Semaglutide ameliorates cardiac remodeling by optimizing energy substrate utilization and through the Creb5/NR4a1 axis in male mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): ExionLC Series UHPLC
ORGANISM(S): Mus <mouse, Genus> (ncbitaxon:10088)
SUBMITTER: 
lan yu ma
PROVIDER: MSV000094408 | MassIVE | Tue Mar 26 21:35:00 GMT 2024
REPOSITORIES: MassIVE
Similar Datasets
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: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:Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis
| PRJNA1090397 | ENA
Project description:Disruption of circadian rhythms during fetal development may predispose mice to developing heart disease later in life. Here, we report that male, but not female, mice that had experienced chronic circadian disturbance (CCD) in utero were more susceptible to pathological cardiac remodeling compared with mice that had developed under normal intrauterine conditions. CCD-treated males showed ventricular chamber dilatation, enhanced myocardial fibrosis, decreased contractility, higher rates of induced tachyarrhythmia, and elevated expression of biomarkers for heart failure and myocardial remodeling. In utero CCD exposure also triggered sex-dependent changes in cardiac gene expression, including upregulation of the secretoglobin gene, Scgb1a1, in males. Importantly, cardiac overexpression of Scgb1a1 was sufficient to induce myocardial hypertrophy in otherwise naive male mice. Our findings reveal that in utero CCD exposure predisposes male mice to pathological remodeling of the heart later in life, likely as a consequence of SCGB1A1 upregulation.
| S-EPMC10863319 | biostudies-literature
Project description:High-mobility group box1 (HMGB1) exerts effects on inflammation by binding to receptor for advanced glycation end products (RAGE) or Toll-like receptor 4. Considering that inflammation is involved in pressure overload-induced cardiac hypertrophy, we herein attempted to investigate whether HMGB1 plays a role in myocardial hypertrophy in RAGE knockout mice as well as in the growth and apoptosis of cardiomyocytes. The myocardial expression of RAGE was not significantly changed while TLR4 mRNA was upregulated in response to transverse aortic constriction (TAC) for 1 week. The myocardial expression of HMGB1 protein was markedly increased in TAC group when compared to the sham group. Heart weight to body weight ratio (HW/BW) and lung weight to body weight ratio (LW/BW) were evaluated in RAGE knockout (KO) and wild-type (WT) mice 1 week after TAC. Significant larger HW/BW and LW/BW ratios were found in TAC groups than the corresponding sham groups, but no significant difference was found between KO and WT TAC mice. Similar results were also found when TAC duration was extended to 4 weeks. Cultured neonatal rat cardiomyocytes were treated with different concentrations of recombinant HMGB1, then cell viability was determined using MTT and CCK8 assays and cell apoptosis was determined by Hoechst staining and TUNEL assay. The results came out that HMGB1 exerted no influence on viability or apoptosis of cardiomyocytes. Besides, the protein expression levels of Bax and Bcl2 in response to different concentrations of HMGB1 were similar. These findings indicate that HMGB1 neither exerts influence on cardiac remodeling by binding to RAGE nor induces apoptosis of cardiomyocytes under physiological condition.
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Project description:Fibrinogen like protein 1(Fgl1) is a secreted protein with mitogenic activity on primary hepatocytes. Fgl1 is expressed in the liver and its expression is enhanced following acute liver injury. In animals with acute liver failure, administration of recombinant Fgl1 results in decreased mortality supporting the notion that Fgl1 stimulates hepatocyte proliferation and/or protects hepatocytes from injury. However, because Fgl1 is secreted and detected in the plasma, it is possible that the role of Fgl1 extends far beyond its effect on hepatocytes. In this study, we show that Fgl1 is additionally expressed in brown adipose tissue. We find that signals elaborated following liver injury also enhance the expression of Fgl1 in brown adipose tissue suggesting that there is a cross talk between the injured liver and adipose tissues. To identify extra hepatic effects, we generated Fgl1 deficient mice. These mice exhibit a phenotype suggestive of a global metabolic defect: Fgl1 null mice are heavier than wild type mates, have abnormal plasma lipid profiles, fasting hyperglycemia with enhanced gluconeogenesis and exhibit differences in white and brown adipose tissue morphology when compared to wild types. Because Fgl1 shares structural similarity to Angiopoietin like factors 2, 3, 4 and 6 which regulate lipid metabolism and energy utilization, we postulate that Fgl1 is a member of an emerging group of proteins with key roles in metabolism and liver regeneration.
