Dietary Protein Reduction During Isocaloric Conditions Reduces Body Weight in Men With Overweight or Obesity

ABSTRACT Objective Dietary protein reduction increases plasma fibroblast growth factor 21 (FGF21) and energy requirements in lean men under eucaloric conditions. Whether these metabolic effects translate to weight loss during isocaloric conditions in men with overweight or obesity remains unclear. Methods Seventeen men with overweight or obesity were randomly allocated to two different highly controlled, isocaloric diets for 5 weeks, receiving either a protein‐reduced diet (0.9 g kg −1 BW day −1 ) substituted with increased carbohydrates or a habitual diet (1.8 g kg −1 BW day −1 ). Results Protein reduction induced a 2.0 ± 0.6 kg weight loss and increased plasma FGF21 concentration compared with higher protein intake, without caloric restriction. Changes in plasma FGF21 concentration were inversely associated with changes in body weight ( r = −0.59, p = 0.02). Expression of key components in the FGF21 receptor complex, FGFR1 and β‐klotho, and downstream targets in subcutaneous adipose tissue remained unchanged. Markers of skeletal muscle mitochondrial oxidative phosphorylation were also unaltered. Fat mass decreased significantly, whereas this level of protein reduction only tended to lower lean body mass. Conclusions These findings suggest that reducing protein intake (0.9 g kg −1 BW day −1 ), substituted with increased carbohydrates, compared with a habitual protein intake (1.8 g kg −1 BW day −1 ), can induce weight loss without restricting total energy intake in men with overweight or obesity. Trial Registration ClinicalTrials.gov identifier: NCT06263725 image