Biased agonism and signal transduction mediated by β-arrestin1/2 at the glucagon-like peptide 1 receptor
Ontology highlight
ABSTRACT:
ORGANISM(S): Cricetulus Griseus
SUBMITTER: 
Hu Zhou
PROVIDER: PXD040259 | iProX | Sat Feb 18 00:00:00 GMT 2023
REPOSITORIES: iProX
Similar Datasets
Project description:Emerging evidence indicates a reduced incidence of multiple cancers in users of Glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models. Two clinical cohorts of overweight and obese NSCLC patients—one undergoing surgical resection (n=1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (ICIs; n=300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR=0.41 [95%CI=0.16-1.04], p=0.026) after lobectomy. Further, GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and anti-tumor immunity. Concurrent GLP-1RA and immunotherapy was associated with improved overall (0.41 [0.16-1.01], 0.027) and progression-free survival (HR=0.31, [0.10-0.94], 0.019) for patients with advanced NSCLC. GLP-1RAs may enhance lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggests this effect is obesity-restricted and mediated by immune modulation of the tumor microenvironment.
2025-08-18 | GSE302656 | GEO
Project description:Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Recently, we demonstrated that brain endothelial cell (EC) aging is transcriptomically and functionally reversible by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist (GLP-1RA)(1). Here, we report that the reversal of transcriptomic aging signatures by GLP-1RA treatment is a generalized phenomenon in multiple major brain cell types, including glial (including astrocyte (AC), oligodendrocyte precursor cell (OPC), microglia (MG) and oligodendrocyte (OLG)) and mural (i.e. pericyte (PC) and smooth muscle cell (SMC)) cells. The age-related expression changes ameliorated by GLP-1RA encompass cell type-shared and specific functional pathways implicated in aging and neurodegeneration. These results show the feasibility of brain ageing reversal by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients(2, 3), and imply that GLP-1RA may be a generally applicable pharmacological intervention for non-diabetic patients at risk of age-related neurodegeneration.
2021-01-31 | GSE160991 | GEO
Project description:Most eukaryotic transmembrane and secreted proteins contain N-terminal signal peptides that mediate insertion of the nascent translation products into the membrane of the endoplasmic reticulum. After membrane insertion, signal peptides typically are cleaved from the mature protein and degraded. Here, we tested whether a small hydrophobic protein selected for growth promoting activity in mammalian cells retained transforming activity while also acting as a signal peptide. We replaced the signal peptide of the PDGF β receptor (PDGFβR) with a previously described 29-residue artificial transmembrane protein named 9C3 that can activate the PDGFβR in trans. We showed that a modified version of 9C3 at the N-terminus of the PDGFβR can function as a signal peptide, as assessed by its ability to support high level expression, glycosylation, and cell surface localization of the PDGFβR. The 9C3 signal peptide retains its ability to interact with the transmembrane domain of the PDGFβR and cause receptor activation and cell proliferation. Cleavage of the 9C3 signal peptide from the mature receptor is not required for these activities. However, signal peptide cleavage does occur in some molecules, and the cleaved signal peptide can persist in cells and activate a co-expressed PDGFβR in trans. Our finding that a hydrophobic sequence can display signal peptide and transforming activity suggest that some naturally occurring signal peptides may also display additional biological activities by interacting with the transmembrane domains of target proteins.
| S-EPMC8530902 | biostudies-literature
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
Project description:Toll-like receptors (TLRs) are essential sensors in innate immunity and among the first to detect invading pathogens. Many studies of TLR responses have focused on the intracellular signaling events that occur upon receptor stimulation. However, proteins released from the cell play a key role in cell-cell communication during an immune response. We have used mass spectrometry-based proteomic methods to investigate both the intracellular and extracellular responses of macrophages stimulated with individual TLR2, TLR4, and TLR7 ligands and whole pathogens. We performed global quantitative analyses of the mouse macrophage proteome and secretome using stable isotope labeling with amino acids and high-resolution mass spectrometry.
2017-03-06 | PXD004113 | Pride
Project description:Meg3 is a long non-coding RNA. It's target genes are unknown. The mouse pancreatic beta cell line MIN6-4N was used to assess the expression of genes upon stable Meg3 overexpression
2015-05-21 | GSE57716 | GEO
Project description:Meg3 is a long non-coding RNA. It's target genes are unknown. The mouse pancreatic beta cell line MIN6-4N was used to assess the expression of genes upon stable Meg3 overexpression Stable cell lines were isolated that have integated pcDNA3.1 or pcDNA3.1-mMeg3.The cells were processed for RNA isolation. The level of Meg3 expression was assessed by RT-PCR. RNA preps were used for microarray analysis.
2015-05-21 | E-GEOD-57716 | biostudies-arrayexpress
Project description:Experiment designed to identify differences in gene expression profile in white adipose tissue upon stimulation by beta 3 adrenergic receptor agonist. This series compares 2 groups of C57BL/6J acutely treated with CL-316,243 or Saline for 3 hours.
2010-06-11 | E-GEOD-2674 | biostudies-arrayexpress
Project description:We investigate the effects of GLP-1 on diabetic cardiomyocytes (DCMs) model established by human induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs). Two subtypes of GLP-1, GLP-17-36 and GLP-19-36, were evaluated for their efficacy on hypertrophic phenotype, impaired calcium homeostasis and electrophysiological properties. RNA-seq was performed to reveal the underlying molecular mechanism of GLP-1. Our results demonstrated that GLP-17-36 and GLP-19-36 were able to ameliorate high glucose-induced hypertrophy phenotype and cardiac dysfunctions in DCM model based on iPSC-CMs. Our study provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, which sheds light on discovering better targets for novel therapeutic interventions.
2022-07-01 | GSE197850 | 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