Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men
Dietary protein restriction increases energy expenditure and enhances insulin sensitivity in mice. However, the effects of a eucaloric protein-restricted diet in healthy humans remain unexplored. Here, we show in lean, healthy men that a protein-restricted diet meeting the minimum protein requirements for 5 weeks necessitates an increase in energy intake to uphold body weight, regardless of whether proteins are replaced with fats or carbohydrates. Upon reverting to the customary higher protein intake in the following 5 weeks, energy requirements return to baseline levels, thus preventing weight gain. We also show that fasting plasma FGF21 levels increase during protein restriction. Proteomic analysis of human white adipose tissue and in FGF21-knockout mice reveal alterations in key components of the electron transport chain within white adipose tissue mitochondria. Notably, in male mice, these changes appear to be dependent on FGF21. In conclusion, we demonstrate that maintaining body weight during dietary protein restriction in healthy, lean men requires a higher energy intake, partially driven by FGF21-mediated mitochondrial adaptations in adipose tissue.
Authors
- Eileen M. Madsen
- Andreas M. Fritzen (ORCID: https://orcid.org/0000-0001-8793-9739)
- Mads Bloch‐Ibenfeldt (ORCID: https://orcid.org/0009-0007-9331-6790)
- Erik A. Richter (ORCID: https://orcid.org/0000-0002-6850-3056)
- Jacob K. Jensen (ORCID: https://orcid.org/0000-0002-5505-5944)
- Daniel T. Haas
- Kim A. Sjøberg (ORCID: https://orcid.org/0000-0001-6880-4804)
- Anne‐Marie Lundsgaard
- Adam J. Rose (ORCID: https://orcid.org/0000-0001-9132-8244)
- Nicolai J. Wewer Albrechtsen (ORCID: https://orcid.org/0000-0003-4230-5753)
- Bente Kiens (ORCID: https://orcid.org/0000-0001-5705-5625)
- Natalie Krahmer (ORCID: https://orcid.org/0000-0003-4063-7367)
- Trine S. Nicolaisen (ORCID: https://orcid.org/0000-0001-5856-6443)
- Casper K. Nielsen (ORCID: https://orcid.org/0009-0000-8923-0643)
- Christoffer Clemmensen (ORCID: https://orcid.org/0000-0003-2456-9667)
- Christian T. Voldstedlund (ORCID: https://orcid.org/0000-0002-6368-8995)
- Aslak Emil Lyster (ORCID: https://orcid.org/0000-0003-4404-0605)
Institutions
- University of Copenhagen (DK)
- Novo Nordisk (Denmark) (DK)
- Novo Nordisk Foundation (DK)
- Frederiksberg Hospital (DK)
- Australian Regenerative Medicine Institute (AU)
- Bispebjerg Hospital (DK)
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- Helmholtz Zentrum München (DE)
- Monash University (AU)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1038/s42255-025-01236-7
- Citations
- 20
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 16.12
Funders
- Eli Lilly and Company
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft
- Novo Nordisk
- Danmarks Frie Forskningsfond
- Copenhagen Graduate School for Nanoscience and Nanotechnology
- Novo Nordisk Fonden
- Novo Nordisk Foundation Center for Basic Metabolic Research