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Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans

Author

Listed:
  • Pavlina Chrysafi

    (Harvard Medical School)

  • Laura Valenzuela-Vallejo

    (Harvard Medical School)

  • Konstantinos Stefanakis

    (Harvard Medical School)

  • Theodoros Kelesidis

    (UCLA)

  • Margery A. Connelly

    (Labcorp)

  • Christos S. Mantzoros

    (Harvard Medical School
    Boston VA Healthcare System)

Abstract

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49366-y
    DOI: 10.1038/s41467-024-49366-y
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    References listed on IDEAS

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    1. 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.
    2. 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.
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