@article{712759929e924aee89727af5a2db8b30,
title = "Crosstalk between KCNK3-Mediated Ion Current and Adrenergic Signaling Regulates Adipose Thermogenesis and Obesity",
abstract = "Adrenergic stimulation promotes lipid mobilization and oxidation in brown and beige adipocytes, where the harnessed energy is dissipated as heat in a process known as adaptive thermogenesis. The signaling cascades and energy-dissipating pathways that facilitate thermogenesis have been extensively described, yet little is known about the counterbalancing negative regulatory mechanisms. Here, we identify a two-pore-domain potassium channel, KCNK3, as a built-in rheostat negatively regulating thermogenesis. Kcnk3 is transcriptionally wired into the thermogenic program by PRDM16, a master regulator of thermogenesis. KCNK3 antagonizes norepinephrine-induced membrane depolarization by promoting potassium efflux in brown adipocytes. This limits calcium influx through voltage-dependent calcium channels and dampens adrenergic signaling, thereby attenuating lipolysis and thermogenic respiration. Adipose-specific Kcnk3 knockout mice display increased energy expenditure and are resistant to hypothermia and obesity. These findings uncover a critical K+-Ca2+-adrenergic signaling axis that acts to dampen thermogenesis, maintain tissue homeostasis, and reveal an electrophysiological regulatory mechanism of adipocyte function. Putting the brakes on adipose thermogenesis takes a potassium channel to limit calcium flux.",
keywords = "Adrenergic signaling, Brown fat, Calcium influx, Kcnk3, PKA signaling, Prdm16, Task-1, Thermogenesis, lipolysis",
author = "Yi Chen and Xing Zeng and Xuan Huang and Sara Serag and Woolf, {Clifford J.} and Spiegelman, {Bruce M.}",
note = "Funding Information: This investigation has been aided by the JPB Foundation and National Institutes of Health (DK31405 to B.M.S.) and grants from the Jane Coffin Childs Memorial Fund for Medical Research (Y.C.), American Heart Association (X.Z.), and Yousef Jameel Ph.D. Scholarship at AUC (S.S.). We acknowledge B. Hu and D. Laznik-Bogoslavski for technical assistance. We thank R. Chang, E.T. Chouchani, P. Cohen, MY. Pecot, P. Purgserver, and ED. Rosen for discussions. We also thank D. Bayliss for providing Kcnk3-floxed and global knockout mice and ED. Rosen for UCP1-cre mice. We thank the Nikon Imaging Center at Harvard Medical School for Microscopy assistance. Funding Information: This investigation has been aided by the JPB Foundation and National Institutes of Health ( DK31405 to B.M.S.) and grants from the Jane Coffin Childs Memorial Fund for Medical Research (Y.C.), American Heart Association (X.Z.), and Yousef Jameel Ph.D. Scholarship at AUC (S.S.). We acknowledge B. Hu and D. Laznik-Bogoslavski for technical assistance. We thank R. Chang, E.T. Chouchani, P. Cohen, MY. Pecot, P. Purgserver, and ED. Rosen for discussions. We also thank D. Bayliss for providing Kcnk3-floxed and global knockout mice and ED. Rosen for UCP1-cre mice. We thank the Nikon Imaging Center at Harvard Medical School for Microscopy assistance. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = nov,
day = "2",
doi = "10.1016/j.cell.2017.09.015",
language = "English (US)",
volume = "171",
pages = "836--848.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}