GSK3 is a negative regulator of the thermogenic program in brown adipocytes
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GSK3 is a negative regulator of the thermogenic program in brown adipocytes. / Markussen, Lasse K.; Winther, Sally; Wicksteed, Barton; Hansen, Jacob B.
In: Scientific Reports, Vol. 8, 3469, 2018, p. 1-12.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GSK3 is a negative regulator of the thermogenic program in brown adipocytes
AU - Markussen, Lasse K.
AU - Winther, Sally
AU - Wicksteed, Barton
AU - Hansen, Jacob B.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-018-21795-y
DO - 10.1038/s41598-018-21795-y
M3 - Journal article
C2 - 29472592
VL - 8
SP - 1
EP - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 3469
ER -
ID: 198725866