Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis

Markan, Kathleen R.; Potthoff, Matthew J.

doi:10.1016/j.semcdb.2015.09.021

Cited by 86 publications

(69 citation statements)

References 116 publications

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“…Importantly, hepatic overexpression of Pparγ2 and Mogat1 can drive liver steatosis even under a normal diet 27 41. While the influence of FGF15 on metabolic regulation in extrahepatic tissues ( eg, adipose tissue) is likely relevant for systemic lipid metabolism,39 42 we believe that the repressive effect of FGF15/19 on liver Pparγ2 expression may be relevant for the metabolic adaptation to fat intake. In support of this, we found that exogenous FGF15/19 administration inhibited hepatic Pparγ2 expression and function ( ie, Pparγ2 target genes expression) and that the expression of PPARγ2 was markedly induced in the liver of obese patients, who also show reduced FGF19 circulating levels 28 .…”

Section: Discussionmentioning

confidence: 90%

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Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

Álvarez‐Sola

Uriarte

Latasa

et al. 2017

Gut

137

122

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Objective Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration. Design Fgf15−/− mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH. Results Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15 −/− mice. Hepatic expression of Pparγ2 was elevated in Fgf15 −/− mice, being reversed by FGF19 treatment. PA induced FGF15/ 19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH. Conclusions FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.

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Section: Discussionmentioning

confidence: 90%

“…In addition to its inhibitory effect on hepatic BA synthesis, FGF15/19 has been implicated in the regulation of energy homeostasis 8 9 39. It was early observed that FGF19 transgenic mice showed reduced fat content on a normal diet and were protected from diet-induced obesity 10.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

Álvarez‐Sola

Uriarte

Latasa

et al. 2017

Gut

137

122

View full text Add to dashboard Cite

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“…Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates energy homeostasis (Markan and Potthoff, 2015). Single-nucleotide polymorphisms in the human FGF21 gene were recently associated with changes in macronutrient intake (i.e., the percentage of diet derived from carbohydrate, fat, or protein) (Chu et al, 2013; Tanaka et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

et al. 2016

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SUMMARY The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal which acts centrally to suppress the intake of “sweets.”

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“…These features make it a promising potential therapy for the treatment of type 2 diabetes [1–3]. Fgf21 is primarily expressed in the liver, white and brown adipose tissues, and the pancreas [4, 5].…”

Section: Introductionmentioning

confidence: 99%

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice

et al. 2016

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Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

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Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis

Cited by 86 publications

References 116 publications

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration

FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver

Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice

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