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Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Author

Listed:
  • Anders B. Klein

    (University of Copenhagen)

  • Trine S. Nicolaisen

    (University of Copenhagen
    University of Copenhagen)

  • Niels Ørtenblad

    (University of Southern Denmark)

  • Kasper D. Gejl

    (University of Southern Denmark)

  • Rasmus Jensen

    (University of Southern Denmark)

  • Andreas M. Fritzen

    (University of Copenhagen)

  • Emil L. Larsen

    (University of Copenhagen)

  • Kristian Karstoft

    (University of Copenhagen
    Rigshospitalet, University of Copenhagen)

  • Henrik E. Poulsen

    (University of Copenhagen)

  • Thomas Morville

    (University of Copenhagen)

  • Ronni E. Sahl

    (University of Copenhagen
    University of Copenhagen)

  • Jørn W. Helge

    (University of Copenhagen)

  • Jens Lund

    (University of Copenhagen)

  • Sarah Falk

    (University of Copenhagen)

  • Mark Lyngbæk

    (Rigshospitalet, University of Copenhagen)

  • Helga Ellingsgaard

    (Rigshospitalet, University of Copenhagen)

  • Bente K. Pedersen

    (Rigshospitalet, University of Copenhagen)

  • Wei Lu

    (Novo Nordisk Research Center Indianapolis)

  • Brian Finan

    (Novo Nordisk Research Center Indianapolis)

  • Sebastian B. Jørgensen

    (Global Obesity and LD Research, Novo Nordisk A/S)

  • Randy J. Seeley

    (University of Michigan)

  • Maximilian Kleinert

    (University of Copenhagen
    German Research Center for Environmental Health)

  • Bente Kiens

    (University of Copenhagen)

  • Erik A. Richter

    (University of Copenhagen)

  • Christoffer Clemmensen

    (University of Copenhagen)

Abstract

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Suggested Citation

  • Anders B. Klein & Trine S. Nicolaisen & Niels Ørtenblad & Kasper D. Gejl & Rasmus Jensen & Andreas M. Fritzen & Emil L. Larsen & Kristian Karstoft & Henrik E. Poulsen & Thomas Morville & Ronni E. Sahl, 2021. "Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21309-x
    DOI: 10.1038/s41467-021-21309-x
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    Cited by:

    1. Camilla Lund & Pablo Ranea-Robles & Sarah Falk & Dylan M. Rausch & Grethe Skovbjerg & Victoria Kamma Vibe-Petersen & Nathalie Krauth & Jacob Lercke Skytte & Vasiliki Vana & Urmas Roostalu & Tune H. Pe, 2024. "Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R," Nature Communications, Nature, vol. 15(1), pages 1-13, 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. Quentin Sastourné-Arrey & Maxime Mathieu & Xavier Contreras & Sylvie Monferran & Virginie Bourlier & Marta Gil-Ortega & Enda Murphy & Claire Laurens & Audrey Varin & Christophe Guissard & Corinne Barr, 2023. "Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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