Browsing by Subject "Metabolic disorders"

Now showing 1 - 6 of 6
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    Correction: Sirt1 coordinates with ERα to regulate autophagy and adiposity
    (Springer Nature, 2023-06-23) Tao, Zhipeng; Shi, Limin; Parke, Jane; Zheng, Louise; Gu, Wei; Dong, X. Charlie; Liu, Dongmin; Wang, Zongwei; Olumi, Aria F.; Cheng, Zhiyong; Biochemistry and Molecular Biology, School of Medicine
    This corrects the article "Sirt1 coordinates with ERα to regulate autophagy and adiposity" in volume 7, 53.
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    FRI009 Microbiome Affects Host Metabolic Homeostasis Via Differential Regulation Of Gene Expression In The Endocrine System
    (The Endocrine Society, 2023-10-05) Milhouse, Wynne; Ren, Hongxia; Pediatrics, School of Medicine
    Dysbiosis has been implicated in many metabolic disorders, but the exact role of microbiota is not completely understood. To address this question, we used germ-free (GF) and conventional (CON) mouse models to examine the expression of genes critical for endocrine regulation of metabolic homeostasis. Samples of the mediobasal hypothalamus (MBH) were obtained from 18 germ-free and 18 conventional C57BL/6 mice (n=9 males, 9 females). Each gene transcript was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). We also collected the serum from both cohorts and measured ad libitum insulin and leptin concentrations by enzyme-linked immunosorbent assay (ELISA). Our results showed that, in the MBH, GF mice had increased expression of neuropeptides involved in feeding regulation, i.e., Neuropeptide Y (Npy) and Proopiomelanocortin (Pomc), compared to CON mice (p < 0.0001). Furthermore, CON mice had increased expression of a negative regulator of leptin signaling, Suppressor of cytokine signaling 3 (Socs3), in the MBH. Consistently, serum leptin in CON male mice was higher than that of male GF mice (p < 0.001). In the gut samples, the GF cohort demonstrated increased expression of gut hormones that promote satiety, such as Peptide yy (Pyy) and Cholecystokinin (Cck), respectively (p < 0.05 and p < 0.0001). The absence of a microbiome had differing effects on the expression of incretin hormones and the G protein-coupled receptors (GPCRs) that stimulate their secretion. In the jejunum, ileum, and colon of CON mice, expression of Glucagon-like peptide 1 (Glp-1) was increased compared to that of GF mice (p < 0.001, p < 0.05, and p < 0.0001, respectively). Conversely, Glucose-dependent insulinotropic polypeptide (Gip) showed increased expression in the duodenum of male and female GF mice (p < 0.0001). G protein-coupled receptor 119 (Gpr119) and G protein-coupled receptor 120 (Gpr120) showed increased expression only in the colon of female GF mice (p < 0.0001 and p < 0.01, respectively). Germ-free and conventional mice demonstrated comparable ad libitum insulin concentrations. We conclude that the increased expression of Pomc, Gip, Cck, and Pyy and the increased leptin sensitivity in GF mice contribute to the lean phenotype observed in these mice. The additional increase in Npy and decrease in Glp-1 likely play a compensatory role in regulating energy consumption and expenditure. Thus, the microbiome may impinge upon diverse effectors of the neuroendocrine and enteroendocrine systems to regulate host metabolism, influencing energy consumption and expenditure in the development of obesity.
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    Leukotriene B4 as a Potential Therapeutic Target for the Treatment of Metabolic Disorders
    (Frontiers Media, 2015-10-08) Filgueiras, Luciano Ribeiro; Serezani, C. Henrique; Jancar, Sonia; Department of Microbiology & Immunology, IU School of Medicine
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    Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy
    (Springer Nature, 2022-09-09) Schmitt, Rebecca E.; Smith, Douglas Y., IV.; Cho, Dong Seong; Kirkeby, Lindsey A.; Resch, Zachary T.; Liewluck, Teerin; Niu, Zhiyv; Milone, Margherita; Doles, Jason D.; Anatomy, Cell Biology and Physiology, School of Medicine
    Hereditary muscle diseases are disabling disorders lacking effective treatments. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy (GNEM) is an autosomal recessive distal myopathy with rimmed vacuoles typically manifesting in late adolescence/early adulthood. GNE encodes the rate-limiting enzyme in sialic acid biosynthesis, which is necessary for the proper function of numerous biological processes. Outside of the causative gene, very little is known about the mechanisms contributing to the development of GNE myopathy. In the present study, we aimed to address this knowledge gap by querying the underlying mechanisms of GNE myopathy using a patient-derived induced pluripotent stem-cell (iPSC) model. Control and patient-specific iPSCs were differentiated down a skeletal muscle lineage, whereby patient-derived GNEM iPSC clones were able to recapitulate key characteristics of the human pathology and further demonstrated defects in myogenic progression. Single-cell RNA sequencing time course studies revealed clear differences between control and GNEM iPSC-derived muscle precursor cells (iMPCs), while pathway studies implicated altered stress and autophagy signaling in GNEM iMPCs. Treatment of GNEM patient-derived iMPCs with an autophagy activator improved myogenic differentiation. In summary, we report an in vitro, iPSC-based model of GNE myopathy and implicate defective myogenesis as a contributing mechanism to the etiology of GNE myopathy.
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    Sirt1 coordinates with ERα to regulate autophagy and adiposity
    (Springer Nature, 2021-03-15) Tao, Zhipeng; Shi, Limin; Parke, Jane; Zheng, Louise; Gu, Wei; Dong, X. Charlie; Liu, Dongmin; Wang, Zongwei; Olumi, Aria F.; Cheng, Zhiyong; Biochemistry and Molecular Biology, School of Medicine
    Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.
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    Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism.
    (PLOS, 2016) Stubblefield, William B.; Alves, Nathan J.; Rondina, Matthew T.; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of Medicine
    Background: We examine the clinical significance and biomarkers of tissue plasminogen activator (tPA)-catalyzed clot lysis time (CLT) in patients with intermediate-risk pulmonary embolism (PE). Methods: Platelet-poor, citrated plasma was obtained from patients with PE. Healthy age- and sex-matched patients served as disease-negative controls. Fibrinogen, α2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen activator Inhibitor 1 (PAI-1), thrombin time and D-dimer were quantified. Clotting was induced using CaCl2, tissue factor, and phospholipid. Lysis was induced using 60 ng/mL tPA. Time to 50% clot lysis (CLT) was assessed by both thromboelastography (TEG) and turbidimetry (A405). Results: Compared with disease-negative controls, patients with PE exhibited significantly longer mean CLT on TEG (+2,580 seconds, 95% CI 1,380 to 3,720 sec). Patients with PE and a short CLT who were treated with tenecteplase had increased risk of bleeding, whereas those with long CLT had significantly worse exercise tolerance and psychometric testing for quality of life at 3 months. A multivariate stepwise removal regression model selected PAI-1 and TAFI as predictive biomarkers of CLT. Conclusion: The CLT from TEG predicted increased risk of bleeding and clinical failure with tenecteplase treatment for intermediate-risk PE. Plasmatic PAI-1 and TAFI were independent predictors of CLT.