Departments of Pharmacology, University of Texas Health San Antonio, San Antonio, TX, USA.
Department of Metabolism and Endocrinology and the Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University and National Clinical Research center for Metabolic Diseases, Changsha, Hunan, China.
Commun Biol. 2020 May 22;3(1):257. doi: 10.1038/s42003-020-0986-1.
Obesity is a global epidemic that is caused by excessive energy intake or inefficient energy expenditure. Brown or beige fat dissipates energy as heat through non-shivering thermogenesis by their high density of mitochondria. However, how the mitochondrial stress-induced signal is coupled to the cellular thermogenic program remains elusive. Here, we show that mitochondrial DNA escape-induced activation of the cGAS-STING pathway negatively regulates thermogenesis in fat-specific DsbA-L knockout mice, a model of adipose tissue mitochondrial stress. Conversely, fat-specific overexpression of DsbA-L or knockout of STING protects mice against high-fat diet-induced obesity. Mechanistically, activation of the cGAS-STING pathway in adipocytes activated phosphodiesterase PDE3B/PDE4, leading to decreased cAMP levels and PKA signaling, thus reduced thermogenesis. Our study demonstrates that mitochondrial stress-activated cGAS-STING pathway functions as a sentinel signal that suppresses thermogenesis in adipose tissue. Targeting adipose cGAS-STING pathway may thus be a potential therapeutic strategy to counteract overnutrition-induced obesity and its associated metabolic diseases.
肥胖是一种全球性的流行病，是由能量摄入过多或能量消耗效率低下引起的。棕色或米色脂肪通过其高密度的线粒体通过非颤抖产热将能量以热量的形式消耗掉。然而，线粒体应激诱导的信号如何与细胞产热程序偶联仍然难以捉摸。在这里，我们表明线粒体 DNA 逃逸诱导的 cGAS-STING 途径的激活负调节脂肪特异性 DsbA-L 敲除小鼠（脂肪组织线粒体应激的模型）中的产热。相反，脂肪特异性过表达 DsbA-L 或敲除 STING 可保护小鼠免受高脂肪饮食诱导的肥胖。在机制上，脂肪细胞中 cGAS-STING 途径的激活激活了磷酸二酯酶 PDE3B/PDE4，导致 cAMP 水平和 PKA 信号降低，从而减少产热。我们的研究表明，线粒体应激激活的 cGAS-STING 途径作为一种哨兵信号，抑制脂肪组织中的产热。因此，靶向脂肪组织 cGAS-STING 途径可能是一种潜在的治疗策略，可对抗营养过剩引起的肥胖及其相关代谢疾病。
