Antagonism of T-type calcium channels inhibits high-fat diet–induced weight gain in mice
Victor N. Uebele, … , Kenneth S. Koblan, John J. Renger
Victor N. Uebele, … , Kenneth S. Koblan, John J. Renger
Published May 18, 2009
Citation Information: J Clin Invest. 2009;119(6):1659-1667. https://doi.org/10.1172/JCI36954.
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Research Article Metabolism

Antagonism of T-type calcium channels inhibits high-fat diet–induced weight gain in mice

Abstract

The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking CaV3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet–induced weight gain, without changes in food intake or sensitivity to high-fat diet–induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet–induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity.

Authors

Victor N. Uebele, Anthony L. Gotter, Cindy E. Nuss, Richard L. Kraus, Scott M. Doran, Susan L. Garson, Duane R. Reiss, Yuxing Li, James C. Barrow, Thomas S. Reger, Zhi-Qiang Yang, Jeanine E. Ballard, Cuyue Tang, Joseph M. Metzger, Sheng-Ping Wang, Kenneth S. Koblan, John J. Renger

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Figure 6

TTA-A2 decreases inactive phase food intake and accentuates diurnal rhythms in core temperature and activity during HFD.

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TTA-A2 decreases inactive phase food intake and accentuates diurnal rhyt...
C57BL/6NTac mice fed HFD for 2 weeks with vehicle treatment were subsequently treated orally with either 10 mg/kg TTA-A2 (open symbols, n = 8) or vehicle (filled symbols, n = 8) 30 minutes prior to lights off. (A and B) Percent body weight change relative to day 0 of TTA-A2 treatment (A) and HFD consumption (B) were assessed every 12 hours at dark-to-light and light-to-dark transitions. #P < 0.05, *P < 0.01, §P < 0.001, TTA-A2 versus vehicle; 2-way ANOVA and Bonferroni post-test. (C and D) Continuous radio telemetry core temperature from individual animals was averaged (C), and beam break–derived locomotor activity was summed over 30-minute intervals (D). Core temperature and activity measures for all 7 days were averaged and plotted on a 24-hour Zeitgeiber time scale, with lights-off periods indicated by black bars along the x axis. Gray bars above denote significant 30-minute time points (P < 0.05, mixed linear effects model for repeated measures). Data are mean ± SEM.