ABSTRACT
Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation 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 up-regulation 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 ß-adrenergic receptors (ßAR) 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 up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1 Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the ßAR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.
Subject(s)
Adipocytes, Beige/metabolism , Cold Temperature , Fatty Acids/metabolism , Glycerol Kinase/metabolism , Second Messenger Systems , Thermogenesis , Transcriptional Activation , Uncoupling Protein 1/biosynthesis , Adipocytes, Beige/cytology , Animals , Cyclic AMP/genetics , Cyclic AMP/metabolism , Fatty Acids/genetics , Glycerol Kinase/genetics , Isoproterenol/pharmacology , Male , Mice , Stearoyl-CoA Desaturase/genetics , Stearoyl-CoA Desaturase/metabolism , Uncoupling Protein 1/geneticsABSTRACT
In this study, we investigated the effects of interleukin-1ß (IL-1ß), a typical proinflammatory cytokine on the ß-adrenoreceptor-stimulated induction of uncoupling protein 1 (UCP1) expression in adipocytes. IL-1ß mRNA expression levels were upregulated in white adipose tissues of obese mice and in RAW264.7 macrophages under conditions designed to mimic obese adipose tissue. Isoproterenol-stimulated induction of UCP1 mRNA expression was significantly inhibited in C3H10T1/2 adipocytes by conditioned medium from lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in comparison with control conditioned medium. This inhibition was significantly attenuated in the presence of recombinant IL-1 receptor antagonist and IL-1ß antibody, suggesting that activated macrophage-derived IL-1ß is an important cytokine for inhibition of ß-adrenoreceptor-stimulated UCP1 induction in adipocytes. IL-1ß suppressed isoproterenol-induced UCP1 mRNA expression in C3H10T1/2 adipocytes, and this effect was partially but significantly abrogated by inhibition of extracellular signal-regulated kinase (ERK). IL-1ß also suppressed the isoproterenol-induced activation of the UCP1 promoter and transcription factors binding to the cAMP response element. Moreover, intraperitoneal administration of IL-1ß suppressed cold-induced UCP1 expression in adipose tissues. These findings suggest that IL-1ß upregulated in obese adipose tissues suppresses ß-adrenoreceptor-stimulated induction of UCP1 expression through ERK activation in adipocytes.
