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Protein-restricted diet increases circulating FGF21 levels and necessitating an increase in energy intake to maintain body weight in healthy human individuals

ABSTRACT: Dietary protein restriction has been shown to increase energy expenditure and to improve insulin sensitivity in mice, but it is unknown whether humans exhibit similar phenotype to a prolonged eucaloric protein-restricted diet that meet daily protein minimum requirements. We hypothesize that a protein-restricted diet would necessitate an increase in energy intake in order to maintain body weight in healthy, lean men. We designed an overall amino acid diluted diet meeting the requirement for daily protein intake and essential amino acids. Healthy, young, lean men adhered to a protein-restricted, high-carbohydrate diet (LPHC: protein 9E%, 70E% carbohydrate, and 21E% fat) or a protein-restricted, high-fat diet (LPHF: 9E% protein, 50E% fat, and 40E% carbohydrate) for 5 weeks, followed by another 5 weeks on a higher, standard protein diet (HPD: 18E% protein), reflecting their habitual diet. The diets were eucaloric, and energy provision was adjusted to maintain body weight throughout the interventions. In addition, wild type (WT), and FGF21 knockout mice were also fed LPHC, LPHF diets, or a standard higher diet (HPD) for a total of 10 weeks. Our results showed that prolonged eucaloric LPHC and LPHF diets necessitated a daily increase of 20-21% (2.5 MJ) in food intake to maintain body weight compared to pre-intervention in healthy, lean men. Additionally, fasting plasma FGF21 levels increased from 90±125 pg/ml and 78±34 pg/ml to 257±99 pg/ml and 160±52 pg/ml at the end of the LPHC and LPHF, respectively. Furthermore, proteomic analysis revealed adaptations in the respiratory chain in human adipose tissue after 5-week protein-restricted diets. This was found to be dependent on FGF21 in mice, indicating increased energy utilization through alternative UCP1-independent futile cycle pathways likely mediated by FGF21. Moreover, whole-body insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp, was increased by 16% after the LPHC intervention while maintained after the LPHF intervention, despite the high fat intake. These findings suggest that a protein-restricted diet could serve as a promising approach to prevent weight gain and comorbidities associated with obesity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): White Fat Cell, White Adipose Tissue

SUBMITTER: Natalie Krahmer

LAB HEAD: Bente Kiens

PROVIDER: PXD047177 | Pride | 2025-04-22

REPOSITORIES: Pride

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			Action	DRS
	Knockouts_HCLP_KO20_01_i_578.raw	Raw
	Knockouts_HCLP_KO20_02_i_589.raw	Raw
	Knockouts_HCLP_KO20_03_i_603.raw	Raw
	Knockouts_HCLP_KO20_04_i_607.raw	Raw
	Knockouts_HCLP_KO20_05_i_611.raw	Raw

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

Nicolaisen Trine S TS Lyster Aslak E AE Sjøberg Kim A KA Haas Daniel T DT Voldstedlund Christian T CT Lundsgaard Anne-Marie AM Jensen Jakob K JK Madsen Ea M EM Nielsen Casper K CK Bloch-Ibenfeldt Mads M Wewer Albrechtsen Nicolai J NJ Rose Adam J AJ Krahmer Natalie N Clemmensen Christoffer C Richter Erik A EA Fritzen Andreas M AM Kiens Bente B

Nature metabolism 20250306 3

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 i ...[more]

PMID: 40050437

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