Obesogenic and diabetogenic effects of high-calorie nutrition require adipocyte BK channels

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Illison, Julia and Tian, Lijun and McClafferty, Heather and Werno, Martin and Chamberlain, Luke H. and Leiss, Veronika and Sassmann, Antonia and Offermanns, Stefan and Ruth, Peter and Shipston, Michael J. and Lukowski, Robert (2016) Obesogenic and diabetogenic effects of high-calorie nutrition require adipocyte BK channels. Diabetes, 65 (12). pp. 3621-3635. ISSN 0012-1797 (https://doi.org/10.2337/db16-0245)

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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.

ORCID iDs

Illison, Julia, Tian, Lijun, McClafferty, Heather, Werno, Martin, Chamberlain, Luke H. ORCID logoORCID: https://orcid.org/0000-0002-8701-4995, Leiss, Veronika, Sassmann, Antonia, Offermanns, Stefan, Ruth, Peter, Shipston, Michael J. and Lukowski, Robert;
  • Item type:Article
    ID code:57760
    Dates:
    Date
    Event
    31 December 2016
    Published
    7 September 2016
    Published Online
    15 August 2016
    Accepted
    Notes:This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version is available at http://dx.doi.org/10.2337/db16-0245
    Subjects:Medicine > Therapeutics. Pharmacology
    Science > Physiology
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:12 Sep 2016 13:36
    Last modified:11 Nov 2024 11:31
    URI:https://strathprints.strath.ac.uk/id/eprint/57760
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