Restored TDCA and valine levels imitate the effects of bariatric surgery

  1. Markus Quante
  2. Jasper Iske
  3. Timm Heinbokel
  4. Bhavna N Desai
  5. Hector Rodriguez Cetina Biefer
  6. Yeqi Nian
  7. Felix Krenzien
  8. Tomohisa Matsunaga
  9. Hirofumi Uehara
  10. Ryoichi Maenosono
  11. Haruhito Azuma
  12. Johann Pratschke
  13. Christine S Falk
  14. Tammy Lo
  15. Eric Sheu
  16. Ali Tavakkoli
  17. Reza Abdi
  18. David Perkins
  19. Maria-Luisa Alegre
  20. Alexander S Banks
  21. Hao Zhou
  22. Abdallah Elkhal
  23. Stefan G Tullius  Is a corresponding author
  1. Division of Transplant Surgery & Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, United States
  2. Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Germany
  3. Institute of Transplant Immunology, Hannover Medical School, Germany
  4. Department of Pathology, Charité Universitätsmedizin Berlin, Germany
  5. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, United States
  6. Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Germany
  7. Department of Urology, The Second Xiangya Hospital, Central South University, China
  8. Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Germany
  9. Department of Urology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Japan
  10. Division of Gastrointestinal and General Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, United States
  11. Renal Division, Brigham and Women’s Hospital, Harvard Medical School, United States
  12. Division of Nephrology, Department of Medicine, University of Illinois at Chicago, United States
  13. Department of Medicine, Section of Rheumatology, The University of Chicago, United States

Peer review process

This article was accepted for publication as part of eLife's original publishing model.

History

  1. Version of Record published
  2. Accepted Manuscript published
  3. Accepted
  4. Received

Decision letter

  1. Ralph J DeBerardinis
    Reviewing Editor; UT Southwestern Medical Center, United States
  2. David E James
    Senior Editor; The University of Sydney, Australia
  3. Ralph J DeBerardinis
    Reviewer; UT Southwestern Medical Center, United States

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.

Acceptance summary:

The authors used metabolomics to identify Valine and TDCA as metabolites depleted in diet-induced obesity (DIO) and replenished after sleeve gastrectomies (SGx) in mice. Intraperioneal injection of these two metabolites mimics many of the benefits of SGx, including weight loss, reduced adipose stores and insulin sensitivity. These benefits are related to Val/TDCA's ability to reduce food intake without altering locomotor activity, leading to a negative energy balance. Val/TDCA injection eliminated the fasting-associated rise in hypothalamic MCH expression in obese mice, and central injections of recombinant MCH blunted weight loss induced by Val/TDCA. Overall, this paper suggests a role for Val and/or TDCA in regulating food intake through MCH.

Decision letter after peer review:

Thank you for submitting your article "Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, including Ralph J DeBerardinis as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by David James as the Senior Editor.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

As the editors have judged that your manuscript is of interest, but as described below that additional experiments are required before it is published, we would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). First, because many researchers have temporarily lost access to the labs, we will give authors as much time as they need to submit revised manuscripts. We are also offering, if you choose, to post the manuscript to bioRxiv (if it is not already there) along with this decision letter and a formal designation that the manuscript is "in revision at eLife". Please let us know if you would like to pursue this option. (If your work is more suitable for medRxiv, you will need to post the preprint yourself, as the mechanisms for us to do so are still in development.)

Summary:

In the paper, the authors used metabolomics to identify Valine and TDCA as metabolites depleted in diet-induced obesity (DIO) and replenished after sleeve gastrectomies (SGx) in mice. Intraperioneal injection of these two metabolites mimics many of the benefits of SGx, including weight loss, reduced adipose stores and insulin sensitivity. These benefits are related to Val/TDCA's ability to reduce food intake without altering locomotor activity, leading to a negative energy balance. Val/TDCA injection eliminated the fasting-associated rise in hypothalamic MCH expression in obese mice, and central injections of recombinant MCH blunted weight loss induced by Val/TDCA. Overall, this paper reports interesting and surprising observations related to the impact of metabolomic disturbances in obesity, and suggests a role for Val and/or TDCA in regulating food intake through MCH.

Essential revisions:

1. It is unclear from the data whether the effects are derived from valine, TDCA, or both. Both reviewers felt that any reader would want to see experiments where either of these metabolites is injected alone.

2. No quantitative metabolite concentration values are provided anywhere, making it difficult to evaluate the robustness of the data. How much do the levels of TDCA and valine change with SGx in mice and humans, and what levels are achieved with the injections of these metabolites in the mice?

https://doi.org/10.7554/eLife.62928.sa1

Author response

Essential revisions:

1. It is unclear from the data whether the effects are derived from valine, TDCA, or both. Both reviewers felt that any reader would want to see experiments where either of these metabolites is injected alone.

We appreciate this comment and have now included novel in vivo experiments in which we treated high fat diet (HFD)-induced obese mice with TDCA alone, valine alone or both TDCA+valine (Supp. Figure 1).

2. No quantitative metabolite concentration values are provided anywhere, making it difficult to evaluate the robustness of the data. How much do the levels of TDCA and valine change with SGx in mice and humans, and what levels are achieved with the injections of these metabolites in the mice?

We agree with the reviewers that absolute concentrations of TDCA and valine constitute essential data. Therefore, we have now quantified absolute concentrations of TDCA and valine in lean, DIO and DIO mice that were treated with TDCA and/or valine. The data have been now included in Figure 3A.

https://doi.org/10.7554/eLife.62928.sa2

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  1. Markus Quante
  2. Jasper Iske
  3. Timm Heinbokel
  4. Bhavna N Desai
  5. Hector Rodriguez Cetina Biefer
  6. Yeqi Nian
  7. Felix Krenzien
  8. Tomohisa Matsunaga
  9. Hirofumi Uehara
  10. Ryoichi Maenosono
  11. Haruhito Azuma
  12. Johann Pratschke
  13. Christine S Falk
  14. Tammy Lo
  15. Eric Sheu
  16. Ali Tavakkoli
  17. Reza Abdi
  18. David Perkins
  19. Maria-Luisa Alegre
  20. Alexander S Banks
  21. Hao Zhou
  22. Abdallah Elkhal
  23. Stefan G Tullius
(2021)
Restored TDCA and valine levels imitate the effects of bariatric surgery
eLife 10:e62928.
https://doi.org/10.7554/eLife.62928

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https://doi.org/10.7554/eLife.62928