Endocrine Fibroblast Growth Factors 15/19 and 21: from feast to famine

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Genes & development (Impact Factor: 10.8). 02/2012; 26(4):312-24. DOI: 10.1101/gad.184788.111
Source: PubMed


We review the physiology and pharmacology of two atypical fibroblast growth factors (FGFs)-FGF15/19 and FGF21-that can function as hormones. Both FGF15/19 and FGF21 act on multiple tissues to coordinate carbohydrate and lipid metabolism in response to nutritional status. Whereas FGF15/19 is secreted from the small intestine in response to feeding and has insulin-like actions, FGF21 is secreted from the liver in response to extended fasting and has glucagon-like effects. FGF21 also acts in an autocrine fashion in several tissues, including adipose. The pharmacological actions of FGF15/19 and FGF21 make them attractive drug candidates for treating metabolic disease.

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    • "Similar metabolic effects were seen in diabetic rhesus monkeys and patients with type 2 diabetes (Gaich et al., 2013; Kharitonenkov et al., 2007; Vé niant et al., 2012b). FGF21 acts through a cell surface receptor comprised of an FGF receptor (FGFR), with FGFR1c the preferred isoform, in complex with bKlotho (reviewed in Potthoff et al., 2012). While the FGFRs are broadly expressed, bKlotho is expressed in a more limited set of tissues, including WAT, BAT, and liver (Fon Tacer et al., 2010). "
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    ABSTRACT: The mechanism by which pharmacologic adminis-tration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that bKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mecha-nistic explanation for the strong pharmacologic ef-fects of FGF21 on energy expenditure and weight loss in obese animals. INTRODUCTION
    Cell Metabolism 08/2014; DOI:10.1016/j.cmet.2014.07.012 · 17.57 Impact Factor
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    • "In fasting, FGF21 expression is induced by peroxisome proliferator-activated receptor α (PPARα) in the liver [15,16] and acts through endocrine mechanisms for adaptive starvation responses including gluconeogenesis, ketogenesis, torpor, and inhibition of somatic growth [12,14,17]. In the fed state, FGF21 expression is induced by PPARγ in white adipose tissue and acts in an autocrine or paracrine fashion to increase PPARγ activity [14,18,19,20]. As a consequence, during feeding, the induction of FGF21 in white adipose tissue fails to increase circulating levels of FGF21 [21]. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is an attractive target for treating metabolic disease due to its wide-ranging beneficial effects on glucose and lipid metabolism. Circulating FGF21 levels are increased in insulin-resistant states; however, endogenous FGF21 fails to improve glucose and lipid metabolism in obesity, suggesting that metabolic syndrome is an FGF21-resistant state. Therefore, transcription factors for FGF21 are potential drug targets that could increase FGF21 expression in obesity and reduce FGF21 resistance. Despite many studies on the metabolic effects of FGF21, the transcriptional regulation of FGF21 gene expression remains controversial and is not fully understood. As the FGF21 transcription factor pathway is one of the most promising targets for the treatment of metabolic syndrome, further investigation of FGF21 transcriptional regulation is required.
    06/2014; 29(2):105-11. DOI:10.3803/EnM.2014.29.2.105
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    • "Fibroblast growth factor 21 (FGF21) is a newly identified hormone that plays a role in mediating adaptive changes in carbohydrate and lipid metabolism in response to nutritional stress [1], [2]. For example, starvation causes a robust increase in FGF21 expression in liver, the predominant site of FGF21 production [3], [4], [5]. "
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    ABSTRACT: Previous studies have shown that whole body deletion of the glucagon receptor suppresses the ability of starvation to increase hepatic fibroblast growth factor 21 (FGF21) expression and plasma FGF21 concentration. Here, we investigate the mechanism by which glucagon receptor activation increases hepatic FGF21 production. Incubating primary rat hepatocyte cultures with glucagon, dibutyryl cAMP or forskolin stimulated a 3-4-fold increase in FGF21 secretion. The effect of these agents on FGF21 secretion was not associated with an increase in FGF21 mRNA abundance. Glucagon induction of FGF21 secretion was additive with the stimulatory effect of a PPARα activator (GW7647) on FGF21 secretion. Inhibition of protein kinase A (PKA) and downstream components of the PKA pathway [i.e. AMP-activated protein kinase and p38 MAPK] suppressed glucagon activation of FGF21 secretion. Incubating hepatocytes with an exchange protein directly activated by cAMP (EPAC)-selective cAMP analog [i.e. 8-(4-chlorophenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (cpTOME)], stimulated a 3.9-fold increase FGF21 secretion, whereas inhibition of the EPAC effector, Rap1, suppressed glucagon activation of FGF21 secretion. Treatment of hepatocytes with insulin also increased FGF21 secretion. In contrast to glucagon, insulin activation of FGF21 secretion was associated with an increase in FGF21 mRNA abundance. Glucagon synergistically interacted with insulin to stimulate a further increase in FGF21 secretion and FGF21 mRNA abundance. These results demonstrate that glucagon increases hepatic FGF21 secretion via a posttranscriptional mechanism and provide evidence that both the PKA branch and EPAC branch of the cAMP pathway play a role in mediating this effect. These results also identify a novel synergistic interaction between glucagon and insulin in the regulation of FGF21 secretion and FGF21 mRNA abundance. We propose that this insulin/glucagon synergism plays a role in mediating the elevation in FGF21 production during starvation and conditions related to metabolic syndrome.
    PLoS ONE 04/2014; 9(4):e94996. DOI:10.1371/journal.pone.0094996 · 3.23 Impact Factor
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