Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice

Children's Health Research Institute, London, Ontario.
Gastroenterology (Impact Factor: 13.93). 08/2009; 137(5):1795-804. DOI: 10.1053/j.gastro.2009.07.064
Source: PubMed

ABSTRACT Fibroblast growth factor 21 (FGF21) acts as a hormonal regulator during fasting and is involved in lipid metabolism. Fgf21 gene expression is regulated by peroxisome proliferator-activated receptor (PPAR)-dependent pathways, which are enhanced during pancreatitis. Therefore, the aim of this study was to investigate FGF21's role in pancreatic injury.
Fgf21 expression was quantified during cerulein-induced pancreatitis (CIP) or following mechanical or thapsigargin-induced stress through Northern blot analysis, in situ hybridization, and quantitative reverse transcription polymerase chain reaction. FGF21 protein was quantified by Western blot analysis. Isolated acinar cells or AR42J acinar cells were treated with recombinant FGF21 protein, and extracellular regulated kinase 1/2 activation was examined. The severity of CIP was compared between wild-type mice and mice overexpressing FGF21 (FGF21Tg) or harboring a targeted deletion of Fgf21 (Fgf21(-/-)).
Acinar cell Fgf21 expression markedly increased during CIP and following injury in vitro. Purified FGF21 activated the extracellular regulated kinase 1/2 pathway in pancreatic acinar cells. The severity of CIP is inversely correlated to FGF21 expression because FGF21Tg mice exhibited decreased serum amylase and decreased pancreatic stellate cell activation, whereas Fgf21(-/-) mice had increased serum amylase and tissue damage. The expression of Fgf21 was also inversely correlated to expression of Early growth response 1, a proinflammatory and profibrotic transcription factor.
These studies suggest a novel function for Fgf21 as an immediate response gene protecting pancreatic acini from overt damage.

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Available from: Alexei Kharitonenkov, Jul 07, 2015
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    • "In addition, secreted FGF21 may also function in an endocrine manner targeting the brain to regulate reproductive behavior, appetite and locomotor activity (Bookout et al., 2013; Owen et al., 2013). Production of FGF21 has subsequently been detected in multiple systemic tissues, including pancreas, brown adipose tissue (BAT), skeletal and cardiac muscle (Hondares et al., 2011; Johnson et al., 2009; Planavila et al., 2013), and appears to have a variety of additional physiological functions. For example, cold-exposure increases FGF21 production in BAT (Chartoumpekis et al., 2011; Hondares et al., 2011) where it stimulates the expression of several thermogenic genes (Fisher et al., 2012). "
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    ABSTRACT: This article is part of a Special Issue "Energy Balance". FGF21 is an endocrine member of the fibroblast growth factor superfamily that has been shown to play an important role in the physiological response to nutrient deprivation. Food restriction enhances hepatic FGF21 production, which serves to engage an integrated response to energy deficit. Specifically, elevated FGF21 levels lead to reduced gluconeogenesis and increased hepatic ketogenesis. However, circulating FGF21 concentrations also paradoxically rise in states of metabolic dysfunction such as obesity. Furthermore, multiple peripheral tissues also produce FGF21 in addition to the liver, raising questions as to its endocrine and paracrine roles in the control of energy metabolism. The objectives of this study were to measure plasma FGF21 concentrations in the Siberian hamster, a rodent which undergoes a seasonal cycle of fattening and body weight gain in the long days (LD) of summer, followed by reduction of appetite and fat catabolism in the short days (SD) of winter. Groups of adult male hamsters were raised in long days, and then exposed to SD for up to 12weeks. Chronic exposure of LD animals to SD led to a significant increase in circulating FGF21 concentrations. This elevation of circulating FGF21 was preceded by an increase in liver FGF21 protein production evident as early as 4weeks of exposure to SD. FGF21 protein abundance was also increased significantly in interscapular brown adipose tissue, with a positive correlation between plasma levels of FGF21 and BAT protein abundance throughout the experimental period. Epididymal white adipose tissue and skeletal muscle (gastrocnemius) also produced FGF21, but levels did not change in response to a change in photoperiod. In summary, a natural programmed state of fat catabolism was associated with increased FGF21 production in the liver and BAT, consistent with the view that FGF21 has a role in adapting hamsters to the hypophagic winter state.
    Hormones and Behavior 06/2014; 66(1):180-185. DOI:10.1016/j.yhbeh.2014.03.013 · 4.51 Impact Factor
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    • "It is difficult to pinpoint the exact contributions that hepatic FGF-21 mRNA expression has on circulating FGF-21 levels (Zhang et al. 2008; Berglund et al. 2010). This is especially challenging as multiple tissues, including liver (Dushay et al. 2010; Fisher et al. 2010), adipose (Fisher et al. 2010), pancreas (Johnson et al. 2009), and possibly muscle (Izumiya et al. 2008), express FGF-21 and could contribute to circulating levels. Because FGF-21 has been shown to act in both a paracrine and endocrine fashion (Fisher et al. 2011), FGF-21 may target both local hepatocytes or may contribute to the FGF-21 serum concentrations. "
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    ABSTRACT: Chronic treatment with fibroblast growth factor 21 (FGF-21) favorably improves obesity and nonalcoholic fatty liver disease (NAFLD) outcomes; however, FGF-21 expression is paradoxically elevated in obese conditions. Here, we sought to determine the effects of obesity prevention by daily exercise (EX) vs. caloric restriction (CR) on hepatic FGF-21 in the hyperphagic, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. Four-week-old male OLETF rats were randomized into groups (n = 7-8 per group) of ad libitum fed, sedentary (OLETF-SED), voluntary wheel running exercise (OLETF-EX), or CR (OLETF-CR; 70% of SED) until 40 weeks of age. Nonhyperphagic, Long-Evans Tokushima Otsuka (LETO-SED) rats served as controls. Both daily EX and CR prevented obesity and NAFLD development observed in the OLETF-SED animals. This was associated with significantly (p < 0.01) lower serum FGF-21 (~80% lower) and hepatic FGF-21 mRNA expression (~65% lower) in the OLETF-EX and OLETF-CR rats compared with the OLETF-SED rats. However, hepatic FGF-21 protein content was reduced to the greatest extent in the OLETF-EX animals (50% of OLETF-SED) and did not differ between the OLETF-SED and OLETF-CR rats. Hepatic FGF-21 signaling mediators - hepatic FGF-21 receptor 2 (FGFR2, mRNA expression), hepatic FGF-21 receptor substrate 2 (FRS2, protein content), and co-receptor β-Klotho (protein content) - were all elevated (60%-100%, ~40%, and +30%-50%, respectively) in the OLETF-EX and OLETF-CR animals compared with the OLETF-SED animals. Daily exercise and caloric restriction modulate hepatic FGF-21 and its primary signaling mediators in the hyperphagic OLETF rat. Enhanced metabolic action of FGF-21 may partially explain the benefits of exercise and caloric restriction on NAFLD outcomes.
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    • "Thus, FGF21 is restricted to acting in an autocrine or paracrine manner in WAT, much like conventional FGFs. FGF21 is also proposed to act through an autocrine mechanism in exocrine pancreas and liver (Fisher et al., 2010; Johnson et al., 2009). In recent human studies, rosiglitazone treatment had no effect on circulating FGF21 concentrations in subjects who were either healthy or had impaired glucose tolerance (Christodoulides et al., 2009; Mai et al., 2009), but significantly decreased circulating FGF21 in patients with type 2 diabetes (Li et al., 2009a). "
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    ABSTRACT: Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ.
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