Hepatic FGF21 is not required for fasting metabolism but guides protein appetite post energy depletion
Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we study mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes does not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncover a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.
Authors
- Sandrine Ellero‐Simatos (ORCID: https://orcid.org/0000-0002-9282-1804)
- Walter Wahli (ORCID: https://orcid.org/0000-0002-5966-9089)
- Marion Régnier (ORCID: https://orcid.org/0000-0002-5005-0597)
- Anne Fougerat (ORCID: https://orcid.org/0009-0000-0305-1880)
- Céline Cruciani‐Guglielmacci (ORCID: https://orcid.org/0000-0002-2562-5360)
- Alexandra Montagner (ORCID: https://orcid.org/0000-0002-4800-5105)
- Laurence Gamet‐Payrastre (ORCID: https://orcid.org/0000-0003-1681-8491)
- Prunelle Perrier
- Justine Bruse
- Frédèric Lasserre (ORCID: https://orcid.org/0000-0001-5220-9787)
- Arnaud Polizzi (ORCID: https://orcid.org/0000-0003-1986-2770)
- Catherine Postic (ORCID: https://orcid.org/0000-0002-1875-6960)
- Clémence Rives
- Fadila Benhamed (ORCID: https://orcid.org/0000-0003-4905-6585)
- Claire Naylies
- Stefan Weger (ORCID: https://orcid.org/0000-0002-0906-5252)
- Michael Schupp (ORCID: https://orcid.org/0000-0003-3720-1052)
- Juliette Salvi (ORCID: https://orcid.org/0000-0001-6457-5864)
- Yannick Lippi (ORCID: https://orcid.org/0000-0003-4717-078X)
- Thierry Levade (ORCID: https://orcid.org/0000-0003-3793-2584)
- Valérie Alquier‐Bacquie
- Alexandre Bénani (ORCID: https://orcid.org/0000-0003-2046-0162)
- Marine Huillet (ORCID: https://orcid.org/0000-0002-6508-4351)
- Hervé Guillou (ORCID: https://orcid.org/0000-0002-5363-9081)
- Mikaël Albin
- Shiou-Ping Chen
- Nicolas Loiseau (ORCID: https://orcid.org/0000-0003-3783-0879)
- Clothilde Marbach
- Caroline Sommer
- Tatiana Landré
- Léon Kautz
- Céline M P Martin (ORCID: https://orcid.org/0009-0000-0215-7982)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- École Nationale Vétérinaire de Toulouse (FR)
- Université Paris Cité (FR)
- Humboldt-Universität zu Berlin (DE)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Toxicologie Alimentaire (FR)
- Institut de Recherche en Santé Digestive (FR)
- Unit of Functional and Adaptive Biology (FR)
- Hôpital Purpan (FR)
- Institut Cochin (FR)
- Hôpital des Enfants (FR)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Centre des Sciences du Goût et de l'Alimentation (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-04-27
- DOI
- https://doi.org/10.1038/s44319-026-00790-9
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale