Effects of semaglutide on the gut microbiota of high-fat diet-fed mice lacking GLP-1Rs in T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): feces metagenome
PROVIDER: GSE202452 | GEO | 2022/08/29
REPOSITORIES: GEO
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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 gut IEL function, we performed bulk RNA-seq on gut IELs isolated from C57BL/6J mice treated with anti-CD3 and with or without exendin-4 for 3 hours.
2022-08-29 | GSE202453 | GEO
Project description:Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to impact glucose homeostasis and, more recently, the somatotropic axis. While the effects of GLP-1RAs have been extensively studied in the context of diet-induced obesity, their impact on physiology in other nutritional contexts have been less explored. We investigated the potential beneficial effects of the GLP-1RA semaglutide during juvenile protein malnutrition, a dietary challenge known to cause stunted growth and to disrupt metabolic homeostasis. We used a murine model to assess the effects of twice-weekly subcutaneous injections of semaglutide during juvenile protein malnutrition. Glucose metabolism was evaluated through in vivo oral glucose tolerance test, ex vivo glucose-stimulated insulin secretion in isolated pancreatic islets and histology of the pancreas. We combined linear growth monitoring, analysis of the growth hormone/insulin-like growth factor 1 signaling pathway and liver bulk RNA sequencing to characterize the effects of semaglutide on the somatotropic axis during juvenile protein malnutrition. Semaglutide improved glucose tolerance in control and malnourished mice, but differentially impacted pancreatic islet physiology depending on the dietary protein intake. While semaglutide did not alter growth in control conditions, it further inhibited growth of malnourished mice associated with reduction in fat but not lean mass. Surprisingly, semaglutide had no discernible effect on the functionality of the somatotropic axis in malnourished mice. Liver transcriptomics revealed that semaglutide could interfere with the growth of malnourished juvenile mice by altering circadian rhythm and thermogenesis. Our data reveal that semaglutide interacts differentially with the physiology of juvenile mice depending on their dietary protein intake. We found that semaglutide influences glucose metabolism and linear growth in a diet-dependent manner, underscoring the importance of examining the effects of GLP-1RAs across various nutritional contexts and developmental stages.
2024-05-07 | GSE266477 | 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: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
Project description:Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups compared to untreated controls. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota-dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with frequencies of CD4+CD8+ IELs and reduced EAU. Notably, IELs in culture suppressed antigen-specific activation of autoreactive T cells.
2023-11-17 | GSE236922 | GEO
Project description:Abstract. Background and aims: Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for treatment of obesity as well. Semaglutide is also postulated to be a promising candidate for treatment of non-alcoholic steatohepatitis (NASH). Here, we evaluated the effects of semaglutide in a translational diet-induced model with advanced NASH and fibrosis. Methods: Ldlr-/-.Leiden mice received a fast food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneously injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined and hepatic transcriptome analysis was performed. Results: In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p<0.001), inflammation (-73%, p<0.001) and completely abolished microvesicular steatosis (-100%, p<0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p<0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Conclusions: Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for treatment of hepatic steatosis and inflammation, while for reversal of advanced fibrosis, combinations with other NASH agents may be necessary.
2023-08-01 | GSE226496 | GEO
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:The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be imprinted on CD4+ T cells at the epithelium. However, the role of the T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4-IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4+ T cells or of MHCII on intestinal epithelial cells prevented CD4-IEL differentiation. However, TCR ablation on differentiated CD4-IELs, or long-term cognate antigen withdraw, did not affect their maintenance. TCR re-engaging of antigen-specific CD4-IELs during Listeria monocytogenes infection did not alter their state but correlated with reduced bacteria invasion. Thus, local antigen recognition is an essential signal for differentiation of T cells at the epithelium but differentiated CD4-IELs are able to preserve an effector program in the absence of TCR signaling.
2020-10-02 | GSE157453 | GEO
Project description:CD8αβ+ intraepithelial lymphocytes (IELs) are a subset of “effector-memory-like” T cells scattered along the intestinal epithelium. To investigate if CD8αβ+ IEL can function in ways other than the conventional cytotoxic effect of CD8αβ+ T cells,CD8αβ+ IELs were compared with CD8αβ+ splenocytes (SPL) by RNA-seq. We used microarrays to identify new functions of CD8αβ+ IELs .
2018-05-30 | GSE105061 | GEO
Project description:Semaglutide (Sema) is a novel glucagon-like peptide-1 receptor (GLP-1R) agonist that is used clinically as a hypoglycemic and bariatric agent, as it regulates the energy metabolic process. In heart failure, mitochondrial oxidative phosphorylation substrates are altered, glycolysis is increased, and intracellular energy production is decreased. However, the responsiveness of Sema-regulated energy metabolism to the metabolic environment of cardiomyocytes stimulated by pressure burden remains unclear. Herein, we used transverse aortic constriction (TAC) surgery as the disease model. We found that Sema improved cardiac dysfunction and attenuated myocardial hypertrophy and fibrosis. This is manifested by reduced myocyte volume and interstitial collagen deposition. We found that Sema treatment maintains mitochondrial morphology and function under conditions of chronic stress load-mediated damage. Untargeted metabolomics analysis revealed that Sema ameliorated mitochondrial lesions and reduced lipid accumulation and ATP insufficiency by promoting glycolytic species products enter the tricarboxylic acid cycle (TCA) and increasing β-oxidation. Transcriptional profiling results revealed that Sema exerted its effects on myocardial energy metabolism by regulating Creb5/NR4a1 in the canonical PI3K/AKT pathway. Specifically, Sema reduced the expression of NR4a1 and its translocation from the nucleus to mitochondria. The disorders of mitochondrial function and myocardial glucolipid metabolism were significantly ameliorated after NR4a1 knockdown. Overall, Sema ameliorates myocardial glucose, lipid, and energy metabolism disorders by regulating Creb5/NR4a1, thereby protecting against pathological myocardial remodeling. This finding provides a new therapeutic agent for improving pathological myocardial remodeling based on energy metabolic switching.
2024-03-26 | GSE262105 | GEO