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.
Original language | English (US) |
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Pages (from-to) | 836-848.e13 |
Journal | Cell |
Volume | 171 |
Issue number | 4 |
DOIs | |
State | Published - Nov 2 2017 |
Externally published | Yes |
Keywords
- Adrenergic signaling
- Brown fat
- Calcium influx
- Kcnk3
- PKA signaling
- Prdm16
- Task-1
- Thermogenesis
- lipolysis
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology