Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA312820 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The genomic analysis of liver from mice fed with standard or methyl and choline deficient (MCD) diet and treated with dual agonist of GLP1R/GCGR during two weeks before 70% partial hepatectomy (PH) and after 2 weeks PH resulted in a set of genes regulated by diet and other set regulated differentially by treatment in MCD treated animals. These genes are apparently responsible for the reversion and prevention of NAS and improvement in hepatic regeneration induced by drug treatment All microarray analyses were performed with RNA samples obtained from four independent liver from animals with different diet and drug treatmens.
2016-02-23 | E-GEOD-78170 | biostudies-arrayexpress
Project description:The genomic analysis of liver from mice fed with standard or methyl and choline deficient (MCD) diet and treated with dual agonist of GLP1R/GCGR during two weeks before 70% partial hepatectomy (PH) and after 2 weeks PH resulted in a set of genes regulated by diet and other set regulated differentially by treatment in MCD treated animals. These genes are apparently responsible for the reversion and prevention of NAS and improvement in hepatic regeneration induced by drug treatment
2016-02-23 | GSE78170 | GEO
Project description:Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions.
2024-06-11 | GSE243681 | GEO
Project description:The genomic analysis of liver from mice fed with standard or MCD diet and treated with FC-GLP-1 during two weeks before 70%partial hepatectomy (PH) and after 2 weeks PH resulted in a set of genes regulated by diet and other set regulated differentially by treatment in MCD treated animals. These genes are apparently responsible for the reversion and prevention of NAS and improvement in hepatic regeneration induced by drug treatment
2018-09-11 | GSE119725 | GEO
Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Cotadutide or GCGR monoagonist treatment resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment.
2025-03-06 | GSE284233 | GEO
Project description:Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Phosphoproteomic analyses of insulin stimulated liver from cotadutide treated diet-induced obese (DIO) mice identified novel phosphorylation sites on key insulin signalling pathway proteins associated with improved insulin sensitivity. Cotadutide or GCGR monoagonist treatment also resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Finally, the cotadutide-induced improvement in insulin sensitivity was associated with reduced insulin secretion from isolated pancreatic islet β-cells indicating reduced insulin secretory demand. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous β-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment
2025-03-28 | PXD057744 | Pride
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
Project description:It is known that administration of MCD induces a severe state of hepatic fibrosis in mice. To attempt to elucidate molecular mechanism of hepatic fibrosis, we performed whole transcriptome analysis by microarray using RNAs prepared from liver of wild-type mice fed with normal diet (ND) or MCD.
2023-12-06 | GSE249485 | GEO
Project description:Objective: Activation of the liver glucagon receptor (GCGR) promotes amino acid catabolism, which provides substrate for glucose production. Inhibition of the receptor downregulates hepatic amino acid catabolism, leading to increases in circulating amino acid levels. Amino acids serve as a potent growth factor for pancreatic alpha cells, where glucagon is produced. Thus, GCGR inhibition-induced hyperaminoacidemia causes alpha cell hyperplasia. This liver-alpha cell feedback loop, mediated by glucagon and amino acids, has been demonstrated across species, including humans. This study was designed to delineate hepatic signaling molecules that lie downstream of GCGR and mediate the liver-alpha cell loop. Methods: We used AAV8-shRNA to knock down GCGR signaling molecules, the G-coupled protein GNAS and two GNAS downstream effectors, PKA and EPAC2 (RAPGEF4), in the liver of diet-induced obese (DIO) mice. We monitored plasma amino acid and blood glucose levels and conducted pancreas histology to derive alpha and beta cell mass. We performed liver RNA-sequencing to assess expression of glucose and amino acid metabolism genes. To examine the contribution of PKA in changes associated with GCGR inhibition, we knocked down PRKAR1A, a major inhibitory subunit of PKA, to activate PKA in liver of mice administered with GCGR blocking or control antibody. Results: Comparable suppression of hepatic amino acid catabolism gene expressions, increases in plasma amino acid levels and alpha cell hyperplasia were observed in mice with hepatic knockdown of GCGR, GNAS, and PKA. Hepatic EPAC2 knockdown did not affect amino acid metabolism or alpha cell mass in mice. Mice with hepatic PKA activation alone developed hypoaminoacidemia, hypoglucagonemia and reduced alpha cell mass. Administering GCGR blocking antibody to the mice did not alter the abnormalities. Conclusions: Hepatic PKA activation in mice fully overrides the effect of GCGR inhibition on amino acids and alpha cells. In the liver, GCGR signals through PKA to control amino acid metabolism and pancreatic alpha cell mass. Hepatic PKA plays a critical role in the liver-alpha cell loop, mediated by circulating glucagon and amino acids.
2025-05-30 | GSE268864 | GEO
Project description:It is known that administration of MCD induces a severe state of hepatic fibrosis in mice. Recently, many microRNAs (miRNAs) with pro- or anti-fibrotic properties have been identified during hepatic fibrosis. To attempt to elucidate molecular mechanism of hepatic fibrosis involved in miRNA fnction, we performed comprehensive analysis of miRNA expression by microarray using RNAs prepared from liver of wild-type mice fed with normal diet (ND) or MCD.
2023-12-06 | GSE249486 | GEO