Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA282087 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:Blockade of the glucagon receptor (GCGR) has been shown to improve glycemic control. However, this therapeutic approach also brings side effects, such as α-cell hyperplasia and hyperglucagonemia, and the mechanisms underlying these side effects remain elusive. Here, we conduct single-cell transcriptomic sequencing of islets from male GCGR knockout (GCGR-KO) mice. Our analysis confirms the elevated expression of Gcg in GCGR-KO mice, along with enhanced glucagon secretion at single-cell level. Notably, Vgf (nerve growth factor inducible) is specifically upregulated in α cells of GCGR-KO mice. Inhibition of VGF impairs the formation of glucagon immature secretory granules and compromises glucagon maturation, lead to reduced α-cell hypersecretion of glucagon. We further demonstrate that activation of both mTOR-STAT3 and ERK-CREB pathways, induced by elevated circulation amino acids, is responsible for upregulation of Vgf and Gcg expression following glucagon receptor blockade. Thus, our findings elucidate a previously unappreciated molecular mechanism underlying hyperglucagonemia in GCGR blockade.
2025-02-11 | GSE253271 | GEO
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
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: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
Project description:Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), and few treatment options are available today to prevent the progressive loss of renal function. Tubular abnormalities may precede glomerular pathology early and indicate the functional progression of DKD, however, pathological mechanisms that initiate tubular abnormalities are poorly understood. Here, we found that glucagon receptor (Gcgr) is specifically and highly expressed in proximal tubular cells (PTEC) of kidney. Glucagon injection exacerbated lipid accumulation, glycogen content, inflammation, fibrosis, and renal injury, along with morphology changes on proximal tubules, podocytes, glomerular basement membrane (GBM), and mitochondria in the early phase of DKD mice. Whereas, the specific knockdown or knockout of Gcgr in PTEC of kidney almost completely halted the development of DKD. In contrary to the effect of short-term glucagon stimulation on fatty acid oxidation, long-term glucagon exposure led to glucagon reversal in PTEC, which is characterized by reduced energy production and promoted lipogenesis, and this effect was through the Gcgr-PKA-Creb-mTOR pathway. Accordingly, anti-GCGR antibody treatment greatly blocked the pathogenesis of DKD induced by both type 2 and type 1 diabetes. Thus, our results revealed a novel role of glucagon/GCGR signaling in PTEC lipogenesis and DKD, and Gcgr would be a promising therapeutic drug target for the treatment of DKD.
2025-07-18 | GSE253774 | GEO
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
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: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:Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, in particular, the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remain poorly defined. We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits. We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, GCGR signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis. These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
2025-06-24 | PXD062962 | Pride