METABOLIC FUNCTIONS OF ADIPOCYTE PEROXISOMES

脂肪细胞过氧化物酶体的代谢功能

• 批准号: 9061674
• 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/9061674
• 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为甘油三酯（TG）来处理循环脂肪酸（FA）的能力具有重要的代谢和临床意义，通过防止潜在有害的FA代谢物在其他器官中的积累，例如肝脏和肌肉。过氧化物酶体整合了脂质储存和去除功能，因为 FA 可以与磷酸二羟丙酮 (DHAP) 结合，合成各种脂质或进入氧化途径，无论是 β 氧化还是 α 氧化。我们和其他人报道过过氧化物酶体在调节脂肪生成和脂肪细胞 FA 代谢中发挥重要作用。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，重点关注很少研究的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和α氧化的促脂肪生成作用的观察，我们假设有限的过氧化物酶体α氧化将减少FA进入脂质储存并增加脂肪细胞中线粒体FA氧化。目标 1 旨在通过操纵 α 氧化来确定原代脂肪细胞中过氧化物酶体在脂肪生成和 FA 代谢中的功能。还将测定肥胖小鼠和抗饮食诱导肥胖小鼠（CD36 无效和 SCD-1 无效）的脂肪组织中 FA α 氧化活性和参与过氧化物酶体功能的酶水平。目标 2 将研究过氧化物酶体 FA α 氧化代谢影响的机制。将研究外源性和内源性 α 羟基化 FA 对映体的代谢命运，以了解影响 FA 代谢的特定细胞途径。将在过氧化物酶体 FA α 氧化受到抑制或增强的原代脂肪细胞中探索过氧化物酶体和线粒体重塑和生物发生及其与脂滴的关联。在目标 3 中，我们将使用过氧化物酶体 FA α 氧化改变的转基因小鼠模型以及用 FA α 氧化抑制剂硫胺素治疗的小鼠来评估脂肪细胞过氧化物酶体 α 氧化对肥胖和胰岛素敏感性的贡献。还将评估瘦人和肥胖者以及减肥后肥胖者的脂肪组织中参与过氧化物酶体 FA 代谢的蛋白质和脂质种类。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，这可以为肥胖相关代谢疾病的病理生理学提供新的见解。