Combined a- and ß-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle.

Noradrenaline regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signaling downstream of ß-adrenergic receptor (ßAR) activation, how noradrenaline promotes thermogenic output is still not fully understood. Here, we show that coordinated a1-adrenergic receptor (a1AR) and ß3AR signaling induces the expression of thermogenic genes of the futile creatine cycle, and that EBFs, ERRs, and PGC1a are required for this response in vivo. Noradrenaline triggers physical and functional coupling between the a1AR subtype (ADRA1A) to Gaq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase b (CKB) and tissue-nonspecific alkaline phosphatase (TNAP). Combined Gaq and Gas signaling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and CKB is required for this effect. Thus, the ADRA1A-Gaq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis. Overall design: Comparative gene expression profiling analysis of RNA-seq data for brown adipose tissue (either 30°C or 6°C) with saline solution or PBZ injections.

去甲肾上腺素（Noradrenaline）可调控冷刺激诱导的脂肪细胞产热过程。除β-肾上腺素能受体（β-adrenergic receptor, βAR）激活下游的环磷酸腺苷（cyclic adenosine monophosphate, cAMP）信号通路外，去甲肾上腺素促进产热输出的完整机制仍未完全阐明。本研究证实，α1-肾上腺素能受体（α1-adrenergic receptor, α1AR）与β3-肾上腺素能受体（β3AR）的协同信号通路可诱导无效肌酸循环相关产热基因的表达，且EBFs、ERRs及PGC1α在体内该应答过程中发挥必需作用。去甲肾上腺素可触发α1AR亚型（ADRA1A）与Gaq的物理与功能偶联，通过依赖于无效肌酸循环效应蛋白——肌酸激酶b（creatine kinase b, CKB）及组织非特异性碱性磷酸酶（tissue-nonspecific alkaline phosphatase, TNAP）的信号轴，促进脂肪细胞产热。在脂肪细胞中联合激活Gaq与Gas信号通路可选择性地促使全身能量消耗持续升高，且该效应依赖于CKB。综上，ADRA1A-Gaq-无效肌酸循环轴是兼性产热与适应性产热的关键调控通路。整体实验设计：对分别置于30℃或6℃环境下的棕色脂肪组织，经生理盐水或PBZ注射处理后，进行RNA测序数据的比较基因表达谱分析。