The central nervous system is acknowledged as a major regulator of both energy and glucose homeostasis. Our data demonstrate that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that the metabolic hormone FGF-21 coordinates these adaptive responses. However, the tissue site mediating these FGF-21-dependent effects is unclear. In this study, mice with dysfunctional FGF-21 signaling in either the central nervous system (CNS) or adipose tissue were fed a control or low protein (LP) diet to assess changes in body weight and associated metabolic endpoints. We first deleted the required FGF co-receptor beta-Klotho (Klb) from neurons to test whether CNS FGF-21 signaling is required for increased energy expenditure or improved glucose homeostasis in mice consuming a low protein diet. Our data show that LP diet increased energy expenditure (p≤0.01) and reduced body weight (p≤0.001) in control littermates, but these effects were lost in mice bearing CNS-specific deletion of Klb (p=0.65). Protein restriction in the context of a high fat diet also improved glucose tolerance (P≤0.001) and insulin sensitivity (p≤0.001) in control littermates, but these effects were also lost in mice lacking Klb in the CNS. We next tested whether FGF-21 signaling within adipose tissue contributed to the metabolic effects of protein restriction. However, in this case LP diet reduced body weight (p=0.90) and increased food intake (p= 0.98) similarly in control littermates and mice bearing adipose-specific deletion of Klb. Collectively, these data highlight CNS FGF-21 signaling as the first known neuroendocrine mechanism to explain the coordinated metabolic changes induced by dietary protein restriction.
C.M. Hill: None. M.V. Dehner: None. D. McDougal: None. H. Berthoud: None. H. Muenzberg: None. C. Morrison: None.