Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure

Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction independently of an animal’s energy status, exerts profound effects on feeding behavior and metabolism. Here, we demonstrate that considering the nutritional contexts within which FGF21 is elevated can help reconcile current controversies over its roles in mediating macronutrient preference, food intake, and energy expenditure. We show that FGF21 is primarily a driver of increased protein intake in mice and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. Under no-choice feeding, FGF21 infusion either increased or decreased energy expenditure depending on whether the animal was fed a high- or low-energy diet, respectively. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust and that the effects on sweet preference and energy expenditure are macronutrient-state-dependent effects of FGF21. [Display omitted] •FGF21 is a key driver of increased protein appetite•Up- or down-regulation of sweet preference depends on carbohydrate balance•Infusion of FGF21 reduces sucrose intake in a dose-dependent manner•The effect of FGF21 on energy expenditure differs according to energy state Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction, exerts profound effects on feeding behavior and whole-body metabolism. Solon-Biet et al. show that FGF21 is a key driver of protein appetite and that its effects on sweet preference and energy expenditure are dependent on background diet.