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GDF15 promotes weight loss by enhancing energy expenditure in muscle

Author

Listed:
  • Dongdong Wang

    (McMaster University
    McMaster University)

  • Logan K. Townsend

    (McMaster University
    McMaster University)

  • Geneviève J. DesOrmeaux

    (University of Guelph)

  • Sara M. Frangos

    (University of Guelph)

  • Battsetseg Batchuluun

    (McMaster University
    McMaster University)

  • Lauralyne Dumont

    (Université de Sherbrooke)

  • Rune Ehrenreich Kuhre

    (Novo Nordisk
    University of Copenhagen)

  • Elham Ahmadi

    (McMaster University
    McMaster University)

  • Sumei Hu

    (Beijing Technology and Business University
    Chinese Academy of Sciences)

  • Irena A. Rebalka

    (McMaster University)

  • Jaya Gautam

    (McMaster University
    McMaster University)

  • Maria Joy Therese Jabile

    (McMaster University
    McMaster University)

  • Chantal A. Pileggi

    (University of Ottawa
    University of Ottawa)

  • Sonia Rehal

    (McMaster University
    McMaster University)

  • Eric M. Desjardins

    (McMaster University
    McMaster University)

  • Evangelia E. Tsakiridis

    (McMaster University
    McMaster University)

  • James S. V. Lally

    (McMaster University
    McMaster University)

  • Emma Sara Juracic

    (University of Waterloo)

  • A. Russell Tupling

    (University of Waterloo)

  • Hertzel C. Gerstein

    (McMaster University
    McMaster University
    Hamilton Health Sciences and McMaster University)

  • Guillaume Paré

    (McMaster University
    Hamilton Health Sciences and McMaster University
    McMaster University, Hamilton Health Sciences
    McMaster University)

  • Theodoros Tsakiridis

    (McMaster University
    McMaster University)

  • Mary-Ellen Harper

    (University of Ottawa
    University of Ottawa)

  • Thomas J. Hawke

    (McMaster University)

  • John R. Speakman

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Aberdeen
    CAS Center for Excellence in Animal Evolution and Genetics (CCEAEG))

  • Denis P. Blondin

    (Université de Sherbrooke
    Université de Sherbrooke)

  • Graham P. Holloway

    (University of Guelph)

  • Sebastian Beck Jørgensen

    (Novo Nordisk
    Novo Nordisk)

  • Gregory R. Steinberg

    (McMaster University
    McMaster University
    McMaster University)

Abstract

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4–7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL–β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15–GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Suggested Citation

  • Dongdong Wang & Logan K. Townsend & Geneviève J. DesOrmeaux & Sara M. Frangos & Battsetseg Batchuluun & Lauralyne Dumont & Rune Ehrenreich Kuhre & Elham Ahmadi & Sumei Hu & Irena A. Rebalka & Jaya Gau, 2023. "GDF15 promotes weight loss by enhancing energy expenditure in muscle," Nature, Nature, vol. 619(7968), pages 143-150, July.
  • Handle: RePEc:nat:nature:v:619:y:2023:i:7968:d:10.1038_s41586-023-06249-4
    DOI: 10.1038/s41586-023-06249-4
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    Cited by:

    1. Xuanming Guo & Pallavi Asthana & Lixiang Zhai & Ka Wing Cheng & Susma Gurung & Jiangang Huang & Jiayan Wu & Yijing Zhang & Arun Kumar Mahato & Mart Saarma & Mart Ustav & Hiu Yee Kwan & Aiping Lyu & Ku, 2024. "Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Pavlina Chrysafi & Laura Valenzuela-Vallejo & Konstantinos Stefanakis & Theodoros Kelesidis & Margery A. Connelly & Christos S. Mantzoros, 2024. "Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Laurent L’homme & Benan Pelin Sermikli & Joel T. Haas & Sébastien Fleury & Sandrine Quemener & Valentine Guinot & Emelie Barreby & Nathalie Esser & Robert Caiazzo & Hélène Verkindt & Benjamin Legendre, 2024. "Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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