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

Scientific Reports
Esther PauloBiao Wang

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 th...Continue Reading

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Citations

Aug 20, 2018·The Journal of Endocrinology·Esther PauloBiao Wang
Feb 28, 2020·The Journal of Clinical Investigation·Austin HsuSaptarsi M Haldar
Dec 7, 2019·Cells·Esther Paulo, Biao Wang
Jun 15, 2019·International Journal of Molecular Sciences·Ziguo SongChao Sun
Nov 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fabrizzio G GuajardoRamón Sotomayor-Zárate
Feb 20, 2021·Stem Cell Reports·Stefania CarobbioAntonio Vidal-Puig
Apr 19, 2021·The Journal of Biological Chemistry·Prasanna K R AlluDavid Pearce

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Datasets Mentioned

BETA
PXD009262

Methods Mentioned

BETA
flow cytometry
FACS

Software Mentioned

MaxQuant
GraphPad Prism

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