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

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

  • 888
    Page views
  • 106
    Downloads
  • 3
    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)

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

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

  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
(2021)
Restored TDCA and valine levels imitate the effects of bariatric surgery
eLife 10:e62928.
https://doi.org/10.7554/eLife.62928

Further reading

    1. Cell Biology
    2. Medicine
    Eric N Jimenez-Vazquez et al.
    Research Article

    Background:

    Patients with cardiomyopathy of Duchenne Muscular Dystrophy (DMD) are at risk of developing life-threatening arrhythmias, but the mechanisms are unknown. We aimed to determine the role of ion channels controlling cardiac excitability in the mechanisms of arrhythmias in DMD patients.

    Methods:

    To test whether dystrophin mutations lead to defective cardiac NaV1.5–Kir2.1 channelosomes and arrhythmias, we generated iPSC-CMs from two hemizygous DMD males, a heterozygous female, and two unrelated control males. We conducted studies including confocal microscopy, protein expression analysis, patch-clamping, non-viral piggy-bac gene expression, optical mapping and contractility assays.

    Results:

    Two patients had abnormal ECGs with frequent runs of ventricular tachycardia. iPSC-CMs from all DMD patients showed abnormal action potential profiles, slowed conduction velocities, and reduced sodium (INa) and inward rectifier potassium (IK1) currents. Membrane NaV1.5 and Kir2.1 protein levels were reduced in hemizygous DMD iPSC-CMs but not in heterozygous iPSC-CMs. Remarkably, transfecting just one component of the dystrophin protein complex (α1-syntrophin) in hemizygous iPSC-CMs from one patient restored channelosome function, INa and IK1 densities, and action potential profile in single cells. In addition, α1-syntrophin expression restored impulse conduction and contractility and prevented reentrant arrhythmias in hiPSC-CM monolayers.

    Conclusions:

    We provide the first demonstration that iPSC-CMs reprogrammed from skin fibroblasts of DMD patients with cardiomyopathy have a dysfunction of the NaV1.5–Kir2.1 channelosome, with consequent reduction of cardiac excitability and conduction. Altogether, iPSC-CMs from patients with DMD cardiomyopathy have a NaV1.5–Kir2.1 channelosome dysfunction, which can be rescued by the scaffolding protein α1-syntrophin to restore excitability and prevent arrhythmias.

    Funding:

    Supported by National Institutes of Health R01 HL122352 grant; ‘la Caixa’ Banking Foundation (HR18-00304); Fundación La Marató TV3: Ayudas a la investigación en enfermedades raras 2020 (LA MARATO-2020); Instituto de Salud Carlos III/FEDER/FSE; Horizon 2020 - Research and Innovation Framework Programme GA-965286 to JJ; the CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation), and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). American Heart Association postdoctoral fellowship 19POST34380706s to JVEN. Israel Science Foundation to OB and MA [824/19]. Rappaport grant [01012020RI]; and Niedersachsen Foundation [ZN3452] to OB; US-Israel Binational Science Foundation (BSF) to OB and TH [2019039]; Dr. Bernard Lublin Donation to OB; and The Duchenne Parent Project Netherlands (DPPNL 2029771) to OB. National Institutes of Health R01 AR068428 to DM and US-Israel Binational Science Foundation Grant [2013032] to DM and OB.

    1. Medicine
    Diane M Harper et al.
    Research Article

    Background:

    Using screen counts, women 50–64 years old have lower cancer screening rates for cervical and colorectal cancers (CRC) than all other age ranges. This paper aims to present woman-centric cervical cancer and CRC screenings to determine the predictor of being up-to-date for both.

    Methods:

    We used the Behavioral Risk Factor Surveillance System (BRFSS), an annual survey to guide health policy in the United States, to explore the up-to-date status of dual cervical cancer and CRC screening for women 50–64 years old. We categorized women into four mutually exclusive categories: up-to-date for dual-screening, each single screen, or neither screen. We used multinomial multivariate regression modeling to evaluate the predictors of each category.

    Results:

    Among women ages 50–64 years old, dual-screening was reported for 58.2% (57.1–59.4), cervical cancer screening alone (27.1% (26.0–28.2)), CRC screening alone (5.4% (4.9–5.9)), and neither screen (9.3% (8.7–9.9)). Age, race, education, income, and chronic health conditions were significantly associated with dual-screening compared to neither screen. Hispanic women compared to non-Hispanic White women were more likely to be up-to-date with cervical cancer screening than dual-screening (adjusted odds ratio [aOR] = 1.39 (1.10, 1.77)). Compared to younger women, those 60–64 years are significantly more likely to be up-to-date with CRC screening than dual-screening (aOR = 1.75 (1.30, 2.35)).

    Conclusions:

    Screening received by each woman shows a much lower rate of dual-screening than prior single cancer screening rates. Addressing dual-screening strategies rather than single cancer screening programs for women 50–64 years may increase both cancer screening rates.

    Funding:

    This work was supported by NIH through the Michigan Institute for Clinical and61 Health Research UL1TR002240 and by NCI through The University of Michigan Rogel Cancer62 Center P30CA046592 grants.