Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.
Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the utilization of fat as an energy source during starvation and is the molecular target for the fibrate dyslipidemia drugs. Here, we identify the endocrine hormone fibroblast growth factor 21 (FGF21) as a mediator of the pleiotropic actions of PPARalpha. FGF21 is induced directly by PPARalpha in liver in response to fasting and PPARalpha agonists. FGF21 in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF21 also reduces physical activity and promotes torpor, a short-term hibernation-like state of regulated hypothermia that conserves energy. These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.
Inagaki
Takeshi
T
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Dutchak
Paul
P
Zhao
Guixiang
G
Ding
Xunshan
X
Gautron
Laurent
L
Parameswara
Vinay
V
Li
Yong
Y
Goetz
Regina
R
Mohammadi
Moosa
M
Esser
Victoria
V
Elmquist
Joel K
JK
Gerard
Robert D
RD
Burgess
Shawn C
SC
Hammer
Robert E
RE
Mangelsdorf
David J
DJ
Kliewer
Steven A
SA
D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005215:Fasting / Q000502:physiology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism*; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D047493:PPAR alpha; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors