title: FGF21 and the late adaptive response to starvation in humans.
abstract: In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases--markers of tissue breakdown--as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.
authors.forename: Pouneh K
authors.initials: PK
authors.lastname: Fazeli
authors.forename: Mingyue
authors.initials: M
authors.lastname: Lun
authors.forename: Soo M
authors.initials: SM
authors.lastname: Kim
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Bredella
authors.forename: Spenser
authors.initials: S
authors.lastname: Wright
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hang
authors.initials: H
authors.lastname: Lee
authors.forename: Ciprian
authors.initials: C
authors.lastname: Catana
authors.forename: Anne
authors.initials: A
authors.lastname: Klibanski
authors.forename: Parth
authors.initials: P
authors.lastname: Patwari
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Steinhauser
mesh_terms: D000222:Adaptation, Physiological; D052242:Adiponectin / Q000097:blood; D000328:Adult; D000818:Animals; D005215:Fasting / Q000097:blood; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D013217:Starvation / Q000097:blood*; D022722:Thermogenesis; D013997:Time Factors
chemical_list: D052242:Adiponectin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors