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LIPOGENIC PATHWAYS IN ADIPOSE TISSUE DEVELOPMENT AND METABOLISM

脂肪组织发育和代谢中的脂肪生成途径

基本信息

批准号：
9126980
负责人：
Irfan J Lodhi
金额：
$ 24.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126980
关键词：
Acyltransferase Adipocytes Adipose tissue Adult Adverse effects Affect Amino Acids Antisense Oligonucleotides Binding Binding Sites Biogenesis Brown Fat Cell Culture Techniques Clinical Complex Cultured Cells Development Development Plans Diabetes Mellitus Diet Dihydroxyacetone Phosphate Disease Embryo Energy Metabolism Enzymes Ethers Exhibits Family Fatty Acids Fatty acid glycerol esters Fatty-acid synthase Fibroblasts Gene Targeting Genes Genetic Genetic Models Heart failure Laboratories Lead Lecithin Ligands Lipid Binding Lipids LoxP-flanked allele Maps Mass Spectrum Analysis Mediating Mentors Metabolic Metabolic Diseases Metabolism Molecular Mus Names Nuclear Receptors Obesity Oxidoreductase PPAR gamma Pathway interactions Peroxisome Proliferation Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Phospholipid Ethers Positioning Attribute Public Health Reaction Research Research Personnel Resistance Risk Role Stable Isotope Labeling Testing Thiazolidinediones Thinness Transgenic Mice Universities Washington Work activating transcription factor adipocyte differentiation adiponectin base career development clay db/db mouse design feeding glucose metabolism improved insulin sensitivity knock-down lipid biosynthesis lipid metabolism medical schools mutant novel novel therapeutic intervention peroxisome rosiglitazone subcutaneous transcription factor

项目摘要

This career development plan will prepare Dr. Irfan Lodhi to transition to a position as an independent academic investigator in metabolic research. The mentored phase (K99) of this 5 year project will be completed in the laboratory of Dr. Clay Semenkovich at Washington University School of Medicine. The overall objective of this project is to understand the role of lipogenic pathways in the activation of PPARg, a key regulator of adipose tissue development and metabolism. PPARg belongs to the peroxisome proliferator- activated receptor (PPAR) family of ligand-activated nuclear receptors, originally identified based on their ability to be activated by agents that promote peroxisome proliferation. Endogenous pathways of PPARg activation have remained unclear. Previous work suggests that de novo lipogenesis mediated by fatty acid synthase (FAS) is important for endogenous activation of PPARg in adipocytes. A mass spectrometry-based approach identified several FAS-dependent complex lipids as putative endogenous ligands for PPARg. These lipids are made in peroxisomes and require a previously unidentified peroxisomal enzyme named PexRAP for their synthesis. Knockdown of PexRAP in cultured cells impaired PPARg activation and adipogenesis, both of which could be rescued with rosiglitazone, a pharmacological activator of PPARg. Antisense oligonucleotide- mediated knockdown of PexRAP in mice decreased expression of PPARg-dependent genes, reduced fat mass, increased leanness, and improved insulin sensitivity. Additional studies suggested that genes involved in peroxisomal biogenesis increase during adipogenesis and are regulated by PPARg. Together, these studies led to the hypothesis that peroxisome-derived lipids activate PPARg and, reciprocally, PPARg promotes peroxisomal biogenesis, resulting in a feed-forward cycle that drives adipocyte differentiation. The following specific aims are designed to test this hypothesis. Aim 1 will determine if mice with adipose-specific deletion of PexRAP are protected from diet-induced and genetic forms of obesity and diabetes. Aim 2 will characterize the molecular mechanism of PexRAP function in adipocytes. Finally, Aim 3 will determine the role of peroxisomal biogenesis in adipocyte differentiation.

该职业发展计划将使 Irfan Lodhi 博士做好过渡到独立职位的准备代谢研究的学术研究者。这个为期 5 年的项目的指导阶段 (K99) 将是在华盛顿大学医学院 Clay Semenkovich 博士的实验室中完成。整体该项目的目标是了解脂肪生成途径在 PPARg 激活中的作用，PPARg 是脂肪组织发育和代谢的调节者。 PPARg属于过氧化物酶体增殖剂- 激活受体（PPAR）家族的配体激活核受体，最初是根据其被促进过氧化物酶体增殖的物质激活的能力。 PPARg 的内源性途径激活情况仍不清楚。先前的工作表明脂肪酸介导的从头脂肪生成合酶 (FAS) 对于脂肪细胞中 PPARg 的内源性激活非常重要。基于质谱分析的方法鉴定了几种 FAS 依赖性复合脂质作为 PPARg 的推定内源性配体。这些脂质是在过氧化物酶体中产生的，并且需要一种先前未被识别的过氧化物酶体酶，名为 PexRAP 他们的合成。培养细胞中 PexRAP 的敲低会损害 PPARg 激活和脂肪生成，这两者可以用罗格列酮（PPARg 的药理激活剂）来挽救。反义寡核苷酸- 小鼠中 PexRAP 介导的敲除降低了 PPARg 依赖性基因的表达，减少了脂肪质量，增加瘦身，并提高胰岛素敏感性。其他研究表明，涉及的基因脂肪生成过程中过氧化物酶体生物发生增加，并受 PPARg 调节。这些研究共同导致了这样的假说：过氧化物酶体衍生的脂质激活 PPARg，并且反过来，PPARg 促进过氧化物酶体生物发生，导致驱动脂肪细胞分化的前馈循环。下列旨在检验这一假设的具体目标。目标 1 将确定是否具有脂肪特异性缺失的小鼠 PexRAP 免受饮食引起的和遗传形式的肥胖和糖尿病的影响。目标 2 将描述 PexRAP 在脂肪细胞中功能的分子机制。最后，目标 3 将确定过氧化物酶体的作用脂肪细胞分化中的生物发生。