GSK3 is a negative regulator of the thermogenic program in brown adipocytes

Sci Rep. 2018 Feb 22;8(1):3469. doi: 10.1038/s41598-018-21795-y.


Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identified glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes. In addition, inhibition of GSK3 also caused increased Ucp1 expression and oxygen consumption. β-Adrenergic stimulation triggered an inhibitory phosphorylation of GSK3 in a protein kinase A (PKA)-dependent manner. Mechanistically, inhibition of GSK3 activated the mitogen activated protein kinase (MAPK) kinase 3/6-p38 MAPK-activating transcription factor 2 signaling module. In summary, our data describe GSK3 as a novel negative regulator of β-adrenergic signaling in brown adipocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / metabolism*
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Energy Metabolism / genetics
  • Fibroblast Growth Factors / genetics*
  • Gene Expression Regulation / drug effects
  • Glucose / metabolism
  • Glycogen Synthase Kinase 3 / genetics*
  • Insulin Resistance / genetics
  • MAP Kinase Signaling System / genetics
  • Mice
  • Oxygen Consumption / genetics
  • Primary Cell Culture
  • Protein Kinase Inhibitors / administration & dosage
  • Receptors, Adrenergic, beta / genetics
  • Signal Transduction / drug effects
  • Thermogenesis / genetics*
  • Uncoupling Protein 1 / genetics*


  • Protein Kinase Inhibitors
  • Receptors, Adrenergic, beta
  • Uncoupling Protein 1
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Cyclic AMP-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Glucose