The Circulating Metabolic Regulator FGF21 Is Induced by Prolonged Fasting and PPARα Activation in Man

Gälman, Cecilia; Lundåsen, Tomas; Kharitonenkov, Alexei; Bina, Holly A.; Eriksson, Mats; Hafström, Ingiäld; Dahlin, Maria; Åmark, Per; Angelin, Bo; Rudling, Mats

doi:10.1016/j.cmet.2008.06.014

Cited by 445 publications

(435 citation statements)

References 35 publications

(69 reference statements)

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“…Indeed, FGF21-TG mice accumulate significantly more hepatic glycogen than WT mice in the fed state. Interestingly, in humans, circulating glucagon concentrations spike after 3-5 days of fasting and then decline, whereas plasma FGF21 levels increase only after a 7-day fast (31)(32)(33). These findings raise the possibility that FGF21 maintains gluconeogenesis and ketogenesis in the context of prolonged fasting and starvation, when glycogen stores are depleted and glucagon levels have fallen.…”

Section: Discussionmentioning

confidence: 67%

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FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

617

564

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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 proliferatoractivated receptor ␥ coactivator protein-1␣ (PGC-1␣), 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-1␣ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis I n mammals, the liver plays a crucial role in maintaining systemic energy balance during fasting and starvation through coordinate effects on carbohydrate and lipid metabolism. During the early stages of fasting, the liver mobilizes glucose from its glycogen stores. As fasting progresses and glycogen reserves are depleted, the liver oxidizes fat to provide both energy for gluconeogenesis and substrate for ketogenesis. This synchronization of hepatic lipid and carbohydrate metabolism is critical for the normal fasting response; disruption of either one of these pathways has profound effects on the other (1-4).Hormones such as glucagon, catecholamines, and glucocorticoids have important roles in controlling substrate utilization and maintaining energy balance during fasting. Recently, the hormone fibroblast growth factor 21 (FGF21) was shown to be induced in the liver during fasting (5-7). FGF21 is an unusual FGF family member in that it lacks the conventional heparinbinding domain (8) and thus can diffuse away from its tissue of origin and function as a hormone. FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with ␤-klotho, a membrane-spanning protein (9-14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5-7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5,6,15) and blocking the growth hormone signaling pathway (16). FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia (6). Pharmacologic administration of FGF21 to insulin-resistant rodents and monkeys improves glucose tolerance and reduces plasma insulin and triglyceride concentrations (15,17).Peroxisome proliferator-activated receptor ␥ coactivator protein-1␣ (PGC-1␣) is a transcriptional coactivator ...

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Section: Discussionmentioning

confidence: 67%

“…Several properties of FGF21 are consistent with this hypothesis. First, circulating FGF21 concentrations are induced in rodents and humans only after prolonged fasting (5,6,33). Second, FGF21 sensitizes mice to torpor, a hibernation-like state that occurs only under severe nutritional stress (6).…”

Section: Discussionmentioning

confidence: 99%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

617

564

View full text Add to dashboard Cite

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“…Recent studies have shown that β-klotho, a single-pass transmembrane protein related to klotho, functions as a cofactor required for FGF21 signaling (17)(18)(19). Because β-klotho acts as an essential cofactor for FGF21 signaling, its expression limits the tissue-specific activities of FGF21 to the liver, pancreas, and adipose tissues, where β-klotho is predominantly expressed (17-19).More recently, the role of FGF21 in the liver has been established; FGF21 has been shown to play an important role in regulating energy homeostasis during starvation (20)(21)(22). FGF21 is induced by fasting and is required for activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis during fasting (20)(21)(22).…”

mentioning

confidence: 99%

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Chau¹,

Gao²,

Yang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

441

344

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Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD + levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/ threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1α-dependent mechanism in adipocytes.A MP-activated protein kinase (AMPK) is a major metabolic energy sensor and master regulator of metabolic homeostasis (1). LKB1, a serine threonine kinase, is a major regulator of AMPK activation. LKB1 directly phosphorylates Thr-172 of AMPK and activates its kinase activity (2). LKB1 expression is induced upon exercise and acts as a critical mediator of gluconeogenesis in the liver (3). Recently, AMPK has been shown to play an important role in the therapeutic benefits of metformin (1, 4), thiazolidinediones (5), and exercise (6, 7), all cornerstones in the management of type 2 diabetes and metabolic syndrome. Activation of AMPK maintains energy balance by switching on catabolic pathways, enhancing oxidative metabolism and mitochondrial biogenesis (1). Recently, AMPK was found to enhance NAD + -dependent type III deacetylase sirtuin 1 (SIRT1) activity by increasing cellular NAD + levels, resulting in modulation of the activity of downstream SIRT1 targets (8).SIRT1 plays an important role in metabolic function and longevity in mammals (9, 10). Activation of SIRT1 also results in selective nutrient utilization and enhanced mitochondrial oxidative function to regulate energy balance. Both AMPK and SIRT1 act in concert with the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), to regulate energy homeostasis in response to environmental and ...

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“…Fibroblast growth factor 21 (FGF21), a secreted protein that acts as a metabolic regulator, is involved in the control of glucose homeostasis, insulin sensitivity and ketogenesis 9,10 . The liver is considered the main site of production and release of FGF21 into the blood 9,11 , but extra-hepatic tissues, such as white adipose tissue (WAT) and brown adipose tissue (BAT) and skeletal muscle also express FGF21 (refs 12-14).…”

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confidence: 99%

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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The Circulating Metabolic Regulator FGF21 Is Induced by Prolonged Fasting and PPARα Activation in Man

Cited by 445 publications

References 35 publications

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

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