FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice

Véniant, Murielle M.; Hale, Clarence; Helmering, Joan; Chen, Michelle; Stanislaus, Shanaka; Busby, Jim; Vonderfecht, Steven; Xu, Jing; Lloyd, D. J.

doi:10.1371/journal.pone.0040164

Cited by 131 publications

(125 citation statements)

References 28 publications

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“…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: 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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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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“…Fibroblast growth factor (FGF)21, a metabolic hormone predominantly produced by liver, has many functional similarities to adiponectin in regulating glucose and lipid metabolism and insulin sensitivity (33)(34)(35)(36)(37). FGF21 acts through a cell-surface receptor composed of a canonical FGF receptor (FGFR) associated with a coreceptor, b-Klotho (KLB) (36)(37)(38).…”

mentioning

confidence: 99%

“…Pharmacologic FGF21 treatment counteracts obesity and its related metabolic disorders including dyslipidemia, glucose intolerance, and insulin resistance (39). In white adipose tissue (WAT), a main target of FGF21 actions, FGF21 stimulates glucoses uptake, modulates lipolysis, and enhances adiponectin expression and secretion (34)(35)(36)(37)39,40). FGF21 also acts directly in the hypothalamus to modulate energy balance and insulin sensitivity (41,42).…”

mentioning

confidence: 99%

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

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Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

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“…Systemic administration and overexpression of FGF21 was shown to reduce diet induced as well as genetic obesity, and FGF21 is now considered to have promising therapeutic potential (Ohta and Itoh 2014). By studying lipodystrophic mice (Veniant et al 2012) or mice with fatspecific deletion of the FGF receptor FGFR1 (Adams et al 2012), it was shown that adipose tissue is the key tissue for the majority of the FGF21-dependent metabolic effects by binding of FGF21 to the FGFR1-KLB complex (Luo and McKeehan 2013). The high-fat-diet-induced increase in FGF21 is thought to be linked to a FGF21 resistance as evident by an attenuation of FGF21 effects on liver and adipocytes (Fisher et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

et al. 2015

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Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia [300 mg/dl) was fully prevented in both F1-and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue.

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FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice

Cited by 131 publications

References 28 publications

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

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

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

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