FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho

Kharitonenkov, Alexei; Dunbar, James D.; Bina, Holly A.; Bright, Stuart W.; Moyers, Julie S.; Zhang, Chen; Ding, Liyun; Micanovic, Radmila; Mehrbod, Sean F.; Knierman, Michael D.; Hale, John E.; Coşkun, Tamer; Shanafelt, Armen B.

doi:10.1002/jcp.21357

Cited by 307 publications

(246 citation statements)

References 27 publications

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“…These 40 genes were considered to be potential direct target genes of Rev-erb␣ in EWAT. In this study we focused on ␤Klotho (Klb) because it was one of the most induced potential target genes of Rev-erb␣ in EWAT and is a critical regulator of FGF21 signaling and intermediate metabolism in vitro (28,29) and in vivo (32,47).…”

Section: Resultsmentioning

confidence: 99%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb␣, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erb␣ for Rev-erb␣-binding sites identified ␤Klotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erb␣ in white adipose tissue but not liver. Rev-erb␣ ablation led to the robust elevated expression of ␤Klotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Reverb␣. A major Rev-erb␣-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) ␥, which regulates its activity in the opposite direction. These findings establish Rev-erb␣ as a specific modulator of FGF21 signaling in adipose tissue.Adipose tissue is an important fat storage and endocrine organ whose dysfunction is closely associated with the development of obesity, diabetes mellitus, and cardiovascular disease (1-5). Nuclear receptors are DNA-binding proteins that directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet, and the environment (6). They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, development, reproduction, energy homeostasis, and metabolism (7,8).The nuclear receptor Rev-erb␣ differs from other members of the nuclear receptor superfamily because it lacks a classical activation domain and thus functions as a constitutive repressor of transcription (9 -11). Acting in this repressive manner, Rev-erb␣ has been described as a core component of the mammalian biological clock (12) that links circadian rhythms to metabolism in diverse tissues. Indeed, studies from different groups have revealed Rev-erb␣ as a key regulator of multiple biological processes in various metabolic tissues, including liver (13-15), macrophages (16), muscle (17), brown fat (18), and brain (19). However, little is known about potential role in white adipose tissue (WAT). 3FGF21 is an atypical member of the FGF superfamily that, because of a lack of a heparin binding domain, is able to escape into the circulation, functioning as a hormone to regulate carbohydrate and lipid metabolism (20,21). In the metabolic context, FGF21 was first discovered to induce glucose uptake in 3T3L1 adipocytes (22). Subsequently it was demonstrated that FGF21 administration to obese rodents and non-human primates improves hyperglycemia, lowers elevated triglyceride levels, and reduces body weight (22)(23)(24)(25). In rodents, the mechanisms underlying FGF21 actions include improving whole-body insulin sensitivity and ␤ cell function, reducing hepatic lipogenesis, and enhancing brown fat thermogenic activity (22,23,(25)(26)(27). These effects identify FGF21 as an attractive therapeutic agent f...

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Section: Resultsmentioning

confidence: 99%

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

Jager

Wang

Fang

et al. 2016

Journal of Biological Chemistry

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“…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)(10)(11)(12)(13)(14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5)(6)(7).…”

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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.

639

570

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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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“…FGF21 also has autocrine/paracrine effects, inducing hepatic ketogenesis 9 and promoting sensitization to antidiabetic agents in WAT 17 . The cellular actions of FGF21 are mediated by FGF receptors (mainly FGFR1 and FGFR4 in adipose tissues and liver, respectively) and b-Klotho, a single-pass transmembrane protein that functions as an obligate coreceptor for FGF21 signalling 18,19 . Despite the importance of FGF21 as an endocrine factor, to date, no studies have focused directly on the role of FGF21 in the heart.…”

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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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FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho

Cited by 307 publications

References 27 publications

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

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

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

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