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

• Published in: Scientific reports 2018-02, Vol.8 (1), p.3469-12, Article 3469
• Main Authors: Markussen, Lasse K., Winther, Sally, Wicksteed, Barton, Hansen, Jacob B.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/44; 13/89; 13/95; 38; 38/1; 38/77; 631/80/86; 692/163/2743; Activating transcription factor 2; Adipocytes; Adipocytes, Brown - metabolism; Adipose tissue; Adipose tissue (brown); Animals; Cyclic AMP-Dependent Protein Kinases - genetics; Down-regulation; Energy Metabolism - genetics; Enzyme inhibitors; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Gene Expression Regulation - drug effects; Glucose - metabolism; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - genetics; Homeostasis; Humanities and Social Sciences; Insulin; Insulin Resistance - genetics; Kinases; MAP kinase; MAP Kinase Signaling System - genetics; Metabolic disorders; Mice; multidisciplinary; Oxygen consumption; Oxygen Consumption - genetics; Phosphorylation; Primary Cell Culture; Protein kinase A; Protein Kinase Inhibitors - administration & dosage; Proteins; Receptors, Adrenergic, beta - genetics; Science; Science (multidisciplinary); Signal Transduction - drug effects; Thermogenesis - genetics; Uncoupling protein 1; Uncoupling Protein 1 - genetics
• ISSN: 2045-2322; 2045-2322
• 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.