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Peer-reviewedCC BYMolecular biomedicine

Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging.

  • Laura Salmón-Gómez1,2,3,4
  • Susanne Keipert5,6
  • Victoria Catalán1,2,3,4
  • Amaia Rodríguez1,2,3,4
  • Sara Becerril1,2,3,4
  • Gema Frühbeck1,2,3,4,7
  • Javier Gómez-Ambrosi8,9,10,11
11 affiliations
  1. 1Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, Pamplona, 31008, Spain.
  2. 2Centro de Investigación Biomédica en Red-Fisiopatología de La Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain.
  3. 3Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
  4. 4Institute for Nutrition & Health, University of Navarra, Pamplona, Spain.
  5. 5Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
  6. 6Center of Brain Behavior and Metabolism (CBBM), Institute for Human Genetics, University of Lübeck, Lübeck, Germany.
  7. 7Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
  8. 8Metabolic Research Laboratory, Clínica Universidad de Navarra, Irunlarrea 1, Pamplona, 31008, Spain. [email protected].
  9. 9Centro de Investigación Biomédica en Red-Fisiopatología de La Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain. [email protected].
  10. 10Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. [email protected].
  11. 11Institute for Nutrition & Health, University of Navarra, Pamplona, Spain. [email protected].
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Abstract

Metabolic diseases and age-related disorders represent a major global health burden driven by the increasing prevalence of obesity and obesity-associated complications. These disorders are characterized by chronic disturbances in energy homeostasis. A key feature linking metabolic disease and aging is the activation of stress-related pathways, which contribute to progressive metabolic dysfunction. Among the endocrine mediators of cellular stress, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) have emerged as key regulators of metabolic homeostasis. Both are induced by similar stress conditions, including nutrient imbalance, inflammation, oxidative and endoplasmic reticulum (ER) stress and mitochondrial dysfunction, and are elevated in pathophysiological conditions such as obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD) and aging. FGF21 and GDF15 also share overlapping regulatory pathways and complementary functions, suggesting a potential coordinated regulation and functional interplay. However, the extent and physiological relevance of this possible interrelationship remain incompletely understood. This review summarizes current knowledge on the regulation, tissue sources, and signaling mechanisms of FGF21 and GDF15 across metabolic diseases and aging, with particular attention to their roles as mediators of adaptive metabolic responses and their overlapping biological actions. We further discuss their context-dependent effects under acute and chronic stress and their relevance as biomarkers of metabolic dysfunction and disease progression. Collectively, this work highlights FGF21 and GDF15 as integrated stress signals linking cellular stress to systemic metabolic adaptation, providing a conceptual framework for understanding their cooperative roles and regulation in metabolic and age-related diseases, which may have therapeutic potential.

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Cite

BibTeXRIS
BibTeX
@article{salmongomez2026biological,
  title = {{Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging.}},
  author = {Laura Salmón-Gómez and Susanne Keipert and Victoria Catalán and Amaia Rodríguez and Sara Becerril and Gema Frühbeck and Javier Gómez-Ambrosi},
  journal = {Molecular biomedicine},
  year = {2026},
  month = oct,
  doi = {10.1186/s43556-026-00627-w},
  url = {https://europepmc.org/article/MED/42957849},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging.
AU  - Laura Salmón-Gómez
AU  - Susanne Keipert
AU  - Victoria Catalán
AU  - Amaia Rodríguez
AU  - Sara Becerril
AU  - Gema Frühbeck
AU  - Javier Gómez-Ambrosi
PY  - 2026
DA  - 2026/10/30
JO  - Molecular biomedicine
DO  - 10.1186/s43556-026-00627-w
UR  - https://europepmc.org/article/MED/42957849
AB  - Metabolic diseases and age-related disorders represent a major global health burden driven by the increasing prevalence of obesity and obesity-associated complications. These disorders are characterized by chronic disturbances in energy homeostasis. A key feature linking metabolic disease and aging is the activation of stress-related pathways, which contribute to progressive metabolic dysfunction. Among the endocrine mediators of cellular stress, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) have emerged as key regulators of metabolic homeostasis. Both are induced by similar stress conditions, including nutrient imbalance, inflammation, oxidative and endoplasmic reticulum (ER) stress and mitochondrial dysfunction, and are elevated in pathophysiological conditions such as obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD) and aging. FGF21 and GDF15 also share overlapping regulatory pathways and complementary functions, suggesting a potential coordinated regulation and functional interplay. However, the extent and physiological relevance of this possible interrelationship remain incompletely understood. This review summarizes current knowledge on the regulation, tissue sources, and signaling mechanisms of FGF21 and GDF15 across metabolic diseases and aging, with particular attention to their roles as mediators of adaptive metabolic responses and their overlapping biological actions. We further discuss their context-dependent effects under acute and chronic stress and their relevance as biomarkers of metabolic dysfunction and disease progression. Collectively, this work highlights FGF21 and GDF15 as integrated stress signals linking cellular stress to systemic metabolic adaptation, providing a conceptual framework for understanding their cooperative roles and regulation in metabolic and age-related diseases, which may have therapeutic potential.
SN  - 2662-8651
ER  -