FGF21 induces PGC-1 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: 9.67). 06/2009; 106(26):10853-10858. DOI: 10.1073/pnas.0904187106


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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    • "In the liver, FGF21 has been reported to be capable of directly inducing PGC1a mRNA expression and protein abundance (Coskun et al. 2008, Adams et al. 2012). Potthoff et al. have also shown using hepatic-specific PGC1 KO mice that this protein is critical to the ability of FGF21 to increase hepatic b-oxidation, ketogenesis and TCA cycle flux (Potthoff et al. 2009). Furthermore, PGC1a has been shown to be capable of directly inducing PDK4 expression in skeletal muscle and hepatocytes (Wende et al. 2005, Attia et al. 2010). "
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    ABSTRACT: The aim of this study was to investigate the mechanisms by which FGF21 affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg/day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through β-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria), and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1 (SIRT-1). These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.
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    • "We used only male adult B6.G6pclox/lox.SACreERT2 (G6pclox/lox), L-G6pc−/− and C57Bl/6J control (+/+ or wild-type, Charles Rivers Laboratories, France) mice for the present studies. Mice with a double knock-out of Fgf21 and G6pc were obtained by crossing B6.Fgf21−/− mice [22] and B6.G6pclox/lox.SACreERT2. Progeny (6–8 weeks old) was then injected once daily with 100 μL of tamoxifen (10 mg/mL) on 5 consecutive days to delete the G6pc exon 3 in the liver. "
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    ABSTRACT: Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.
    Molecular Metabolism 08/2014; 3(5). DOI:10.1016/j.molmet.2014.05.005
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    • "Fasting drives the production of FGF21 in the liver, where it induces PGC-1α expression, thereby stimulating fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis . In effect, mice lacking FGF21 are unable to fully induce PGC-1α expression in response to a prolonged fast and show impaired gluconeogenesis and ketogenesis (Potthoff et al., 2009). Thus, FGF21 plays an important role in ensuring metabolic regulation during progression from fasting to starvation. "

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