Summary: Reduced dietary protein intake induces adaptive physiological changes in macronutrient preference, energy expenditure, growth, and glucose homeostasis. We demonstrate that deletion of the FGF21 co-receptor βKlotho (Klb) from the brain produces mice that are unable to mount a physiological response to protein restriction, an effect that is replicated by whole-body deletion of FGF21. Mice forced to consume a low-protein diet exhibit reduced growth, increased energy expenditure, and a resistance to diet-induced obesity, but the loss of FGF21 signaling in the brain completely abrogates that response. When given access to a higher protein alternative, protein-restricted mice exhibit a shift toward protein-containing foods, and central FGF21 signaling is essential for that response. FGF21 is an endocrine signal linking the liver and brain, which regulates adaptive, homeostatic changes in metabolism and feeding behavior during protein restriction. : Dietary protein restriction induces changes in macronutrient preference, energy expenditure, growth, and metabolism. Hill et al. show that deletion of the FGF21 co-receptor from the brain produces mice that are unable to mount a physiological response to dietary protein restriction. FGF21 acts in the brain to coordinate homeostatic responses to protein restriction. Keywords: dietary protein restriction, FGF21, Klb, central nervous system, macronutrient, nutrition
