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Nicolaisen, T.S.* ; Lyster, A.E.* ; Sjøberg, K.A.* ; Haas, D. ; Lundsgaard, A.M.* ; Jensen, J.K.* ; Madsen, E.M.* ; Nielsen, C.K.* ; Bloch-Ibenfeldt, M.* ; Wewer Albrechtsen, N.J.* ; Rose, A.J.* ; Krahmer, N. ; Clemmensen, C.* ; Richter, E.A.* ; Fritzen, A.M.* ; Kiens, B.*

Dietary protein restriction elevates FGF21 levels and energy requirements to maintain body weight in lean men.

Nat. Metab. 7, 602–616 (2025)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Basal Metabolic-rate; Beta-klotho; Fat Thermogenesis; Expenditure; Tissue; Mass; Expression; Insulin; Humans

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 7, Pages: 602–616

Publisher Springer

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants Novo Nordisk Foundation Center for Basic Metabolic Research
European Foundation for the Study of Diabetes - Novo Nordisk Foundation
European Foundation for the Study of Diabetes
DFG BATenergy
Independent Research Fund Denmark/Medicine
Novo Nordisk Foundation
Novo Nordisk Fonden (Novo Nordisk Foundation)