Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes.

Browning, of adipose tissue is induced by specific stimuli such as cold exposure and consists of upregulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 upregulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo. Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the beta-adrenergic receptors (betaAR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was upregulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 downregulation and POA treatment downregulated Iso-activated Ucp1. Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the betaAR-cAMP-CREB pathway and on Gyk-mediated regulation of fatty acid metabolism.