METABOLIC FUNCTIONS OF ADIPOCYTE PEROXISOMES

脂肪细胞过氧化物酶体的代谢功能

• 批准号: 8870347
• 负责人: Xiong Su
• 金额: $ 36.22万
• 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: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870347
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Biogenesis; Body Weight decreased; Body fat; CD36 gene; Clinical; Data; Developed Countries; Diabetes Mellitus; Diet; Dihydroxyacetone Phosphate; Energy Metabolism; Enzymes; Etiology; Euglycemic Clamping; Excision; Fatty Acids; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Glucose Clamp; Glycolysis; Health; Homeostasis; Hydroxylation; Lipids; Liver; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mus; Muscle; Obese Mice; Obesity; Organ; Oxythiamine; Pathway interactions; Peroxisome Proliferation; Phospholipids; Play; Population; Process; Proteins; Regulation; Reporting; Resistance; Role; Signal Transduction; Sphingolipids; Techniques; Testing; Tissue Sample; Transgenic Mice; Triglycerides; adipocyte differentiation; base; enantiomer; fatty acid metabolism; fatty acid oxidation; human subject; hydroxy fatty acid; inhibitor/antagonist; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; mouse model; novel; oxidation; peroxisome; prevent; protein B; receptor

DESCRIPTION (provided by applicant): The ability of adipose tissue to dispose of circulating fatty acids (FA) by oxidation or storage as triglyceride (TG) has important metabolic and clinical implications, by preventing the accumulation of potentially harmful FA metabolites in other organs, such as the liver and muscle. Peroxisomes integrate lipid storage and removal since FA can be conjugated with dihydroxyacetone phosphate (DHAP) to synthesize various lipids or be shuttled into oxidative pathways, either beta or alpha oxidation. We and others have reported that peroxisomes play important roles in regulating adipogenesis and adipocyte FA metabolism. Our current application aims to understand the metabolic functions of peroxisomes in adipocytes with a focus on the little studied alpha oxidation pathway. Based on our observation of the increased peroxisomes during adipogenesis and the pro- lipogenic effects of alpha oxidation, we hypothesize that limited peroxisomal alpha oxidation will decrease FA into lipid storage and increase mitochondrial FA oxidation in adipocytes. Aim 1 seeks to determine functions of peroxisomes in adipogenesis and in FA metabolism in primary adipocytes with manipulated alpha oxidation. FA alpha oxidation activities and levels of enzymes involved in peroxisomal functions in adipose tissues from obese mice and mice resistant to diet-induced obesity (CD36 null and SCD-1 null) will also be determined. Aim 2 will examine mechanisms responsible for the metabolic effects of peroxisomal FA alpha oxidation. Metabolic fates of exogenous and endogenous alpha hydroxylated FA enantiomers will be studied to understand specific cellular pathways contributing to its effects on FA metabolism. Peroxisomal and mitochondrial remodeling and biogenesis and their association with lipid droplets will be explored in primary adipocytes with inhibited or enhanced peroxisomal FA alpha oxidation. In aim 3, we will evaluate contribution of adipocyte peroxisomal alpha oxidation to adiposity and insulin sensitivity using transgenic mouse models with altered peroxisomal FA alpha oxidation and in mice treated with the FA alpha oxidation inhibitor oxythiamine. Proteins involved in and lipid species resulting from peroxisomal FA metabolism in adipose tissues from lean and obese people and from obese people after weight loss will also be evaluated. The studies outlined in this proposal will provide new information regarding the role of peroxisomes in regulating adipocyte lipid and energy metabolism, which could provide novel insights into the pathophysiology of obesity-related metabolic diseases.

描述（由申请人提供）：脂肪组织通过氧化或储存作为甘油三酸酯（TG）的循环脂肪酸（FA）的能力具有重要的代谢和临床意义，通过预防其他器官（例如Liver and Muscle）中潜在有害的FA代谢物的积累。过氧化物酶体会整合脂质的储存和去除，因为FA可以与二羟基乙酮磷酸（DHAP）结合以合成各种脂质，或将其穿梭为氧化途径，即β或α氧化。我们和其他人报告说，过氧化物体在调节脂肪生成和脂肪细胞FA代谢方面起着重要作用。我们当前的应用旨在了解脂肪细胞中过氧化物酶体的代谢功能，重点是研究的α氧化途径。根据我们对脂肪生成过程中过氧化物酶体增加的观察以及α氧化的促产作用，我们假设有限的过氧化物酶体α氧化剂将降低FA中的FA，并增加脂质细胞中线粒体FA的氧化。 AIM 1旨在确定过氧化物酶体在脂肪生成和FA代谢中的功能，并具有操纵的α氧化。还将确定FAα氧化活性和涉及肥胖小鼠脂肪组织中过氧化物酶体功能的酶的水平，以及对抗饮食诱导的肥胖症具有抗性的小鼠（CD36 NULL和SCD-1 NULL）。 AIM 2将检查负责过氧化物酶体FA氧化代谢作用的机制。将研究外源性和内源性α-羟化FA对映体的代谢命运，以了解特定的细胞途径，从而有助于其对FA代谢的影响。过氧化物酶体和线粒体的重塑和生物发生及其与脂质液滴的关联将在抑制或增强的过氧化物酶体FAα氧化的原代脂肪细胞中探索。在AIM 3中，我们将使用转基因小鼠模型对脂肪度和胰岛素敏感性的脂肪细胞α氧化的贡献，使用过氧化物酶体FAα氧化和用FAα氧化抑制剂氧化剂治疗的小鼠中的转基因小鼠模型。还将评估来自瘦和肥胖者的脂肪组织中的过氧化物酶体FA代谢以及体重减轻后肥胖者的蛋白质和脂质物种。该提案中概述的研究将提供有关过氧化物酶体在调节脂肪细胞脂质和能量代谢中的作用的新信息，这些信息可以为与肥胖相关的代谢疾病的病理生理学提供新的见解。