Endocrine fibroblast growth factors 15/19 and 21: from feast to famine

Potthoff, Matthew J.; Kliewer, Steven A.; Mangelsdorf, David J.

doi:10.1101/gad.184788.111

Cited by 397 publications

(422 citation statements)

References 139 publications

(197 reference statements)

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“…Furthermore, we observed a pronounced reduction in the level of circulating fibroblast growth factor 21 (FGF21) in fasted LKO animals (Fig. 2h), a liver-secreted hormone that has critical roles in lipid homoeostasis during starvation [27][28][29] . Given that FGF21 is a key endocrine regulator of adipocyte lipolysis 28 , this may account for, at least partially, the decreased levels of circulating FFAs in fasted LKO mice (Fig.…”

Section: Resultsmentioning

confidence: 98%

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

et al. 2014

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Although the mammalian IRE1a-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1a signalling in vivo remains poorly understood. Here we show that hepatic IRE1a functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1a-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1a results in impairment of fatty acid b-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1a null mice. XBP1s directly binds to and activates the promoter of PPARa, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1a promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial b-oxidation and ketogenesis through the XBP1s-PPARa axis.

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Section: Resultsmentioning

confidence: 98%

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

et al. 2014

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“…Many studies have established the importance of FGF21 that functions as a hormone to regulate carbohydrate and lipid metabolism (24). Despite its remarkable pharmacological beneficial effects in improving metabolic parameters such as body weight, insulin sensitivity, and hyperlipidemia, increased circulating levels of FGF21 have been shown to be associated with human obesity, type 2 diabetes, and NAFLD (34 -40).…”

Section: Discussionmentioning

confidence: 99%

“…As a hepatokine, FGF21 expression is responsive to nutritional states (24), and animal model studies have shown that hepatic FGF21 is transcriptionally controlled by the nuclear receptor PPAR␣ FIGURE 8. XBP1s transactivates the transcriptional activity of the Fgf21 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Fibroblast growth factor 21 (FGF21), an atypical member of the FGF family, functions as a hormone that has a wide range of endocrine, autocrine, and pharmacological actions on carbohydrate and lipid metabolism (24). It has been shown in mouse models that FGF21 is secreted from the liver in response to extended periods of fasting, and its expression is controlled by PPAR␣, a master regulator of the starvation response (25,26).…”

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confidence: 99%

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Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis

Jiang

Cheng

Fang

et al. 2014

Journal of Biological Chemistry

160

144

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Background: Although both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1␣-XBP1 pathway, FGF21 could alleviate ER stress-induced liver steatosis. Conclusion: FGF21 acts as a metabolic effector of the UPR program, exerting feedback effects upon lipid metabolism. Significance: These findings reveal a regulatory mechanism linking FGF21 actions to metabolic ER stress.

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“…FGF21 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).…”

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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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Endocrine fibroblast growth factors 15/19 and 21: from feast to famine

Cited by 397 publications

References 139 publications

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis

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

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