ACE2 pathway regulates thermogenesis and energy metabolism
- Capital Medical University, China
- University of Texas Meical Center at Dallas, United States
- Chinese Academy of Sciences, China
- National Institutes of Health, United States
- University of Hong Kong, Hong Kong
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file.
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Author details
Funding
National Natural Science Foundation of China (81930019,81561128015)
- Jinkui Yang
National Natural Science Foundation of China (81670774,82070850)
- Xi Cao
Beijing natural science foundation (7162047)
- Xi Cao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal protocols used in this study were reviewed and approved by the Ethics Committee of Animal Research at Beijing Tongren Hospital, Capital Medical University (#2017-0107).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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ACE2 pathway regulates thermogenesis and energy metabolism
eLife 11:e72266.
https://doi.org/10.7554/eLife.72266
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