Crosstalk between KCNK3-Mediated Ion Current and Adrenergic Signaling Regulates Adipose Thermogenesis and Obesity

Abstract

Summary 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 counter-balancing 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 to dampen thermogenesis and maintain tissue homeostasis and reveal an electrophysiological regulatory mechanism of adipocyte function.

The Protective Effects of Danggui-Baizhu-Tang on High-Fat Diet-Induced Obesity in Mice by Activating Thermogenesis

“…And the emergency of beige adipocytes in white fat depots is named browning of white adipose tissue ( Harms and Seale, 2013 ). In recent years, strategies that regulate WAT browning remain an alternative approach for increasing energy expenditure and decreasing obesity ( Tseng et al, 2010 ; Harms and Seale, 2013 ; Chen Y. et al, 2017 ). Herbal medicines are explored to combat obesity by promoting thermogenesis ( Zhang et al, 2014 ; Chen G. et al, 2017 ).…”

The glycoprotein follistatin-like 1 promotes brown adipose thermogenesis

“…While most current medications and surgery for obesity target calorie intake and absorption, increasing energy consumption is being considered an attractive alternative [1,2]. Brown adipose tissue (BAT) has a remarkable energy dissipating capacity and actively promotes triglyceride clearance, glucose disposal, and generation of heat for thermogenesis [3,4]. The thermogenic activity of BAT depends on its high mitochondrial content and uncoupling protein 1 (UCP1), which uncouples the mitochondrial proton gradient from ATP synthesis to generate heat [5,6].…”

Role of Thermo-Sensitive Transient Receptor Potential Channels in Brown Adipose Tissue

“…53) Membrane hyperpolarization by activation of a two-pore domain potassium channel (KCNK3) reduced Ca 2+ -influx and impaired adrenergic receptor-mediated thermogenesis in brown adipocytes. 54 …”