Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels

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Abstract

Elevated adipose tissue expression of the Ca2+- and voltage-activated K+ (BK) channel was identified in morbidly obese men carrying a BK gene variant, supporting the hypothesis that K+ channels affect the metabolic responses of fat cells to nutrients. To establish the role of endogenous BKs in fat cell maturation, storage of excess dietary fat, and body weight (BW) gain, we studied a gene-targeted mouse model with global ablation of the BK channel (BKL1/L1) and adipocyte-specific BK-deficient (adipoqBKL1/L2) mice. Global BK deficiency afforded protection from BW gain and excessive fat accumulation induced by a high-fat diet (HFD). Expansion of white adipose tissue–derived epididymal BKL1/L1 preadipocytes and their differentiation to lipid-filled mature adipocytes in vitro, however, were improved. Moreover, BW gain and total fat masses of usually superobese ob/ob mice were significantly attenuated in the absence of BK, together supporting a central or peripheral role for BKs in the regulatory system that controls adipose tissue and weight. Accordingly, HFD-fed adipoqBKL1/L2 mutant mice presented with a reduced total BW and overall body fat mass, smaller adipocytes, and reduced leptin levels. Protection from pathological weight gain in the absence of adipocyte BKs was beneficial for glucose handling and related to an increase in body core temperature as a result of higher levels of uncoupling protein 1 and a low abundance of the proinflammatory interleukin-6, a common risk factor for diabetes and metabolic abnormalities. This suggests that adipocyte BK activity is at least partially responsible for excessive BW gain under high-calorie conditions, suggesting that BK channels are promising drug targets for pharmacotherapy of metabolic disorders and obesity.

Footnotes

• This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0245/-/DC1.

• Received February 26, 2016.
• Accepted August 16, 2016.

• © 2016 by the American Diabetes Association.

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January 2017, 66(1) Article Alerts Email Article Citation Tools Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels Julia Illison, Lijun Tian, Heather McClafferty, Martin Werno, Luke H. Chamberlain, Veronika Leiss, Antonia Sassmann, Stefan Offermanns, Peter Ruth, Michael J. Shipston, Robert Lukowski

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