Comparing the transcriptome profiling of ob/ob mice treated with the GLP-1 receptor agonist liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls
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PROVIDER: PRJEB67837 | ENA |
REPOSITORIES: ENA
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Project description:B6.Cg-Lep ob/ob mice females were surgically implanted in an age of 10-12 weeks with Alzet osmotic mini pumps (model 1002, 0,25l/h, Cupertino, CA, USA) in two groups of ten mice each to perform continuous subcutaneous infusions of Dulbecco's phosphate buffered saline (vehicle; n = 8) or GLP-1 (GLP-1; n = 9) agonist Liraglutide (Victoza, batch# CS6C214, Novo Nordisk A/S, Bagsvaerd, Denmark) to investigate the effects of the respective treatment on peri-gonadal epididymal white adipose tissue gene expression. Vehicle or Liraglutide at a dose of 600 g/kg/d were continuously infused (at a dose of 600 g/kg/d) over a 14 days period. On the morning after the osmotic mini pump reservoirs liquid content should have been consumed mice were dissected to remove the peri-gonadal epididymal fat pad for white adipose tissue gene expression analysis. At least 220 mg of white adipose tissue was quickly removed, shock-frozen in liquid nitrogen and thereafter stored at -80C for mRNA extraction. To perform RNA-Seq analysis, samples were single-end sequenced at a depth of 75 80M reads per sample with a read-length of 51 bp using an Illumina Hiseq2500. Raw sequencing files were quality controlled with FastQC. Alignment and trimming of reads was performed using the OSA algorithm against the mouse reference genome b38.1 with RefSeq as the gene model as implemented in OmicSoft ArraySuite software, version 8. RNA transcripts were quantified using RSEM methods as implemented in Arraystudio counting count the read fragments mapping to each individual gene and quantify expression by the corresponding FPKM. In summary, expression was measured as FPKM for 25,054 unique genes. Principal component analysis was then performed to check for possible batch effects and outliers complemented by calculating the RNA-Seq 5'->3' trend for each sample. One sample for the vehicle control as well as for the Liraglutide group were identified as outliers and removed from subsequent analysis, resulting in 7 and 8 samples remaining for each group respectively. Abundance values (counts) were normalized and compared between liraglutide treated mice versus baseline controls using DESeq2. All P-values were adjusted for multiple testing by the Benjamini-Hochberg method.
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Project description:Obesity and its co-morbidities, such as diabetes and hypertension, can significantly reduce a person’s quality of life and place huge pressure on healthcare resources. When we eat a meal our gut and brain release hormones to control the amount of food and fluid we ingest to prevent overeating. One of these hormones is called glucagon-like peptide 1 (GLP-1) and is released from intestinal cells in response to food intake, but also produced and released in the brain. Drug analogues of GLP-1 are already in use in the clinic to treat both diabetes and obesity. The aim of this work was to obtain fundamental knowledge about a GLP-1 receptor population in nerve terminals of the posterior pituitary gland. We have investigated the pharmacological actions of GLP-1 using a selective receptor agonist called liraglutide, a drug that is approved for diabetes and obesity treatment in humans. Our work has focussed on the phosphoproteome of the neurointermediate lobe (posterior pituitary + intermediate lobe) of the rat pituitary gland 30 minutes after intraperitoneal injection of liraglutide (100 µg/kg) compared to vehicle controls (n = 6 animals per group). New understanding of this GLP-1 receptor population is essential for our knowledge of current treatments of diabetes and obesity that use stable peptide analogues in humans.
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Project description:GLP-1 agonists are potent glucose-lowering agents, however, their effect on adolescent organisms needs to be clarified Transgenic pigs expressing a dominant-negative GLP receptor randomly assigned for a 90 day treatment trial with liraglutide (0.6-1.8 mg per day)/placebo
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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.
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Project description:the changes of cardiac proteomics in diabetic cardiomyopathy mice treated with GLP-1 receptor agonist
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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:GLP-1 based diabetes drugs are effective to reduce hepatic lipid accumulation beyong glycemic control. As GLP-1 receptor (GLP-1R) is not expressed in hepatocytes, the mechanism behind the beneficial effects of GLP-1 based drugs on the liver remained elusive. Several studies have shown that the expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based drugs. Therefore, the present study aimed to assess such stimulation in mice and in mouse primary hepatocytes, determine whether hepatic FGF21 mediates functions of the GLP-1R agonist liraglutide, and to explore the potential mechanisms of liraglutide regulating the expression of FGF21. In high-fat diet induced obese mice, we observed hepatic and plasma FGF21 elevation, improved glucose disposal, and reduced plasma triglyceride levels by liraglutide treatment. Moreover, RNA-sequencing on the liver suggested that Fgf21 was the most upregulated gene after liraglutide treatment. In liver-specific FGF21 knock-out mice on high-fat and high-fructose diet, the body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced. These studies implied that hepatic FGF21 was the critical mediator of liraglutide-induced metabolic improvement.
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Project description:Comparing the transcriptome profiling of ob/ob mice treated with the GLP-1 receptor agonist liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls
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Project description:GLP-1 agonists are potent glucose-lowering agents, however, their effect on adolescent organisms needs to be clarified
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Project description:Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning and fibrosis and inhibits activation of hepatic stellate cells. Glucagon like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared to clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
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