ACE2 pathway regulates thermogenesis and energy metabolism

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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 Lepr^db/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.

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All data generated or analysed during this study are included in the manuscript and supporting file.

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Xi Cao

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Tingting Shi

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Chuanhai Zhang

Department of Physiology, University of Texas Meical Center at Dallas, Dallas, United States

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7644-2436
Wanzhu Jin

Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Lini Song

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Yichen Zhang

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Jingyi Liu

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Fangyuan Yang

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Charles N Rotimi

National Human Genome Research Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Aimin Xu

Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong

Competing interests
The authors declare that no competing interests exist.
Jinkui Yang

Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China

For correspondence
jkyang@ccmu.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5430-2149

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.