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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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 metabolic responses of fat cells to nutrients. To establish the role of endogenous BKs for fat cell maturation, storage of excess dietary fat and body-weight (BW) gain we studied a gene-targeted mouse model with a global ablation of the BK channel (BKL1/L1) and adipocyte-specific BK-deficient (adipoqBKL1/L2) mice. Global BK deficiency afforded protection from high-fat-diet (HFD) induced BW gain and excessive fat accumulation. Expansion of white adipose tissue-derived epididymal BKL1/L1 pre-adipocytes and their differentiation to lipid-filled mature adipocytes in vitro, however, were improved. Moreover, BW gain and total fat masses of usually super-obese 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 mutants presented with a reduced total BW and overall body fat mass, smaller adipocytes and reduced leptin levels. Protection from pathologic weight gain in the absence of adipocyte BKs was beneficial for glucose handling and related to an increase in body core temperature due to higher levels of uncoupling protein 1 as well as low abundance of the proinflammatory interleukin-6 as 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-caloric conditions suggesting BK channels as promising drug targets for pharmacotherapy of metabolic disorders and obesity.
Original languageEnglish
JournalDiabetes
DOIs
Publication statusPublished - 7 Sep 2016

Keywords

  • white adipose tissue
  • brown adipose tissue
  • epididymal WAT
  • interscapular WAT
  • interscapular BAT
  • 3T3-L1 cells
  • pre-adipocytes
  • hormone-sensitive lipase
  • interleukin-6
  • uncoupling protein 1
  • adiponectin

Cite this

Illison, J., Tian, L., McClafferty, H., Werno, M., Chamberlain, L. H., Leiss, V., Sassmann, A., Offermanns, S., Ruth, P., Shipston, M. J., & Lukowski, R. (2016). Obesogenic and diabetogenic effects of high-calorie nutrition require adipocyte BK channels. Diabetes. https://doi.org/10.2337/db16-0245