FGF21 Is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype

Abstract

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a 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 diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h 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 threefold 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 6 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.

Figure 1

Plasma FGF21 concentrations before and after 24-h dietary interventions. A: Plasma FGF21 concentrations before and after each dietary intervention. Bars represent geographic means with 95% CIs. B: Individual changes in plasma FGF21 concentration after each dietary intervention. The red lines represent arithmetic means with 95% CIs. Macronutrient composition of diets: energy balance diet and NormalPro/NormalCHO overfeeding diet: 50% carbohydrate, 30% fat, 20% protein; NormalPro/HighCHO overfeeding diet: 75% carbohydrate, 5% fat, 20% protein; NormalPro/HighFat overfeeding diet: 20% carbohydrate, 60% fat, 20% protein; HighPro/HighFat overfeeding diet: 26% carbohydrate, 44% fat, 30% protein; LowPro/HighFat overfeeding diet: 51% carbohydrate, 46% fat, 3% protein; and LowPro/HighCHO overfeeding diet: 75% carbohydrate, 22% fat, 3% protein.

Figure 2

Relationships between the change in plasma FGF21 concentration after 24-h low-protein high-fat overfeeding and the percentage change in 24-h EE from energy balance (A) and free-living weight change after 6 months (B). The macronutrient composition of LowPro/HighFat overfeeding diet was: 51% carbohydrate, 46% fat, and 3% protein. The percentage change in 24-h EE was calculated as: (24-h EE_{overfeeding diet} − 24-h EE_{energy balance})/24-h EE_{energy balance} × 100. One subject found to have impaired fasting glucose on the OGTT and one subject with benign glycosuria were excluded from these analyses because these conditions are known to affect 24-h EE. Associations were quantified by the Pearson correlation index.