ACE2 pathway regulates thermogenesis and energy metabolism

eLife

Xi Cao¹  Fang-Yuan Yang¹  Yi-Chen Zhang¹  Ting-Ting Shi¹  Jing-Yi Liu¹  Jin-Kui Yang¹  Li-Ni Song¹  Charles N Rotimi²  Chuan-Hai Zhang³  Wan-Zhu Jin⁴  Aimin Xu⁵ 

[1] Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China;Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States;Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, United States;Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, and State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, Hong Kong, China;

关键词: ACE2;    angiotensin-(1-7);    obesity;    brown adipose tissue;    diabetes;    thermogenesis;   

DOI  :  10.7554/eLife.72266

来源: DOAJ

【 摘 要 】

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids, and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

【 授权许可】

Unknown