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: 8827465
• 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/8827465
• 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; Lipids; Maps; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Names; Nuclear Receptors; Obesity; Oxidoreductase; Pathway interactions; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phospholipid Ethers; Positioning Attribute; Public Health; Reaction; Receptor Activation; 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; receptor binding; 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.

这一职业发展计划将为Irfan Lodhi博士过渡到一个独立的职位做准备 代谢研究方面的学术研究员。这个5年项目的指导阶段(K99)将是 在华盛顿大学医学院克莱·塞门科维奇博士的实验室完成。整体而言 这个项目的目的是了解造脂途径在PPARg激活中的作用，PPARg是一个关键的 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- 激活受体(PPAR)家族配体激活的核受体，最初是根据它们的 被促进过氧化物酶增殖剂激活的能力。PPARg的内源性途径 激活情况仍不清楚。以往的工作表明，脂肪酸介导的从头脂肪生成 合成酶(Fas)对脂肪细胞中PPARg的内源性激活起重要作用。一种基于质谱学的 方法确定了几种依赖于Fas的复合脂类作为PPARg的内源性配体。这些 脂质是在过氧化体中产生的，需要一种以前未知的称为PexRAP的过氧化物体酶来实现 它们的合成。在培养细胞中敲除PexRAP会损害PPARg的激活和脂肪生成，两者都 PPARg的药理激活剂罗格列酮可以挽救这种情况。反义寡核苷酸- PexRAP介导的小鼠基因敲除降低PPARg依赖基因的表达，降低脂肪含量 体重增加，苗条增加，并改善胰岛素敏感性。更多的研究表明，基因与 在脂肪生成过程中，过氧化体的生物合成增加，并受PPARg调节。总而言之，这些研究 导致了一种假说，即过氧化物酶体衍生的脂类激活PPARg，反过来，PPARg促进 过氧化体生物发生，导致驱动脂肪细胞分化的前馈循环。以下是 为了检验这一假设，我们设计了具体的目标。目标1将确定脂肪特异性缺失的小鼠 PexRAP可以预防饮食诱导的和遗传形式的肥胖和糖尿病。目标2将描述 PexRAP在脂肪细胞中作用的分子机制最后，目标3将确定过氧化物酶的作用。 脂肪细胞分化中的生物发生。