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Sci Rep. 2018 Jul 20;8(1):11001. doi: 10.1038/s41598-018-29333-6.

Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis.

Author information

1
Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA, 94158, USA.
2
Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, 52 Haidian Road, Beijing, 100871, China.
3
Department of Diabetes Complications and Metabolism, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
4
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, 94158, USA.
5
California Institute for Quantitative Biosciences, QBI, University of California, San Francisco, San Francisco, CA, 94158, USA.
6
J. David Gladstone Institutes, San Francisco, CA, 94158, USA.
7
Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA, 94158, USA. biao.wang@ucsf.edu.

Abstract

Various physiological stimuli, such as cold environment, diet, and hormones, trigger brown adipose tissue (BAT) to produce heat through sympathetic nervous system (SNS)- and β-adrenergic receptors (βARs). The βAR stimulation increases intracellular cAMP levels through heterotrimeric G proteins and adenylate cyclases, but the processes by which cAMP modulates brown adipocyte function are not fully understood. Here we described that specific ablation of cAMP production in brown adipocytes led to reduced lipolysis, mitochondrial biogenesis, uncoupling protein 1 (Ucp1) expression, and consequently defective adaptive thermogenesis. Elevated cAMP signaling by sympathetic activation inhibited Salt-inducible kinase 2 (Sik2) through protein kinase A (PKA)-mediated phosphorylation in brown adipose tissue. Inhibition of SIKs enhanced Ucp1 expression in differentiated brown adipocytes and Sik2 knockout mice exhibited enhanced adaptive thermogenesis at thermoneutrality in an Ucp1-dependent manner. Taken together, our data indicate that suppressing Sik2 by PKA-mediated phosphorylation is a requisite for SNS-induced Ucp1 expression and adaptive thermogenesis in BAT, and targeting Sik2 may present a novel therapeutic strategy to ramp up BAT thermogenic activity in humans.

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