AIDA Regulates Adaptive Thermogenesis Of Brown Adipose Tissue Through UCP1

Adaptive thermogenesis is an important way used by homeothermic organisms to maintain body temperature in cold environment.The thermoregulatory center in the hypothalamus activates non-shivering thermogenesis through forcing sympathetic nervous system to secrete catecholamines after sensing cold stimulation.Non-shivering thermogenesis of the whole body mainly occurs in brown adipose tissue,which contains a large number of mitochondria,by which thermogenic protein UCP1 can consume proton gradient across the mitochondrial inner membrane for heat generation.However,the details of UCP1 activation by catecholamines are still unclear until now.We found that Aida global knockout(Aida-GKO)mice or Aida adipocyte-specific knockout(Aida-AKO)mice were significantly more sensitive to cold compared with their control mice.We also found that AIDA regulates body temperature via mediating the thermogenic activation of brown adipocytes caused by catecholamines.Mechanistically,we showed that upon norepinephrine treatment,AIDA is phosphorylated at Ser161 by PKA downstream the adrenergic signaling pathway in brown adipocytes.Phosphorylated AIDA interacts with UCP1 directly and promotes the uncoupling activity of UCP1 ultimately by enhancing cysteine oxidation of UCP1.In addition,PKA-AIDA-UCP1 axis is highly conserved in mammals.These findings indicate that AIDA plays an important role in UCP1-mediated thermogenic pathway activated by sympathetic nervous system.