Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels.
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/L1preadipocytes 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/L2mutant 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.
Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, Tübingen, Germany.
Julia
J
Illison
Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, U.K.
Lijun
L
Tian
Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, U.K.
Heather
H
McClafferty
Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, U.K.
Martin
M
Werno
Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, U.K.
Luke H
LH
Chamberlain
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany.
Veronika
V
Leiss
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Antonia
A
Sassmann
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Stefan
S
Offermanns
Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, Tübingen, Germany.
Peter
P
Ruth
Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, U.K.
Michael J
MJ
Shipston
Pharmakologie, Toxikologie und Klinische Pharmazie, Institut für Pharmazie, Tübingen, Germany robert.lukowski@uni-tuebingen.de.
Robert
R
Lukowski
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004435:Eating / Q000235:genetics / Q000502:physiology; D004594:Electrophysiology; D005951:Glucose Tolerance Test; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D013696:Temperature
D051036:Large-Conductance Calcium-Activated Potassium Channels; D020738:Leptin