Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329738 | GEO | 2026/06/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other
	GSE329738_RAW.tar	Raw
	filelist.txt	Txt

Items per page:

1 - 3 of 3

Similar Datasets

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

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

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 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

RNAseq of 6 Different Rat Brain Areas after Treatment with a GLP-1 Receptor Agonist

Project description:In this study, we compared the treatment with one of 2 GLP-1 receptor agonists, Liraglutide and Semaglutide on the gene expression in 6 different DIO rat brain areas known to express the GLP-1 receptor. DIO rats were treated with vehicle, liraglutide, semaglutide or weight-matched for 23 days and tissue from the brain areas LS, PVH, ARH, DMH, AP and NTS was obtained with LCM.

2020-03-26 | E-MTAB-8078 | biostudies-arrayexpress

Dissecting Semaglutide-dependent transcriptome response in obesity and osteoarthritis across tissues at single-cell resolution

Project description:The clinical observations of semaglutide cannot be fully explained by the classical GLP-1R signaling, indicating that semaglutide may exert its effects through a more complex multi tissue regulatory network. Based on this background, this study utilized high-fat diet (HFD) - induced obesity and surgery induced osteoarthritis (OA) models to simulate metabolic joint complications. By systematically collecting peripheral blood (PB), bone marrow (BM), liver, brain tissue, and skeletal muscle from C57BL/6 mice, and integrating 10x Genomics single-cell transcriptome sequencing, we constructed a cross tissue cell atlas that covers the immune, nervous, and motor metabolic systems under treatment with semaglutide. In addition, we compared the gene expression disturbances in mouse tissues after administration of semaglutide. Through these comparisons, we can more accurately decipher the specific effects of semaglutide treatment on gene expression in mice, thereby gaining a deeper understanding of their mechanisms of action in vivo.

2026-05-06 | GSE310028 | GEO

GIPR-Ab/GLP-1 Peptide-antibody Conjugate Requires CNS GIPRs and GLP-1Rs to Engage Anorexigenic Circuitry for Additive Weight Loss in Obese Mice

Project description:Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for additive effects on body weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR KO mice compared to WT mice, and the extent of weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. WT mice treated with GIPR-Ab/GLP-1 or CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodeling, lipid metabolism, and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signaling are required for the full effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate, with loss of CNS GIPR activity potentiating the actions of GLP-1R agonism.

2025-04-29 | GSE293291 | GEO

A proteomics-based exploration of the neuroprotective mechanism of Semaglutide in acute ischemic stroke mice

Project description:Glucagon-like Peptide-1 receptor agonists (GLP-1RA) are gaining increasing momentum as possible neuroprotective agents in acute ischemic stroke. In this study, we investigate the neuroprotective effects of a novel GLP-1RA, Semaglutide, in the treatment of acute ischemic stroke and their underlying mechanisms. The current study first mapped comprehensive proteomic changes after acute ischemic stroke treated with Semaglutide, providing a foundation for developing potentially therapeutic targets for anti-acute ischemic stroke and clinically prognostic biomarkers of stroke.

2024-05-08 | PXD052130 |

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

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data