Molecular determinants of FGF‐21 activity—synergy and cross‐talk with PPARγ signaling

Moyers, Julie S.; Shiyanova, Tatiyana; Mehrbod, Farrokh; Dunbar, James D.; Noblitt, Timothy W.; Otto, Keith A.; Reifel‐Miller, Anne; Kharitonenkov, Alexei

doi:10.1002/jcp.20847

Cited by 170 publications

(144 citation statements)

References 29 publications

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“…Addition of recombinant FGF21 to adipocytes was found to stimulate insulin-independent glucose uptake by enhancing the expression of GLUT1 (7). A recent study has demonstrated a profound synergy between FGF21 and the antidiabetic agent rosiglitazone (a peroxisome proliferator-activated receptor ␥ [PPAR␥] agonist) in stimulating glucose uptake (14). The metabolic effects of FGF21 in adipocytes were mediated by ␤-Klotho, a single-pass transmembrane protein whose expression is induced during adipogenesis (15).…”

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confidence: 99%

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans

et al. 2008

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OBJECTIVE-Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans. RESEARCH DESIGN AND METHODS-A newly developedimmunoassay was used to measure serum FGF21 levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF21 in the liver and adipose tissues were quantified by real-time PCR.RESULTS-Serum FGF21 levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF21 correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF21 and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF21 was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations in humans.CONCLUSIONS-FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF21, warrants further investigation.

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confidence: 99%

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans

et al. 2008

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“…Ligand activation of PPAR␥ acted in the opposite direction, inducing the transcription of Klb and its eRNAs. KLB was also found to be up-regulated in EWAT of mice treated with PPAR␥ ligands (58,59). Moreover, knockdown of PPAR␥ led to a decrease in KLB mRNA level in 3T3-L1 adipocytes.…”

Section: Discussionmentioning

confidence: 89%

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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“…However, this finding may not necessarily mean that the impact of FGF21 on glucose metabolism is insignificant. The effect of FGF21 on glucose uptake becomes evident several hours after the stimulation and lasts for 24 h or longer (7) even though FGF21-induced Akt phosphorylation diminishes within 30 min in 3T3-L1 adipocytes (17). In contrast, insulin-induced glucose uptake becomes evident within minutes after stimulation in these cells and attenuates within hours.…”

Section: Fgf21 Activity Depends On ␤Klotho Expression In Adipocytesmentioning

confidence: 99%

βKlotho is required for metabolic activity of fibroblast growth factor 21

Ogawa

Kurosu

Yamamoto

et al. 2007

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

556

470

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Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine factor that stimulates glucose uptake in adipocytes. Here, we show that FGF21 activity depends on ␤Klotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. ␤Klotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and activate the MAP kinase cascade. Knockdown of ␤Klotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF21. Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without ␤Klotho expression. Thus, ␤Klotho functions as a cofactor essential for FGF21 activity.Klotho ͉ glucose ͉ adipocyte ͉ siRNA ͉ GLUT1

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Molecular determinants of FGF‐21 activity—synergy and cross‐talk with PPARγ signaling

Cited by 170 publications

References 29 publications

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans

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

βKlotho is required for metabolic activity of fibroblast growth factor 21

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