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Project description:Although all brain cells bear in principle a comparable potential in terms of energetics, in reality they exhibit different metabolic profiles. The specific biochemical characteristics explaining such disparities and their relative importance are largely unknown. Using a modeling approach, we show that modifying the kinetic parameters of pyruvate dehydrogenase and mitochondrial NADH shuttling within a realistic interval can yield a striking switch in lactate flux direction. In this context, cells having essentially an oxidative profile exhibit pronounced extracellular lactate uptake and consumption. However, they can be turned into cells with prominent aerobic glycolysis by selectively reducing the aforementioned parameters. In the case of primarily oxidative cells, we also examined the role of glycolysis and lactate transport in providing pyruvate to mitochondria in order to sustain oxidative phosphorylation. The results show that changes in lactate transport capacity and extracellular lactate concentration within the range described experimentally can sustain enhanced oxidative metabolism upon activation. Such a demonstration provides key elements to understand why certain brain cell types constitutively adopt a particular metabolic profile and how specific features can be altered under different physiological and pathological conditions in order to face evolving energy demands.
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Project description:Gastric cancer is one of the most common malignant tumors. Asia has a high incidence of gastric cancer globally. South Korea, Mongolia, Japan and China are the four countries with the highest incidence of gastric cancer in the world. Gansu province in China has the estimated age-standardized incidence rates and mortality rates by Chinese standard population of 62.34/100,000 and 36.94/100,000, respectively, in 2012, which are much higher than the average level of China (22.06/100,000 and 15.16/100,000) in the same year. As a high incidence area of gastric cancer in China, Wuwei city in Gansu province has the prevalence of gastric cancer almost 5 times higher than the average level nationwide. In this study, the cancer tissues and matched adjacent normal mucosa tissues of 5 patients with early gastric cancers who were treated with ESD in Gansu Wuwei Tumor Hospital and the First Hospital of Lanzhou University were collected. All of the patients are from Gansu, China. MicroRNA array was used to find the differences in microRNAs expression profile between the early gastric cancer tissues and the para-cancer normal tissues. It is expected to explore the reasons of the abnormal high incidence of gastric cancer in Gansu Province, China, from the aspect of microRNAs expression profile characteristics.
2021-07-01 | GSE158315 | GEO
Project description:To test whether a genomic classifier (GC) predicts development of metastatic disease in patients treated with salvage radiation therapy (SRT) after radical prostatectomy (RP).
2017-04-04 | GSE79915 | GEO
Project description:ObjectiveLoss of function mutations in the insulin receptor substrate 4 (IRS4) gene cause a rare form of X-linked congenital central hypothyroidism in boys and men. Affected individuals show decreased thyroid-stimulation hormone (TSH) secretion. Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and downstream effectors. How loss of IRS4 affects TSH synthesis or secretion is unresolved. We therefore assessed IRS4's role in the hypothalamic-pituitary-thyroid axis of Irs4 knockout mice.MethodsWe generated two global Irs4 knockout mouse lines harboring either two or four base-pair deletions that result in frameshifts and loss of most of the IRS4 protein.ResultsUnder normal laboratory conditions, Irs4 knockout males did not exhibit impairments in pituitary expression of TSH subunit genes (Tshb or Cga) or in the thyrotropin-releasing hormone (TRH) receptor. Additionally, their serum thyroid hormone, T3 (triiodothyronine) and T4 (thyroxine), and hypothalamic Trh expression levels were normal. When Irs4 knockouts were rendered hypothyroid with a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks, their serum TSH increased similarly to wild-type males.ConclusionsOverall, Irs4 knockout mice do not exhibit central hypothyroidism or otherwise appear to phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these animals.
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