Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis
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ABSTRACT:
PROVIDER: PRJNA1090397 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28406300_1.fastq.gz | Fastqsanger.gz | |||
| SRR28406300_2.fastq.gz | Fastqsanger.gz | |||
| SRR28406280_1.fastq.gz | Fastqsanger.gz | |||
| SRR28406280_2.fastq.gz | Fastqsanger.gz | |||
| SRR28406281_1.fastq.gz | Fastqsanger.gz |
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Project description:Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
2024-03-26 | GSE262105 | GEO
Project description:Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
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Project description:Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
2024-03-26 | MSV000094408 | GNPS
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: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:The aim of this research was to confirm the regulatory effect of CREB5 on gene expression in the development of prostate cancer.
2022-10-10 | GSE186380 | GEO
Project description:Zhang et al. identify Creb5 as a transcription factor that is required for induction of Prg4 expression by TGFbeta and EGFR ligands. They show that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, working together with a more distal regulatory element to drive induction of Prg4 by TGFbeta. These findings provide new insight into the molecular regulation of Prg4 expression in superficial zone articular chondrocytes.
2021-03-16 | GSE132379 | GEO
Project description:While prior work has established that articular cartilage arises from Prg4-expressing perichondrial cells, it is not clear how this process is specifically restricted to the perichondrium of synovial joints. We document that the transcription factor Creb5 is necessary to initiate the expression of signaling molecules that both direct the formation of synovial joints and guide perichondrial tissue to form articular cartilage instead of bone. Creb5 promotes the generation of articular chondrocytes from perichondrial precursors in part by inducing expression of Wif1, which blocks a Wnt5a autoregulatory loop in the perichondrium. Postnatal deletion of Creb5 in the articular cartilage leads to loss of both flat superficial zone articular chondrocytes coupled with a loss of both Prg4 and Wif1 expression; and a non-cell autonomous up-regulation of Ctgf. Our findings indicate that Creb5 promotes both joint formation and the subsequent development of articular chondrocytes by disrupting a Wnt5a positive-feedback loop in the perichondrium.
2022-11-07 | GSE181883 | GEO
Project description:Patients with heart failure with preserved ejection fraction (HFpEF) often have an unfavorable cardiometabolic profile, and obesity-related HFpEF has become a well-recognized HFpEF sub-phenotype. Targeting this unfavorable cardiometabolic profile may therefore represent a rational treatment strategy. The glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide has been shown to induce significant weight loss and to improve cardiovascular outcomes. In this study, we investigated the cardiometabolic effects of semaglutide in a representative mouse model of HFpEF and compared it to the effects of weight loss by caloric restriction.
2024-01-26 | PXD034625 | Pride
Project description:Inhibition of androgen-receptor (AR)signaling is the foundation of therapeutic regimens for advanced prostate cancers. However, nearly all patientsdevelop resistance and some never respond. To identify genes that mediate resistance to androgen ablation therapy, we performed an open reading frame (ORF) expression screen of17,255 ORFs and found that the transcription factorCREB5robustly conferred resistance to androgen deprivation and AR inhibition by enzalutamide. CREB5 overexpressionincreased enzalutamide-resistance 45-fold, enhanced resistance of tumor xenografts. CREB5 expression was also essential for enzalutamide-resistance patient-derived organoids. In clinical mCRPC, CREB5is frequently amplified and itsoverexpression positively correlated with castration resistance gene signatures including those of MYC and cell cycle. Mechanistically, CREB5 directly interacted at AR binding sites andenhanced site-specific AR bindingin enzalutamide. This dysregulated expression of 393 AR target genes including MYC and CDK1.These observations identifyCREB5asadriver of enzalutamide-resistance in a subset of advancedprostate cancer.
2019-09-21 | GSE137775 | GEO