RRC ID 73024
Author Harada N, Kubo K, Onishi T, Kitakaze T, Goto T, Inui H, Yamaji R.
Title Androgen receptor suppresses β-adrenoceptor-mediated CREB activation and thermogenesis in brown adipose tissue of male mice.
Journal J Biol Chem
Abstract Thermoregulation is a process by which core body temperature is maintained in mammals. Males typically have a lower body temperature than females. However, the effects of androgens, sex hormones that show higher levels in males, on adrenergic receptor-mediated thermogenesis remains unclear. Here, we demonstrate that androgen-androgen receptor (AR) signaling suppresses the β-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 temperature induced by the β-adrenergic agonist CL316243 was higher in ARKO and castrated mice than in control mice. Similarly, CL316243 induced a greater increase in Uncoupling protein 1 (Ucp1) expression and CREB phosphorylation in the brown adipose tissue (BAT) of ARKO mice than in that of controls. We determined that activation of AR by dihydrotestosterone suppressed β3-agonist- or forskolin-induced CRE-mediated transcription, which was prevented by AR antagonist bicalutamide. 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 β-adrenoceptor-induced UCP1-mediated BAT thermogenesis by suppressing CREB phosphorylation, presumably owing to a protein complex with AR and CREB. This mechanism explains sex differences in body temperature, at least partially.
Volume 298(12)
Pages 102619
Published 2022-10-19
DOI 10.1016/j.jbc.2022.102619
PII S0021-9258(22)01062-6
PMID 36272644
PMC PMC9700029
IF 4.238
Mice RBRC01828