FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response.
The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferator-activated receptor gamma coactivator protein-1alpha (PGC-1alpha), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1alpha expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1alpha and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.
Potthoff
Matthew J
MJ
Department of Pharmacology, Howard Hughes Medical Institute, Advanced Imaging Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Inagaki
Takeshi
T
Satapati
Santhosh
S
Ding
Xunshan
X
He
Tianteng
T
Goetz
Regina
R
Mohammadi
Moosa
M
Finck
Brian N
BN
Mangelsdorf
David J
DJ
Kliewer
Steven A
SA
Burgess
Shawn C
SC
D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D050260:Carbohydrate Metabolism; D005215:Fasting / Q000097:blood / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000235:genetics; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013217:Starvation / Q000097:blood / Q000503:physiopathology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors