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.

Data availability

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

Article and author information

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.

Reviewing Editor

  1. Nicola Napoli, Campus Bio-Medico University of Rome, Italy

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).

Version history

  1. Received: July 16, 2021
  2. Preprint posted: August 10, 2021 (view preprint)
  3. Accepted: January 9, 2022
  4. Accepted Manuscript published: January 11, 2022 (version 1)
  5. Version of Record published: January 20, 2022 (version 2)
  6. Version of Record updated: January 25, 2022 (version 3)
  7. Version of Record updated: March 22, 2022 (version 4)

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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    Relationship between circulating FSH levels and body composition and bone health in patients with prostate cancer who undergo androgen deprivation therapy: The BLADE study

    Marco Bergamini, Alberto Dalla Volta ... Alfredo Berruti
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    Background:

    Among its extragonadal effects, follicle-stimulating hormone (FSH) has an impact on body composition and bone metabolism. Since androgen deprivation therapy (ADT) has a profound impact on circulating FSH concentrations, this hormone could potentially be implicated in the changes of fat body mass (FBM), lean body mass (LBM), and bone fragility induced by ADT. The objective of this study is to correlate FSH serum levels with body composition parameters, bone mineral density (BMD), and bone turnover markers at baseline conditions and after 12 months of ADT.

    Methods:

    Twenty-nine consecutive non-metastatic prostate cancer (PC) patients were enrolled from 2017 to 2019 in a phase IV study. All patients underwent administration of the luteinizing hormone-releasing hormone antagonist degarelix. FBM, LBM, and BMD were evaluated by dual-energy x-ray absorptiometry at baseline and after 12 months of ADT. FSH, alkaline phosphatase, and C-terminal telopeptide of type I collagen were assessed at baseline and after 6 and 12 months. For outcome measurements and statistical analysis, t-test or sign test and Pearson or Spearman tests for continuous variables were used when indicated.

    Results:

    At baseline conditions, a weak, non-significant, direct relationship was found between FSH serum levels and FBM at arms (r = 0.36) and legs (r = 0.33). Conversely, a stronger correlation was observed between FSH and total FBM (r = 0.52, p = 0.006), fat mass at arms (r = 0.54, p = 0.004), and fat mass at trunk (r = 0.45, p = 0.018) assessed after 12 months. On the other hand, an inverse relationship between serum FSH and appendicular lean mass index/FBM ratio was observed (r = −0.64, p = 0.001). This is an ancillary study of a prospective trial and this is the main limitation.

    Conclusions:

    FSH serum levels after ADT could have an impact on body composition, in particular on FBM. Therefore, FSH could be a promising marker to monitor the risk of sarcopenic obesity and to guide the clinicians in the tailored evaluation of body composition in PC patients undergoing ADT.

    Funding:

    This research was partially funded by Ferring Pharmaceuticals. The funder had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data and in preparation, review, or approval of the manuscript.

    Clinical trial number:

    clinicalTrials.gov NCT03202381, EudraCT Number 2016-004210-10.

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    Research Article

    Background:

    End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.

    Methods:

    The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.

    Results:

    Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.

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    Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.

    Funding:

    F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.