AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1

• Published in: Nature cell biology Vol. 23; no. 3; pp. 268 - 277
• Main Authors: Shi, Meng, Huang, Xiao-Yu, Ren, Xin-Yi, Wei, Xiao-Yan, Ma, Yue, Lin, Zhi-Zhong, Liu, Dong-Tai, Song, Lintao, Zhao, Tong-Jin, Li, Guang, Yao, Luming, Zhu, Mingxia, Zhang, Cixiong, Xie, Changchuan, Wu, Yaying, Wu, Han-Ming, Fan, Li-Ping, Ou, Jingxing, Zhan, Yi-Hong, Lin, Shu-Yong, Lin, Sheng-Cai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2021; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/106; 13/109; 13/44; 13/89; 13/95; 14/19; 14/28; 38/70; 38/77; 631/337/458; 631/443/319; 631/80/86; 64/60; 82/29; 82/80; 82/83; 96/34; Adaptive systems; Adipocytes, Brown - metabolism; Adiponectin - genetics; Adiponectin - metabolism; Adipose Tissue, Brown - innervation; Animals; Autonomic nervous system; Biomedical and Life Sciences; Cancer Research; Carrier proteins; Catecholamine; Catecholamines; Cell Biology; Cells, Cultured; Cellular signal transduction; Cold; Cyclic AMP-Dependent Protein Kinases - metabolism; Denervation; Depletion; Developmental Biology; Energy Metabolism; Fibers; Hypothermia; Innervation; Kinases; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Nervous system, Sympathetic; Non-shivering; Oxidation; Oxidation-Reduction; Phospholipid Transfer Proteins - deficiency; Phospholipid Transfer Proteins - genetics; Phospholipid Transfer Proteins - metabolism; Phosphorylation; Physiological aspects; Physiological research; Protein kinase A; Protein kinases; Proteins; Shivering; Signal Transduction; Signaling; Stem Cells; Sympathetic nervous system; Sympathetic Nervous System - physiology; Thermogenesis; Uncoupling protein 1; Uncoupling Protein 1 - deficiency; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism; China
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-021-00642-9

The sympathetic nervous system–catecholamine–uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida -knockout mice. The PKA–AIDA–UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis. Shi et al. show that following adrenergic signalling, PKA phosphorylates AIDA, which in turn interacts with and promotes oxidation of UCP1 to regulate UCP1-dependent adaptive thermogenesis.