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The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen hydroxyprolination and favoring immune infiltration.

ABSTRACT: The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen hydroxyprolination and favoring immune infiltration.

PROVIDER: PRJNA1108693 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28955873_1.fastq.gz	Fastqsanger.gz
	SRR28955873_2.fastq.gz	Fastqsanger.gz
	SRR28955874_1.fastq.gz	Fastqsanger.gz
	SRR28955874_2.fastq.gz	Fastqsanger.gz
	SRR28955875_1.fastq.gz	Fastqsanger.gz

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GLP-1R agonist semaglutide protects developing human forebrain organoids from cholesterol-induced neurotoxicity—scRNA sequence

Project description:Neurological disorders are increasingly linked to disrupted lipid metabolism. The GLP-1R agonist semaglutide is well-established for improving systemic lipid profiles and is gaining attention for its clinical neuroprotective potential; however, the mechanisms underlying its direct action on neural cells remain poorly understood. Using hiPSC-derived forebrain organoids, we modeled cholesterol-induced metabolic stress to investigate direct drug-cell interactions. We show that semaglutide protects neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engages the cAMP-PKA and PI3K-AKT-mTOR signaling, contributing to the reduction of lipid droplet and ROS levels. Intercellularly, single-cell transcriptomics indicates that semaglutide partially reestablishes disrupted cellular communication, including the Midkine signaling network associated with progenitor support. Functionally, semaglutide mitigates excitotoxicity and stabilizes calcium dynamics. In summary, these findings highlight the importance of cholesterol homeostasis during early brain development and suggest that GLP-1R signaling may represent a candidate neuroprotective axis in the central nervous system, offering insights into therapeutic strategies for neurological disorders.

2026-06-20 | GSE329738 | GEO

Effect of semaglutide treatment in aged mice

Project description:Semaglutide is a GLP-1R agonist. We investigated the effect of semaglutide in aged mice. We treated 20-month-old female C57BL/6 mice with semaglutide for three months and performed RNA-sequencing analysis of liver samples.

2026-07-19 | GSE338091 | GEO

The hepatoprotective benefits of semaglutide in MASH require the intrahepatic endothelial GLP-1 receptor

Project description:GLP-1 receptor agonists such as semaglutide improve metabolic dysfunction-associated liver disease (MASLD), yet the hepatic cell types mediating these effects remain unclear. GLP-1R expression in the liver is restricted to non-parenchymal cells, but its detection by conventional single-cell RNA sequencing is limited due to low transcript abundance. We performed GEM-X Flex-seq (10x Genomics) single-cell RNA sequencing on liver single-cell suspensions from wild-type C57BL/6J mice fed a standard chow diet, a choline-deficient high-fat diet (CDHFD), or CDHFD with semaglutide treatment. This dataset enables cell type-resolved mapping of Glp1r expression across the hepatic niche and characterization of transcriptomic changes associated with semaglutide treatment, revealing pericentral liver sinusoidal endothelial cells (LSECs) as direct targets mediating weight loss-independent improvements in hepatic inflammation, fibrosis, and immune remodeling.

2026-04-14 | GSE325222 | GEO

Effects of semaglutide on the gut microbiota of high-fat diet-fed mice lacking GLP-1Rs in T cells

Project description:Gut intraepithelial lymphocytes (IELs) are one of the few immune cell populations in the body that expresses glucagon-like 1 receptors (GLP-1R). To test the potential effects of GLP-1 on the gut microbiota through the gut IEL GLP-1R, we performed 16s rRNA seq on the DNA isolated from the fecal pellet of Lck-Cre; Glp1rfl/fl mice (Glp1rTcell-/-) or controls (Glp1rTcell+/+) fed a high-fat diet (HFD) for 12 weeks followed by 1 week of HFD plus semaglutide (10 ug/kg) or vehicle treatment. Fecal pellets from a group of age-matched, sex-matched control mice were included as a chow control group.

2022-08-29 | GSE202452 | GEO

The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen hydroxyprolination and favoring immune infiltration.

