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Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

ABSTRACT: Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

PROVIDER: PRJNA560395 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9973560_1.fastq.gz	Fastqsanger.gz
	SRR9973560_2.fastq.gz	Fastqsanger.gz
	SRR9973570_1.fastq.gz	Fastqsanger.gz
	SRR9973570_2.fastq.gz	Fastqsanger.gz
	SRR9973561_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Glucagon-receptor signaling regulates energy metabolism via hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21

Project description:Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism increases plasma bile acid levels. We hypothesized that GcgR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole body and liver-specific FXR knockout (FXR∆liver) mice. Chronic GcgR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21 and Fxr whole body or liver-specific knockout (∆liver) mice failed to reduce body weight (BW) when compared to wildtype (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not FXR∆liver mice. GcgR agonism increased [14C]-palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from FXR∆liver mice. Our data clearly demonstrate that control of whole body energy expenditure by GcgR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in the therapy of metabolic disorders.

2019-08-16 | GSE135881 | GEO

Glucagon Receptor Signaling Regulates Energy Metabolism via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21.

Project description:Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from glucagon receptor (GCGR) activation, prompting us to search for additional pathways. Intriguingly, chronic GCGR agonism increases plasma bile acid levels. We hypothesized that GCGR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole-body and liver-specific FXR-knockout (Fxr∆liver) mice. Chronic GCGR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21, and Fxr whole-body or liver-specific knockout (∆liver) mice failed to reduce body weight when compared with wild-type (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not Fxr∆liver mice. GCGR agonism increased [14C]palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from Fxr∆liver mice. Our data clearly demonstrate that control of whole-body energy expenditure by GCGR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GCGR agonism in the therapy of metabolic disorders.

| S-EPMC6110317 | biostudies-literature

Dietary protein defends lean mass and maintains metabolic benefits of glucagon receptor agonist G108 in mice

Project description:Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained in contexts that permit the defence of lean mass.

2024-09-09 | GSE273658 | GEO

Glucagon receptor blocked liver gene signature

Project description:Glucagon receptor blocked liver gene signature

| PRJNA504671 | ENA

BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

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

Glucagon receptor blocked liver gene signature

Project description:Liver RNA-seq in lean or diet-induced obese mice administered with glucagon receptor blocking antibody

2018-11-09 | GSE122348 | GEO

Glucagon receptor signaling in GCGR KO mice

Project description:GCGR wt and ko mice Glucagon receptor signaling in GCGR KO mice: fig 2a in Solloway et al.

2015-06-02 | GSE68143 | GEO

Glucagon receptor deficient liver during postnatal development

Project description:Glucagon receptor deficient liver during postnatal development: fig S5a-S5c in Solloway et al. livers from ko and wt GCGR mice at various developmental stages

2015-06-02 | GSE68141 | GEO

Disruption of glucagon receptor increase α-cell glucagon expression and secretion beyond hyperplasia in zebrafish

Project description:Glucagon receptor (GCGR) is a potential target for diabetes therapy. Several emerging GCGR antagonism-based therapies are under pre-clinical and clinical development. However, the GCGR antagonism as well as GCGR deficient animal accompanied with α-cell hyperplasia and hyperglucagonemia, which may limit the application of GCGR antagonism. To better understand the physiological changes in the α cells during the GCGR disruption, we performed the single cell sequencing of α cells isolated from control and gcgr-/- zebrafish. We found that α cells in gcgr-/- zebrafish dramatically increased glucagon (both gcga and gcgb) expression, we also found that several transcriptional factors that regulate glucagon expression were also increased. Based on the sequencing data, we further experimentally confirmed that gcgr-/- up-regulated glucagon mRNA level by in situ hybridization, and the gcgr-/- increased glucagon promoter activity indicated by reporter line Tg(gcga: GFP). Moreover, our results also revealed that α cells increased glucagon granule population and glucagon level in gcgr-/- zebrafish. These data suggested that hyperglucagonemia in the organism of GCGR antagonism not only contributed by the α-cell hyperplasia but also contributed by the increased glucagon expression and secretion from α cells. Our study provided more comprehensive understanding of physiological changes of α-cell during the GCGR disruption.

2022-10-26 | GSE179894 | GEO

RNA-seq of kidneys from mice treated for eight weeks with the glucagon receptor antibody, REGN1193, compared to mice treated with a control antibody, REGN1945.

Project description:Chronic glucagon receptor inhibition induced by a glucagon receptor antibody causes decrease in mesangial cell area and increases kidney weight. To dissect the molecular mechanism underlying these effects, RNA sequencing of kidney biopsies from female mice treated for eight weeks with the glucagon receptor antibody, REGN1193, or a control antibody, REGN1945, were performed.

2023-12-01 | E-MTAB-12518 | biostudies-arrayexpress

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