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: 8443043
• 负责人: Irfan J Lodhi
• 金额: $ 9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443043
• 关键词: Adipocytes; Adipose tissue; Antisense Oligonucleotides; Biogenesis; Complex; Cultured Cells; Development; Development Plans; Diabetes Mellitus; Diet; Disease; Enzymes; Family; Fatty acid glycerol esters; Fatty-acid synthase; Genes; Genetic; Laboratories; Lead; Ligands; Lipids; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Names; Nuclear Receptors; Obesity; Pathway interactions; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Phase; Positioning Attribute; Public Health; Research; Research Personnel; Role; Testing; Thinness; Universities; Washington; Work; adipocyte differentiation; base; career development; clay; design; feeding; improved; insulin sensitivity; lipid biosynthesis; medical schools; novel therapeutic intervention; peroxisome; public health relevance; rosiglitazone

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该职业发展计划将为 Irfan Lodhi 博士做好过渡到代谢研究领域的独立学术研究者的准备。这个为期 5 年的项目的指导阶段 (K99) 将在华盛顿大学医学院 Clay Semenkovich 博士的实验室中完成。该项目的总体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关键调节因子。 PPARg 属于配体激活核受体的过氧化物酶体增殖物激活受体 (PPAR) 家族，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而鉴定的。 PPARg 激活的内源性途径仍不清楚。先前的工作表明，脂肪酸合酶 (FAS) 介导的从头脂肪生成对于脂肪细胞中 PPARg 的内源性激活非常重要。基于质谱的方法鉴定了几种 FAS 依赖性复合脂质作为 PPARg 的推定内源配体。这些脂质是在过氧化物酶体中产生的，需要一种先前未鉴定的过氧化物酶体酶（名为 PexRAP）来合成。培养细胞中 PexRAP 的敲低会损害 PPARg 激活和脂肪生成，而这两种情况都可以用 PPARg 药理激活剂罗格列酮来挽救。反义寡核苷酸介导的小鼠 PexRAP 敲低可降低 PPARg 依赖性基因的表达，减少脂肪量，增加瘦度并改善胰岛素敏感性。其他研究表明，参与过氧化物酶体生物合成的基因在脂肪生成过程中增加，并受到 PPARg 的调节。总之，这些研究得出了这样的假设：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，从而形成驱动脂肪细胞分化的前馈循环。以下具体目标旨在检验这一假设。目标 1 将确定脂肪特异性缺失 PexRAP 的小鼠是否能够免受饮食诱导和遗传形式的肥胖和糖尿病的影响。目标 2 将描述脂肪细胞中 PexRAP 功能的分子机制。最后，目标 3 将确定过氧化物酶体生物发生在脂肪细胞分化中的作用。