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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.

Pubmed ID: 19541642


  • Potthoff MJ
  • Inagaki T
  • Satapati S
  • Ding X
  • He T
  • Goetz R
  • Mohammadi M
  • Finck BN
  • Mangelsdorf DJ
  • Kliewer SA
  • Burgess SC


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 30, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 1RL1GM084436-01
  • Agency: NIDCR NIH HHS, Id: DE13686
  • Agency: NIDDK NIH HHS, Id: DK067158
  • Agency: NIDDK NIH HHS, Id: DK076269
  • Agency: NIDDK NIH HHS, Id: DK078184
  • Agency: NCRR NIH HHS, Id: P20RR20691
  • Agency: NCRR NIH HHS, Id: RR02584
  • Agency: NIDDK NIH HHS, Id: U19DK62434
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Adaptation, Physiological
  • Animals
  • Blood Glucose
  • Blotting, Western
  • Body Weight
  • Carbohydrate Metabolism
  • Fasting
  • Fatty Acids
  • Female
  • Fibroblast Growth Factors
  • Gene Expression Regulation
  • Gluconeogenesis
  • Insulin
  • Lipid Metabolism
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidation-Reduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Starvation
  • Trans-Activators
  • Transcription Factors
  • Triglycerides