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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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    • "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. "
    Frontiers in Aging Neuroscience 07/2014; 6:156. DOI:10.3389/fnagi.2014.00156 · 2.84 Impact Factor
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    • "FGF21 has an endocrine function in the body and plays a role in cell metabolism by stimulating glucose uptake (Kharitonenkov et al. 2005) by influencing fatty acid metabolism (Potthoff et al. 2009) and by controlling lipoprotein receptor (LDLR) levels and lipoprotein uptake in liver cells (Do et al. 2012). FGF21 was shown to increase PGC-1α in liver and fat tissue (Potthoff et al. 2009; Fisher et al. 2012) and to regulate energy homeostasis in adipocytes via the SIRT1-PGC1 pathway (Chau et al. 2010). The expression and functions of FGF21 in brain cells are so far unknown. "
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    ABSTRACT: Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD + -dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.
    SpringerPlus 01/2014; 3(2). DOI:10.1186/2193-1801-3-2
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    • "The physiological and pharmacological role of FGF21 is not well understood, but the action of FGF21 seems to depend on the nutritional state of the animal. In physiology where hepatic FGF21 is increased in response to fasting [27], FGF21 might play an important role in induction of gluconeogenesis [28]; while the insulin sensitizing effect of FGF21 treatment in an insulin-resistant diabetic animal might override the physiological effect of FGF21 and thereby leads to a decrease in hepatic glucose production and blood glucose [3]. Therefore, a significant increase in hepatic FGF21 in a diabetic animal could in addition to decrease hepatic glucose production, reach adipocytes, and lead to an increase in glucose uptake [3]. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of glucose and lipid metabolism; however, the exact mechanism of action and regulation of FGF21 is not fully understood. Metabolic status plays an important role in the regulation of FGF21, and we therefore examined whether metformin, an indirect AMPK-activator, regulates FGF21 expression in hepatocytes. FGF21 mRNA and protein expression were determined after incubation of primary cultured rat and human hepatocytes with metformin for 24 hours. To study the role of AMPK in the putative regulation of FGF21, hepatocytes were incubated with Compound C (an AMPK inhibitor) in the presence of metformin. A strong dose-dependent increase in FGF21 expression was observed in both rat and human hepatocytes treated with metformin. This effect was blocked by addition of the AMPK-inhibitor Compound C. The study shows that metformin is a potent inducer of hepatic FGF21 expression and that the effect of metformin seems to be mediated through AMPK activation. As FGF21 therapy normalizes blood glucose in animal models of type 2 diabetes, the induction of hepatic FGF21 by metformin might play an important role in metformin's antidiabetic effect.
    Experimental Diabetes Research 10/2012; 2012:465282. DOI:10.1155/2012/465282 · 3.54 Impact Factor
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