA.
Abstract:
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.
Insights
Calcium channel blockade may help reduce obesity caused by the agouti gene. This treatment decreased fat pad weight and fatty acid synthase activity in obese mice, suggesting a role for calcium in agouti-driven metabolic changes.
Area of Science:
- Biochemistry
- Genetics
- Physiology
Background:
- Obese viable yellow (Avy/a) mice show increased intracellular calcium ([Ca2+]i) and fatty acid synthase (FAS) gene expression.
- Recombinant agouti protein increases in cultured adipocytes, with effects inhibited by calcium channel blockade.
Purpose of the Study:
- To investigate the effect of calcium channel blockade on fatty acid synthase (FAS) and obesity in transgenic mice ubiquitously expressing the agouti gene.
- To determine if calcium plays a role in agouti-mediated obesity and metabolic regulation.
Main Methods:
- Utilized transgenic mice expressing the agouti gene ubiquitously.
- Administered nifedipine (a calcium channel blocker) for 4 weeks to assess its impact on obesity and FAS.
- Compared physiological parameters (weight, core temperature, fat pad weight, FAS activity, insulin levels) between treated and control groups.
Main Results:
- Transgenic mice exhibited higher weight, lower core temperature, increased fat pad weights, elevated adipose FAS activity, and higher plasma insulin levels compared to controls.
- Nifedipine treatment significantly decreased fat pad weights and adipose FAS activity in transgenic mice.
- Nifedipine normalized insulin levels and insulin sensitivity and transiently elevated core temperature in transgenic mice, with no effect on control mice.
Conclusions:
- Agouti appears to regulate FAS, fat storage, and potentially thermogenesis, at least partially through a calcium-dependent mechanism.
- Calcium channel blockade demonstrates potential in partially attenuating agouti-induced obesity.
- These findings highlight the role of intracellular calcium in metabolic regulation influenced by the agouti protein.