Environmental chemicals promote adipogenesis by targeting THY1

环境化学物质通过靶向 THY1 促进脂肪生成

• 批准号: 9261102
• 负责人: E'Lissa Marie Flores
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261102
• 关键词: Adipocytes; Adolescent; Alpha Cell; Animal Model; Binding; Biological; Biological Assay; Blood Glucose; Bone Marrow; Calories; Cell Differentiation process; Cell Line; Cell Surface Proteins; Cell physiology; Cells; Chemicals; Country; DNA Methylation; Data; Diabetes Mellitus; Diet; Effector Cell; Electronics; Endocrine Disruptors; Endocrine system; Epidemic; Epigenetic Process; Fatty acid glycerol esters; Fellowship; Fibroblasts; Flame Retardants; Flow Cytometry; Funding; Future; Gene Expression; Genes; Health Care Costs; High Fat Diet; Histology; Human; Immunofluorescence Immunologic; In Vitro; Industrial fungicide; Industrialization; Intake; Knock-out; Knockout Mice; Knowledge; Lead; Link; Measures; Mesenchymal Stem Cells; Messenger RNA; Methods; Methylation; MicroRNAs; Molecular; Mus; Obesity; Obesity associated disease; Oils; Organism; Physical activity; Plasticizers; Plastics; Population; Positioning Attribute; Post-Transcriptional Regulation; Postdoctoral Fellow; Prediabetes syndrome; Proteins; Public Health; Research; Research Project Grants; Role; Science Policy; Spleen; Staining method; Stains; Stem cells; Stromal Cells; Tissues; Untranslated RNA; Weight Gain; Western Blotting; Work; chemical function; environmental chemical; exposed human population; fatty acid-binding proteins; global health; human stem cells; in vivo; in vivo Model; induced pluripotent stem cell; insight; lipid biosynthesis; mouse model; obesogen; obesogenic; physical inactivity; precursor cell; promoter; skills; stem cell fate; stem cell population; tetrabromobisphenol A

Abstract Obesity has been classically linked to poor diet/excessive calorie intake and insufficient physical activity. However, it has recently been discovered that environmental components may contribute significantly to the widespread obesity epidemic. The rapidly increasing obese populations in industrialized, developed and even undeveloped countries cannot be strictly accounted for by poor diet and physical inactivity. Environmental chemicals, termed “obesogens” are endocrine disruptors, that can trigger adipogenesis (fat cell formation). However, their mechanism(s) of action remain unknown. Tetrabromobisphenol-A (TBBPA) and tributylin (TBT) are known obesogenic chemicals. We hypothesize that TBBPA and TBT promote adipogenesis by decreasing levels of THY1 (CD90), a cell surface protein present on pre-adipocytes, certain fibroblasts, and stem cells, (e.g. human mesenchymal stem cells (hMSCs)). Our lab previously discovered fibroblasts are heterogeneous for THY1 expression, where only THY1-/low fibroblasts differentiate into adipocytes, which identified THY1’s crucial role during adipogenesis and cell fate determination. Using a well-established mouse pre-adipocyte cell line (3T3-L1), I show that TBBPA reduces THY1 mRNA and protein and promotes adipogenesis. However, whether this occurs in human stem cells, such as hMSCs and induced pluripotent stem cells (iPSCs) is unknown. Obesity and adipogenesis are also subject to epigenetic and post- translational changes, which include increases in both global DNA methylation and the abundance of specific regulatory microRNAs (miRNA). My supporting data in hMSCs shows obesogens increase certain miRNAs that are predicted to bind THY1 mRNA. Gene expression can also be regulated by DNA methylation. My supporting data shows that TBBPA increases methylation on the THY1 promoter in hMSCs. Therefore, I hypothesize that obesogens, such as TBBPA, alter post-transcriptional regulation of THY1 to decrease its expression, thereby priming precursor cells to become adipocytes. Therefore, I will determine the in vitro effects and underlying molecular mechanisms of obesogens on THY1 expression in human stem cells. (AIM 1). I will also determine the environmental obesogen effects on THY1 expression in vivo (AIM 2). The results from this project will help determine the obesogenic effects on stem cell function and will offer insight on as to how post-translational changes alter stem cell fate and lineage. Studies of environmental obesogens should be made a priority, since they likely overwhelmingly contribute to the growing worldwide obesity epidemic.

摘要