FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Department of Pharmacology, Howard Hughes Medical Institute, Advanced Imaging Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2009; 106(26):10853-10858. DOI: 10.1073/pnas.0904187106

ABSTRACT 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 γ coactivator protein-1α (PGC-1α),
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-1α expression
in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship
between FGF21 and PGC-1α and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid
metabolism during the progression from fasting to starvation.

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    ABSTRACT: Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here, we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to adrenocorticotropic hormone. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a non-canonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, PPARα, to stimulate Fgf21 transcription. GR and PPARα ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation.
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