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

Yi Chen, Xing Zeng, Xuan Huang, Sara Serag, Clifford J. Woolf, Bruce M. Spiegelman

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)836-848.e13
JournalCell
Volume171
Issue number4
DOIs
StatePublished - Nov 2 2017
Externally publishedYes

Keywords

  • Adrenergic signaling
  • Brown fat
  • Calcium influx
  • Kcnk3
  • lipolysis
  • PKA signaling
  • Prdm16
  • Task-1
  • Thermogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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