1. Medicine
Download icon

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 L Perkins
  19. Maria-Luisa Alegre
  20. Alexander S Banks
  21. Hao Zhou
  22. Abdallah Elkhal
  23. Stefan G Tullius  Is a corresponding author
  1. Brigham and Women's Hospital, United States
  2. Beth Israel Deaconess Medical Center, United States
  3. Charité Universitätsmedizin Berlin, Germany
  4. Osaka Medical College, Japan
  5. Hannover Medical School, Germany
  6. University of Illinois at Chicago, United States
  7. Beth Israel Deaconess Medical Center and Harvard Medical School, United States
Research Article
  • Cited 2
  • Views 779
  • Annotations
Cite this article as: eLife 2021;10:e62928 doi: 10.7554/eLife.62928

Abstract

Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.

Methods: Metabolic profiling was performed on diet induced obese (DIO) mice, lean mice and DIO mice that underwent sleeve gastrectomies. In addition, mice were subjected to i.p. injections with TDCA and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with an MCH antagonist and intrathecal administration of melanin-concentrating hormone were performed and weight loss was monitored.

Results: Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-Valine levels were restored after sleeve gastrectomies (SGx) in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone.

Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

Data availability

All relevant data supporting the findings of this study are available as source data files.

Article and author information

Author details

  1. Markus Quante

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jasper Iske

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Timm Heinbokel

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bhavna N Desai

    Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hector Rodriguez Cetina Biefer

    Departrment of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Yeqi Nian

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Felix Krenzien

    Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Tomohisa Matsunaga

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Hirofumi Uehara

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ryoichi Maenosono

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Haruhito Azuma

    Urology, Osaka Medical College, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Johann Pratschke

    Department of Visceral, Abdominal and Transplantation Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Christine S Falk

    Hannover Medical School, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Tammy Lo

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Eric Sheu

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Ali Tavakkoli

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Reza Abdi

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. David L Perkins

    Department of Medicine, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Maria-Luisa Alegre

    Department of Medicine, University of Illinois at Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Alexander S Banks

    Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1787-6925
  21. Hao Zhou

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Abdallah Elkhal

    Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Stefan G Tullius

    Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Boston, United States
    For correspondence
    stullius@partners.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3058-3166

Funding

National Institutes of Health (UO-1 A1 132898)

  • Stefan G Tullius

Deutsche Forschungsgemeinschaft (QU 420/1-1)

  • Markus Quante

Deutsche Forschungsgemeinschaft (HE 7457/1-1)

  • Timm Heinbokel

Deutsche Forschungsgemeinschaft (KR 4362/1-1)

  • Felix Krenzien

Chinese Scholarship Council (201606370196)

  • Yeqi Nian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal use and care were in accordance with institutional and National Institutes of Health guidelines. The study protocol was approved by the Brigham and Women´s Hospital Institutional Animal Care and use Committee (IACUC) animal protocol (animal protocol 2016N000371).

Human subjects: Serum samples from patients prior to and 3 months post sleeve gastrectomy were obtained with approval of the Brigham and Women's Hospital (BWH) Institutional Review Board and through cooperation with Dr. Eric G. Sheu and the Center for Metabolic and Bariatric Surgery at BWH. Informed consent was obtained from all patients and samples were collected following BWH ethical regulations.

Reviewing Editor

  1. Ralph J DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: September 9, 2020
  2. Accepted: May 20, 2021
  3. Accepted Manuscript published: June 22, 2021 (version 1)
  4. Version of Record published: July 5, 2021 (version 2)

Copyright

© 2021, Quante et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 779
    Page views
  • 95
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Computational and Systems Biology
    2. Medicine
    James A Timmons et al.
    Short Report

    Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.

    1. Cell Biology
    2. Medicine
    Yo Han Lee et al.
    Research Article Updated

    Background:

    Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear.

    Methods:

    Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high-fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by Mir20b and the synergic effect of combination of fenofibrate with anti-Mir20b in NAFLD mouse model.

    Results:

    We revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice.

    Conclusions:

    Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD.

    Funding:

    This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940, 2016M3C9A394589324), and the Future-leading Project Research Fund (1.210034.01) of UNIST.