Current understanding and controversies on the clinical implications of fibroblast growth factor 21

Badakhshi, Yasaman; Jin, Tianru

doi:10.1080/10408363.2020.1864278

“…As discussion above, clinical trials using FGF21 analogues proved their therapeutic potential for attenuating hyperlipidemia. ( 8‐11 ) We suggest that further clinical investigations should test the application of GLP‐1RAs and other GLP‐1–based therapies to the treatment and prevention of NAFLD. Our observations also support a therapeutic strategy in pharmacology: the development of GLP‐1–based multiagonists including the liver hormone FGF21.…”

Section: Discussionmentioning

confidence: 99%

“…( 2,3 ) Intensive investigations also revealed multiple effects of exogenous FGF21 administration on energy homeostasis in animal models, including nonhuman primates, ( 3‐7 ) whereas several clinical trials using FGF21 analogues have proven their therapeutic potential for attenuating hyperlipidemia in subjects with obesity‐associated metabolic disorders. ( 8‐11 ) FGF21‐knockout mice, however, showed reduced hepatic fatty acid activation and β‐oxidation, and these defects can be reversed by exogenous FGF21 administration. ( 12 )…”

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confidence: 99%

“…(14) Other stimulators of Fgf21 expression include fructose feeding, endoplasmic reticulum stress, and the hepatic lipogenic transcription factor carbohydrate response elementbinding protein (ChREBP). (8,15) Furthermore, studies have shown that Fgf21 expression can be positively regulated by dietary polyphenols, including curcumin and resveratrol. (16,17) Glucagon-like peptide 1 (GLP-1) is released by gut endocrine L cells, which stimulate insulin secretion in a plasma glucose concentration-dependent manner.…”

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confidence: 99%

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Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

Liu

¹

,

Pang

²

,

Shao

³

et al. 2021

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Background and Aims Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon‐like peptide 1 (GLP‐1)–based diabetes drugs. As GLP‐1 receptor (GLP‐1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP‐1R, and clarify whether FGF21 mediates certain functions of the GLP‐1R agonist liraglutide. Approach and Results Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high‐fat diet (HFD)‐fed mice and compared with the effects of the dipeptidyl‐peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r−/− mice and liver‐specific FGF21‐knockout (lFgf21‐KO) mice. In wild‐type mouse liver that underwent RNA sequencing and quantitative reverse‐transcription PCR, we observed liraglutide‐stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD‐induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body‐weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide‐treated mice but was not observed in sitagliptin‐treated mice. In HFD‐fed Glp1r−/− mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21‐KO mice undergoing dietary challenge, the body‐weight‐gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. Conclusions We suggest that liraglutide‐stimulated hepatic Fgf21 expression may require GLP‐1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP‐1–based drugs in NAFLD.

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“…However, FGF21 is also recognized as a "stress hormone" and varies among different populations and fluctuate tremendously with fasting and refeeding. So it is essential to unify the technique for its clinical measurement [38].…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Li

¹

,

Wu

²

,

Jia

³

et al. 2021

Journal of Diabetes Research

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Purposes. In this study, we aimed to verify plasma fibroblast growth factor 21 (FGF21) elevation in newly diagnosed overweight patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) and to evaluate the effectiveness of liraglutide on reducing liver fat content and serum (FGF21) levels in those patients. Methods. A 12-week, single-center, prospective study was conducted. Twenty newly diagnosed overweight patients with T2DM and NAFLD were recruited. Twenty healthy age, sex, and body mass index (BMI) matched subjects were enrolled as the control group. Enzyme-linked immunosorbent assay was used to measure serum FGF21 levels. Liver fat content was determined using the 3.0 T whole-body MRI scanner. Results. Those newly diagnosed overweight patients with T2DM and NAFLD had a BMI of 27.6 ± 0.5 kg/m2. They had higher levels of FGF21 ( 159.6 ± 35.7 vs. 124.1 ± 42.9 pg/ml, P < 0.001 ) and increased liver fat content ( 19.3 ± 9.4 vs. 4.5 ± 0.6 %, P < 0.001 ) compared to the controls. Liraglutide treatment for 12 weeks induced a significant 4.9 kg weight loss (95% confidence interval (CI): -6.1, -3.7, P < 0.001 ), which was equivalent to a relative reduction of 6.8% (95% CI: 5.3%, 8.3%, P < 0.001 ). FGF21 levels decreased after the 12-week liraglutide treatment ( 159.6 ± 35.7 vs. 124.2 ± 27.8 pg/ml, P = 0.006 ). There was a positive correlation between relative changes of liver fat content and relative change of FGF21 ( r = 0.645 , P = 0.002 ). FGF21 levels significantly decreased in patients who had a significant decrease in liver fat content (≥29%) (95% CI: -262.8, -55.1, P = 0.006 ); however, there was no significant change in the patients without a significant decrease in liver fat content (<29%) (95% CI: -60.0, 54.1, P = 0.899 ). Conclusions. Liraglutide treatment reduced both liver fat content and FGF21 levels in newly diagnosed overweight patients with T2DM and NAFLD. FGF21 may be a potential biomarker for evaluating the effects of liraglutide treatment on hepatic fat and glucose metabolism.

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“…1 Among the FGF family members, FGF21, FGF19 (the murine orthologue is FGF15) and FGF23, form a special subfamily for possessing low heparin-/heparan sulfate-binding ability. 2 Thus, they can be released into the circulation, serving as endocrine hormones, [2][3][4] while other members exert their functions mainly in paracrine, intracrine, or autocrine manners. 1 Human and mouse FGF21 cDNAs were initially cloned in 2000 by Nishimura and colleagues, and were found to be predominantly expressed in the liver, in contrast to other members of the FGF family.…”

Section: Brief Summary On Fgf2structure and Signaling Pathways That M...mentioning

confidence: 99%

Hepatic hormone FGF21 and its analogues in clinical trials

Shao

¹

,

Jin

²

2022

Chronic Diseases and Translational Medicine

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Fibroblast growth factor 21 (FGF21) is a fasting or stress inducible metabolic hormone produced mainly in the liver. It plays important roles in regulating both glucose and lipid homeostasis via interacting with a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β‐klotho (KLB). For the past decade, great effort has been made on developing FGF21 derivatives or specific FGF21 receptor agonists into therapeutic agents for various metabolic disorders including type 2 diabetes (T2D), obesity, and more importantly, nonalcoholic fatty liver disease (NAFLD). Here we have reviewed FGF21 gene and protein structures, its expression pattern, cellular signaling cascades that mediate FGF21 production and function. We have then summarized the six clinical trials utilizing four FGF21 analogues. Finally, two recent literatures on the development of GLP‐1 and FGF21 dual agonists were presented briefly.

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Current understanding and controversies on the clinical implications of fibroblast growth factor 21

Cited by 13 publications

References 152 publications

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease

Hepatic hormone FGF21 and its analogues in clinical trials

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