Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change after low-protein overfeeding in rodent models. The change in EE after low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 hours of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by 3-fold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after six months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain
