Abstract
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.
Highlights
The discovery of active brown adipose tissue (BAT) in healthy adults has revitalized the concept of combating metabolic dysfunction via recruitment and activation of brown adipocytes[1,2,3]
Fgf[21] expression is controlled by activating transcription factor 2 (ATF2), which in turn is activated by β-adrenergic stimulation in a cAMP-protein kinase A (PKA)-mitogen activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK-dependent manner[10]
In line with previous reports[10,11,12], we found that cold exposure strongly increased Fgf[21] expression in thermogenesis-capable adipose tissue depots (BAT and inguinal WAT (iWAT)) and only to a smaller extent in epididymal WAT (eWAT) (Fig. 1b)
Summary
The discovery of active brown adipose tissue (BAT) in healthy adults has revitalized the concept of combating metabolic dysfunction via recruitment and activation of brown adipocytes[1,2,3]. BAT is classically activated by cold, which through sympathetic nervous system-mediated release of norepinephrine at the surface of brown adipocytes activates β-adrenergic receptors. This activation results in augmented lipolysis, mitochondrial uncoupling, oxygen consumption and thermogenesis. In mice, activated BAT promotes glucose and triacylglycerol clearance, improves insulin sensitivity and glucose tolerance, and counteracts obesity[1,2,3] Most of these effects of brown adipocytes depend on their high mitochondrial density, the unique presence of uncoupling protein 1 (UCP1) in the inner mitochondrial membrane and a high oxidative capacity[1,2,3]. Inhibition of GSK3 unleashes thermogenic signaling in brown adipocytes, an observation pointing to GSK3 as a potentially interesting target in metabolic diseases
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