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RNA-Seq analysis on the liver of mice treated with high-fat diet and liraglutide

ABSTRACT: GLP-1 based diabetes drugs are effective to reduce hepatic lipid accumulation beyong glycemic control. As GLP-1 receptor (GLP-1R) is not expressed in hepatocytes, the mechanism behind the beneficial effects of GLP-1 based drugs on the liver remained elusive. Several studies have shown that the expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based drugs. Therefore, the present study aimed to assess such stimulation in mice and in mouse primary hepatocytes, determine whether hepatic FGF21 mediates functions of the GLP-1R agonist liraglutide, and to explore the potential mechanisms of liraglutide regulating the expression of FGF21. In high-fat diet induced obese mice, we observed hepatic and plasma FGF21 elevation, improved glucose disposal, and reduced plasma triglyceride levels by liraglutide treatment. Moreover, RNA-sequencing on the liver suggested that Fgf21 was the most upregulated gene after liraglutide treatment. In liver-specific FGF21 knock-out mice on high-fat and high-fructose diet, the body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced. These studies implied that hepatic FGF21 was the critical mediator of liraglutide-induced metabolic improvement.

ORGANISM(S): Mus musculus

PROVIDER: GSE168937 | GEO | 2021/03/16

REPOSITORIES: GEO

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Hepatic fibroblast growth factor 21 is required for two polyphenols in exerting their metabolic beneficial effect in mice

Project description:Recent studies have shown that FGF21 is a common target for dietary polyphenol intervention and nutritional restriction. FGF21 is also a newly recognized target of GLP-1R agonists (GLP-1RAs). Here we ask whether hepatic FGF21 is required for dietary polyphenols in exerting their metabolic beneficial effects. Liver-specific FGF21 null mice (lFgf21-/-) were utilized in current study. We found that on chow diet, no appreciable defect on glucose disposal was observed in male or female lFgf21-/- mice, while fat tolerance was impaired in male but not female lFgf21-/- mice, associated with elevated serum TG level, reduced hepatic expression of Ehhadh and Ppargc1. On high-fat-high-fructose (HFHF) diet challenge, Fgf21fl/fl mice but not lFgf21-/- mice exhibited response to curcumin intervention on reducing body weight and serum TG, and on improving fat tolerance. Resveratrol intervention also affected hepatic FGF21 expression and its downstream effectors. Metabolic beneficial effects of resveratrol intervention observed in HFHF diet challenged Fgf21fl/fl mice were either absent or attenuated in lFgf21-/- mice. Thus, hepatic FGF21 is required for curcumin and resveratrol in exerting their metabolic beneficial effect. Recognition that FGF21 is the common target of GLP-1RAs and dietary intervention brings us a novel angle in studying metabolic disease treatment and prevention.

2023-12-15 | GSE241713 | GEO

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [NASH Custom panel]

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2023-08-09 | GSE240409 | GEO

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on NASH and hepatic fibrosis [Fibrosis panel]

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GLP-1 receptor signaling increases PCSK1 and beta-cell features in human alpha-cells

Project description:Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances alpha-cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which alpha-cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increases alpha-cell GLP-1 expression in a beta cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide is translationally relevant in human islets through application of a new scRNA-sequencing technology, DART-seq. We find that the effect of liraglutide to increase alpha-cell PC1/3 mRNA expression occurs in a sub-cluster of alpha-cells and is associated with increased expression of other beta-cell-like genes, which we confirm by IHC. Finally, we find that the effect of liraglutide to increase bi-hormonal insulin+ glucagon+ cells is mediated by the beta-cell GLP-1R in mice. Together, our data validate a new high-sensitivity method for scRNA-sequencing in human islets and identify a novel GLP-1 mediated pathway regulating human alpha-cell function.

2020-12-24 | GSE163744 | GEO

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Project description:Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism.

2022-12-09 | GSE211105 | GEO

Acute effects of liraglutides on gene expression in the hearts of mice with experimental myocardial infarction

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2022-11-21 | GSE217736 | GEO

Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice

Project description:Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21â??s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver. Male C57Bl/6J mice were divided to 3 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR) and medium fat (MF; AIN-93W-MF; 25% energy from fat). Dietary interventions started at the age of 9 weeks and sacrifice was performed at the age of 6, 12, 24 and 28 months. We performed various measurements on metabolic parameters and gene expression analysis. This entry represents the microarray data.

2016-08-09 | E-GEOD-84495 | biostudies-arrayexpress

Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice

Project description:Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancer-related pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARalpha challenge demonstrated the dysregulation of PPARalpha signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21’s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver.

2016-08-09 | GSE84495 | GEO

Rapid increase of fibroblast growth factor 21 under protein malnutrition and its impact on growth and lipid metabolism

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2015-01-15 | E-GEOD-64970 | biostudies-arrayexpress

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2023-10-11 | PXD037472 | Pride

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