Project description:Metabolic syndrome represents a risk factor of pancreatic ductal adenocarcinoma (PDAC), the gastrointestinal cancer with the lowest survival rate and therapeutic outcome. PDAC results bidirectional interconnected with metabolic alteration, which favors its onset and occurs during early phases of its development. Pancreatic neoplastic lesions evolve within a highly dense desmoplastic stroma, characterized by abundant extracellular matrix deposition consequence of a prominent cancer associated fibroblast (CAF) activation. Here, the complex association between dysmetabolism and PDAC has been analyzed with a specific focus on CAFs to unveil novel targets exploitable for diagnostic and therapeutic purposes. Methods: PDAC development upon dysmetabolic conditions was investigated in: 1) wild type immunocompetent syngeneic mice by orthotopic transplantation of PanIN-bearing Pdx1-Cre; Kras+/LSL-G12D; Trp53+/LSL-R172H organoids (KPC mice) fed with high fat diet to recapitulate dysmetabolism-dependent alterations; and 2) primary pancreatic CAFs isolated from chemotherapy naïve PDAC patients with or without an history of metabolic syndrome. Results: The dysmetabolic-associated higher PDAC aggressiveness was paralleled by an enrichment of collagen fibrils due to an increased function of the prolyl 4-hydroxylase subunit alpha 1 (P4HA1). Upon dysmetabolic conditions, P4HA1 boosts collagen hydroxy-prolination, intensifying collagen contraction strength and thus preventing CD3 positive lymphocyte PDAC infiltration. Interestingly, semaglutide, an incretin agonist with anti-diabetic and anti-obesity properties, is able to prevent the higher stromal deposition of PDAC observed in dysmetabolic conditions, preventing CAF contraction, allowing immune infiltration and reducing tumor development. Conclusion: These results shed light on novel therapeutic options for PDAC patients affected by metabolic syndrome aimed at pancreatic cancer stroma reshape

2025-01-29 | GSE266899 | GEO

GLP-1R and GIPR heterodimerization and expression determine downstream signaling and metabolic phenotypes

Project description:Advancements in unimolecular drugs co-targeting the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) have demonstrated remarkable clinical efficacy in treating type 2 diabetes (T2D) and obesity. However, the paradoxical ability of both GIPR agonism and antagonism to complement GLP-1R agonism underscores the need to elucidate molecular mechanisms underlying incretin receptor pharmacology and crosstalk. Here, we show that GLP-1 promotes heterodimerization via interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics profiling and molecular dynamics simulations reveal that dimerizing and non-dimerizing GLP-1R agonists differentially engage with GLP-1R and elicit distinct regulation of downstream signaling networks in human islets. Co-expression of GLP-1R and GIPR amplifies GIPR-mediated signaling in a β-arrestin-dependent manner, while GLP-1R-mediated signaling is suppressed by GIPR expression. Additionally, upregulation or downregulation of GIPR expression was associated with adiposity and diabetic traits, respectively. Collectively, these findings uncover mechanisms underlying the interplay between GLP-1R and GIPR and highlight heterodimerization as an innovative strategy for incretin-based therapies and personalized treatment.

2026-05-13 | PXD063931 | Pride

The GLP-1R agonist semaglutide reshapes pancreatic cancer associated fibroblasts reducing collagen proline hydroxylation and favoring T lymphocyte infiltration.

Project description: Not available

| S-EPMC11744909 | biostudies-literature

GLP-1R agonist semaglutide protects developing human forebrain organoids from cholesterol-induced neurotoxicity—scRNA sequence

Project description:GLP-1R agonist semaglutide protects developing human forebrain organoids from cholesterol-induced neurotoxicity—scRNA sequence

| PRJNA1460827 | ENA

Semaglutide Exacerbates Stunting in Growth-Impaired Juvenile Male Mice via Reduced Energy Metabolism

Project description:Animals rely on linear growth to attain their full adult size. The regulators of this multifactorial process, including environmental and endocrine cues, are still incompletely understood. Notably, GLP-1, glucagon-like peptide 1 (GLP-1) has emerged as a potential player in this process. Here, we employ semaglutide, a pharmaceutical GLP-1R agonist as a tool to mechanistically dissect the interplay between GLP-1 receptor activation, energy metabolism, and linear growth during the juvenile period, independent of its clinical applications. Using a juvenile mouse model, we show that chronic semaglutide treatment lowers blood glucose without affecting food intake or weight gain in juveniles with a normal growth pattern. However, in growth-stunted juveniles, semaglutide treatment exacerbates linear growth impairment through at least 2 concomitant mechanisms: a moderate reduction in food intake, and a decreased catabolic activity incompatible with tissue growth. These data suggest a complex interplay between GLP-1 signaling, energy metabolism, and growth during juvenile development. Overall, these findings highlight the value of semaglutide as a mechanistic tool for understanding how GLP-1 receptor activation modulates growth and metabolism in juveniles, emphasizing the importance of developmental context for interpreting its effects.

2024-05-07 | GSE266477 | GEO

GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function

Project description:Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic -cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and -cell functional adaptation. Here, we present a comprehensive study in -cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and -cell functional adaptation, with important consequences for the regulation of -cell insulin secretion and survival to stress.

2025-09-30 | PXD056782 | Pride

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