Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects

Xu, Jing; Stanislaus, Shanaka; Chinookoswong, Narumol; Lau, Yvonne; Hager, Todd; Patel, Jennifer; Ge, Hongfei; Weiszmann, Jen; Lu, Shu-Chen; Graham, Melissa; Busby, Jim; Hecht, Randy; Li, Yuesheng; Yang, Li; Lindberg, Richard A.; Véniant, Murielle M.

doi:10.1152/ajpendo.00348.2009

Cited by 296 publications

(286 citation statements)

References 24 publications

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“…Our present data clearly establish that FGF21 has a strong impact on cardiac function. FGF receptors are highly expressed in the heart, as shown here and observed previously 25 . We found in heart significant levels of b-Klotho protein, the coreceptor required for the biological action of FGF21 (refs 19,21).…”

Section: Discussionsupporting

confidence: 88%

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

et al. 2013

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Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21 À / À mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21 À / À mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21 À / À neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy.

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Section: Discussionsupporting

confidence: 88%

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

et al. 2013

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“…In adipose tissue, FGF21 simultaneously induces lipid accumulation, uncoupling, biogenesis and inhibition of lipolysis, indicative of a state of futile cycling (11,16).…”

Section: Introductionmentioning

confidence: 99%

Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21

Chartoumpekis

Habeos

Ziros

et al. 2011

Mol Med

222

157

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Fibroblast growth factor-21 (FGF21) is a pleiotropic protein involved in glucose, lipid metabolism and energy homeostasis, with main tissues of expression being the liver and adipose tissue. Brown adipose tissue (BAT) is responsible for cold-induced thermogenesis in rodents. The role of FGF21 in BAT biology has not been investigated. In the present study, wild-type C57BL/6J mice as well as a brown adipocyte cell line were used to explore the potential role of cold exposure and β3-adrenergic stimulation in the expression of FGF21 in BAT. Our results demonstrate that short-term exposure to cold, as well as β3-adrenergic stimulation, causes a significant induction of FGF21 mRNA levels in BAT, without a concomitant increase in FGF21 plasma levels. This finding opens new routes for the potential use of pharmaceuticals that could induce FGF21 and, hence, activate BAT thermogenesis.

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“…When FGF21 expression was strongly induced in response to chemical ER stress inducers, such as tunicamycin, a rapid decline in increased FGF21 expression was observed even in the presence of these chemical inducers (data not shown). In addition, it is well known that circulating FGF21 protein is labile and has a short halflife (20,21). In contrast, adenovirus-mediated expression is thought to keep its circulating concentration steady at relatively high levels.…”

Section: Discussionmentioning

confidence: 99%

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

Maruyama

Shimizu

Hashidume

et al. 2018

Journal of Nutritional Science and Vitaminology

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Summary Fibroblast growth factor 21 (FGF21), mainly synthesized and secreted from the liver, is an endocrine FGF that regulates glucose and fatty acid metabolism to maintain whole body energy homeostasis. Gene expression of FGF21 was previously reported to be induced by endoplasmic reticulum (ER) stress through activating transcription factor 4 (ATF4). It has been reported that drug-induced ER stress is reduced by overexpression of FGF21. However, the function of endogenous FGF21 under physiological conditions such as the postprandial state remains unknown. Here, we examined the effects of both endogenous and exogenous FGF21 on postprandial hepatic ER stress. In mice, postprandial and tunicamycin-induced ER stress was significantly reduced by overexpression of FGF21 using a recombinant adenovirus. FGF21-deficient mice exhibited a more considerable increase in drug-induced ER stress target gene expression than wild-type mice. Following refeeding after fasting, FGF21 deficiency caused severe ER stress in the liver. The postprandial ER stress response was significantly reduced when hepatic FGF21 gene expression was increased by feeding a diet containing the soy protein b-conglycinin which activates ATF4. Together, these results demonstrate that FGF21 reduces the increased expression of a subset of genes in the liver in response to ER stress and may correct metabolic disorders caused by ER stress. Key Words FGF21, ER stress, ATF4, b-conglycinin Fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily (also known as the FGF19 subfamily), is mainly produced by the liver. FGF21 is secreted into the blood circulation, after which it acts on target tissues through a cell-surface FGF receptor (FGFR) together with its coregulator, bKlotho (1). In adipose tissues, FGF21 induces lipolysis and glucose uptake by activation of hormone sensitive lipase and glucose transporter 4, respectively (2, 3). Some hepatic energy metabolic pathways, including ketogenesis and gluconeogenesis, are also regulated by FGF21 in response to fasting. Expression of FGF21 is transcriptionally regulated during fasting via peroxisome proliferator-activated receptor a (PPARa), a nuclear hormone receptor (2, 4). More importantly, several studies revealed that FGF21 improves whole-body insulin sensitivity, inhibits high-fat diet-induced body weight gain and reduces fatty liver disease. Thus, FGF21 is an attractive target molecule for the prevention of metabolic diseases.Endoplasmic reticulum (ER) stress is triggered by excess accumulation of either unfolded or misfolded proteins in the ER, which in turn activates three ER membrane proteins: activating transcription factor 6a (ATF6a), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK). During ER stress, activation of PERK results in the phosphorylation of eukaryotic initiation factor 2a (eIF2a) and translational activation of activating transcription factor 4 (ATF4). Subsequently, ATF4 induces a series of target genes involved in amino acid metabolism, red...

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Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects

Cited by 296 publications

References 24 publications

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21

FGF21 Alleviates Hepatic Endoplasmic Reticulum Stress under Physiological Conditions

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