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

• 批准号: 8914598
• 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
• 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/8914598
• 关键词: 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; 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; glycerone-phosphate O-acyltransferase; improved; insulin sensitivity; lipid biosynthesis; lipid metabolism; medical schools; mutant; novel; novel therapeutic intervention; peroxisome; rosiglitazone; subcutaneous; transcription factor

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.

这项职业发展计划将使Irfan Lodhi博士准备过过渡为独立的职位 代谢研究的学术研究者。这个5年项目的指导阶段（K99）将是 在华盛顿大学医学院的Clay Semenkovich博士实验室完成。总体 该项目的目的是了解脂源途径在PPARG激活中的作用，PPARG是一个关键 脂肪组织发育和代谢的调节剂。 PPARG属于过氧化物酶体增殖物 - 配体激活的核受体的活化受体（PPAR）家族，最初是根据它们的 能够被促进过氧化物酶体增殖的药物激活。 PPARG的内源性途径 激活尚不清楚。先前的工作表明，脂肪酸介导的从头脂肪生成 合成酶（FAS）对于脂肪细胞中PPARG的内源性激活很重要。基于质谱的 方法将几种依赖Fas的复合脂质鉴定为PPARG的假定内源配体。这些 脂质是用过氧化物组制成的，需要先前未鉴定的过氧化物酶体酶，称为PEXRAP 它们的综合。培养细胞中PEXRAP的敲低损害了PPARG激活和脂肪形成，这两者都 可以用PPARG的药理学激活剂Rosiglitazone营救。反义寡核苷酸 - 小鼠中介导的PEXRAP敲低降低了PPARG依赖性基因的表达，脂肪减少了 质量，增加瘦弱和提高胰岛素敏感性。其他研究表明涉及的基因 在掺杂的过程中，过氧化物酶体生物发生增加，并由PPARG调节。在一起，这些研究 导致了过氧化物酶体衍生的脂质激活PPARG的假设，而PPARG会促进PPARG 过氧化物酶体生物发生，导致喂养前循环驱动脂肪细胞分化。下列 具体目的旨在检验这一假设。 AIM 1将确定是否具有脂肪特异性缺失的小鼠 PEXRAP受到肥胖和糖尿病的饮食诱导和遗传形式的保护。 AIM 2将表征 脂肪细胞中PEXRAP功能的分子机制。最后，AIM 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。