1. Medicine

ACE2 pathway regulates thermogenesis and energy metabolism

  1. Xi Cao
  2. Tingting Shi
  3. Chuanhai Zhang
  4. Wanzhu Jin
  5. Lini Song
  6. Yichen Zhang
  7. Jingyi Liu
  8. Fangyuan Yang
  9. Charles N Rotimi
  10. Aimin Xu
  11. Jinkui Yang  Is a corresponding author
  1. Capital Medical University, China
  2. University of Texas Meical Center at Dallas, United States
  3. Chinese Academy of Sciences, China
  4. National Institutes of Health, United States
  5. University of Hong Kong, Hong Kong
https://doi.org/10.7554/eLife.72266
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Cite this article
  1. Xi Cao
  2. Tingting Shi
  3. Chuanhai Zhang
  4. Wanzhu Jin
  5. Lini Song
  6. Yichen Zhang
  7. Jingyi Liu
  8. Fangyuan Yang
  9. Charles N Rotimi
  10. Aimin Xu
  11. Jinkui Yang
(2022)
ACE2 pathway regulates thermogenesis and energy metabolism
eLife 11:e72266.
https://doi.org/10.7554/eLife.72266
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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 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.

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

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Author details

  1. 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.

  2. 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.

  3. Chuanhai Zhang

    Department of Physiology, University of Texas Meical Center at Dallas, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7644-2436

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Aimin Xu

    Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong
    Competing interests
    The authors declare that no competing interests exist.

  11. 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.
    ORCID icon "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.

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  1. Xi Cao
  2. Tingting Shi
  3. Chuanhai Zhang
  4. Wanzhu Jin
  5. Lini Song
  6. Yichen Zhang
  7. Jingyi Liu
  8. Fangyuan Yang
  9. Charles N Rotimi
  10. Aimin Xu
  11. Jinkui Yang
(2022)
ACE2 pathway regulates thermogenesis and energy metabolism
eLife 11:e72266.
https://doi.org/10.7554/eLife.72266

Share this article

https://doi.org/10.7554/eLife.72266

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    Pyrotinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (PERSIST): A multicenter phase II trial

    Feilin Cao, Zhaosheng Ma ... Shifen Huang
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    Background:

    Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.

    Methods:

    This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate.

    Results:

    Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%).

    Conclusions:

    Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit.

    Funding:

    No external funding was received for this work.

    Clinical trial number:

    ClinicalTrials.gov: NCT05880927

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