title: FGF21 is an endocrine signal of protein restriction.
abstract: Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.
authors.forename: Thomas
authors.initials: T
authors.lastname: Laeger
authors.forename: Tara M
authors.initials: TM
authors.lastname: Henagan
authors.forename: Diana C
authors.initials: DC
authors.lastname: Albarado
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Redman
authors.forename: George A
authors.initials: GA
authors.lastname: Bray
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Heike
authors.initials: H
authors.lastname: Münzberg
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutson
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Morrison
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D055423:Diet, Ketogenic; D004044:Dietary Proteins / Q000008:administration & dosage*; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004044:Dietary Proteins; D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases