βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism

Ding, Xunshan; Boney-Montoya, Jamie; Owen, Bryn M.; Bookout, Angie L.; Coate, Katie C.; Mangelsdorf, David J.; Kliewer, Steven A.

doi:10.1016/j.cmet.2012.08.002

Cited by 340 publications

(355 citation statements)

References 33 publications

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“…Mice lacking KLB are resistant to both acute and chronic effects of FGF21. However, the acute insulin-sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB (32) or FGFR1 (33), consistent with the notion that direct adipose tissue activation is required for FGF21 action (34).…”

supporting

confidence: 58%

“…The beneficial effects of FGF21 on glucose metabolism and body weight have identified it as a central player in regulating metabolic processes, and adipose tissue is required for its antidiabetic actions (32,33,63). These findings show that FGF21 signaling is modulated by Rev-erb␣ in WAT, not by altering FGF21 levels but through the regulation of its co-receptor KLB in WAT but not in liver.…”

Section: Discussionmentioning

confidence: 55%

“…FGF21 Action Is Enhanced in WAT of Rev-erb␣ KO MicePrevious work has demonstrated that KLB is essential for FGF21 activity both in vitro (28,29) and in vivo (32,47) and that KLB in adipose tissue contributes to the beneficial metabolic actions of FGF21 (32). Therefore, we tested whether the upregulation of KLB in the WAT of Rev-erb␣ KO mice sensitized the mice to the effect of FGF21 by treating WT and Rev-erb␣ KO mice with either vehicle or recombinant human FGF21 protein and then measuring the expression of FGF21 target genes in WAT.…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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supporting

confidence: 58%

Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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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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“…FGFRs are tyrosine kinase receptors, and seven isoforms have been described (1b, 1c, 2b, 2c, 3b, 3c and 4). FGFR1c has been defined as the main mediator of FGF21 response in vivo [10] through an obligate dimerization with the co-receptor β-klotho (KLB) [11]. The co-expression of these two receptors determines the sensitivity of a tissue or organ to FGF21 signaling.…”

Section: Fgf21 Signal Transductionmentioning

confidence: 99%

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Pérez-Martí

Sandoval

Marrero

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21-KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

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National Registry Data and Record Linkage to Inform Postmarket Surveillance of Prosthetic Aortic Valve Models Over 15 Years

et al. 2017

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Post-market evidence generation for medical devices is important yet limited for prosthetic aortic valve devices in the United Kingdom (UK). Objective: To identify prosthetic aortic valve models that display unexpected patterns of mortality or re-intervention using routinely collected national registry data and record linkage. Design: Observational study using the UK National Adult Cardiac Surgery Audit (NACSA) registry for procedures performed between 1998 and 2013. Valves were classified into series of related models. Outcome tracking was performed using multifaceted record linkage. The median follow-up was 4.1 years (maximum 15.3 years). Cox proportional hazards regression with random effects (frailty models) were used to model valve effects on the outcomes, with and without adjustment for (pre-)operative covariates. Setting: All National Health Service and private hospitals in England and Wales who submit data to the NACSA registry. Patients and Interventions: All patients undergoing first-time elective and urgent aortic valve replacement surgery (± coronary artery bypass graft) with a mechanical (n=10 series) or biological (n=15 series) prosthetic valve from 5 primary suppliers, and satisfying pre-specified data quality criteria were included (n=43,782 biological, n=11,084 mechanical). Main Outcome Measures: Time to all-cause mortality or aortic valve re-intervention (surgical or trans-catheter). There were 13,104 deaths and 723 re-interventions during follow-up. Results: Two series of valves were associated with significantly increased hazard of death or reintervention were identified: Sorin Biological Series (frailty 1.18 [95%PI: 1.06 to 1.32]) and 4 Sorin Mitroflow series (frailty 1.19 [95%PI: 1.09 to 1.31]). These results were robust to covariate adjustment, and sensitivity analyses. Three biological valve series were associated with significantly decreased hazard. Conclusions: Meaningful evidence from the analysis of routinely-collected registry data can inform post-market surveillance of medical devices. Although the findings are associated with a number of caveats, two specific biological aortic valve series identified in this study may warrant further investigation.

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βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism

Cited by 340 publications

References 33 publications

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

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

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

National Registry Data and Record Linkage to Inform Postmarket Surveillance of Prosthetic Aortic Valve Models Over 15 Years

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