Androgen receptor suppresses ?-adrenoceptor-mediated CREB activation and thermogenesis in brown adipose tissue of male mice

Thermoregulation is a process by which core body temper-ature is maintained in mammals. Males typically have a lower body temperature than females. However, the effects of androgens, which show higher levels in males, on adrenergic receptor-mediated thermogenesis remain unclear. Here, we demonstrate that androgen-androgen receptor (AR) signaling suppresses the beta-adrenergic agonist-induced rise of core body temperature using castrated and AR knockout (ARKO) male mice. Furthermore, in vitro mechanistic studies show that activated AR inhibits cAMP response element (CRE)-mediated transcription by suppressing cAMP response element-binding protein (CREB) phosphorylation. The elevation of body tem-perature induced by the beta-adrenergic agonist CL316243 was higher in ARKO and castrated mice than in the control mice. Similarly, CL316243 induced a greater increase in Uncoupling protein 1 (Ucp1) expression and CREB phosphorylation in the brown adipose tissue of ARKO mice than in that of controls. We determined that activation of AR by dihydrotestosterone suppressed beta 3-agonist-or forskolin-induced CRE-mediated transcription, which was prevented by AR antagonist. AR activation also suppressed CREB phosphorylation induced by forskolin. Moreover, we found AR nuclear localization, but not transcriptional activity, was necessary for the suppression of CRE-mediated transcription. Finally, modified mammalian two-hybrid and immunoprecipitation analyses suggest nuclear AR and CREB form a protein complex both in the presence and absence of dihydrotestosterone and forskolin. These results suggest androgen-AR signaling suppresses beta-adrenoceptor-induced UCP1-mediated brown adipose tissue thermogenesis by suppressing CREB phosphorylation, presumably owing to a protein complex with AR and CREB. This mechanism explains sexual differences in body temperature, at least partially.

Automated summary

This study found that males have lower body temperature compared to females, and the androgen-androgen receptor (AR) signaling suppresses adrenergic receptor-mediated thermogenesis, providing an explanation for sexual differences in body temperature.