Project Summary Dietary protein intake alters energy expenditure and remodels adipose tissue, but the cellular mechanisms mediating these effects are largely undescribed. We recently discovered that the hormone FGF21 is robustly increased by dietary protein restriction and that mice lacking FGF21 fail to exhibit the expected changes in growth, energy expenditure or glucose homeostasis in response to dietary restriction. In addition, selective deletion of the FGF21 co-receptor beta-Klotho (Klb) from the brain also blocks the metabolic response to protein restriction. This discovery has redefined FGF21's physiological role by suggesting that it acts directly in the brain to coordinate the adaptive, homeostatic response to protein restriction. This project extends these data by 1) Identifying the FGF21-dependent neurobiological mechanisms that mediate changes in energy expenditure during protein restriction, and 2) Determining the mechanism through which protein restriction, via brain FGF21 signaling, remodels adipose tissue and thereby influences energy expenditure and metabolic health. This project will define the mechanism through which animals sense and respond to protein restriction while also delineating the mechanisms through which FGF21 acts in the brain to stimulate energy expenditure.