The Control of Fatty Acid Release in Adipocytes

脂肪细胞中脂肪酸释放的控制

• 批准号: 7847738
• 负责人: Hong Ruan
• 金额: $ 19.5万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2010-03-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847738
• 关键词: 1,2-diacylglycerol; Address; Adipocytes; Adipose tissue; Automobile Driving; Binding; Cell physiology; Cells; Cloning; Co-Immunoprecipitations; Data; Development; Diglycerides; Enzymes; Epidemic; Equilibrium; Esterification; Esterified Fatty Acids; Excision; Fatty Acids; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Transcription; Germ Lines; Glycerides; Glycerol; Goals; Hematopoietic; Hydrolysis; Inflammation; Insulin Resistance; Intervention; JUN gene; Kinetics; Link; Lipase; Lipolysis; MAPK8 gene; MAPK9 gene; Mediating; Modeling; Molecular; Monoglycerides; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Phenotype; Plant Roots; Plasma; Principal Investigator; Production; Proteins; Regulation; Research; Role; Signal Pathway; Stream; Testing; Triglycerides; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; adipocyte biology; effective therapy; fatty acid oxidation; improved; in vivo; insight; insulin sensitivity; interest; novel therapeutics; oxidation; prevent; resistance mechanism; stress-activated protein kinase 1; transcription factor

Principal Investigator: Ruan, Hong Project Summary Despite extensive evidence implicating excess circulating non-esterified fatty acids (NEFA) in the induction of systemic insulin resistance, the mechanisms underlying elevated plasma NEFA levels remain unclear. Adipose tissue is the largest NEFA depot. The amount of NEFA released from adipocytes, determined mainly by the balance between lipolysis and intra-adipocyte NEFA re-esterification, is linearly related to plasma NEFA levels. Thus, identification of the regulatory mechanisms controlling adipocyte NEFA release should provide a guide to new therapies for insulin resistance. The JNK1 and JNK2 pathways have been implicated in obesity-linked type 2 diabetes. We recently demonstrated that 1) removal of JNK1 and JNK2 stimulates both the kinetics and magnitude of baseline lipolysis while decreasing NEFA release over 24 h; 2) JNK1/JNK2-deficiency increases NEFA re-esterification and oxidation; and 3) JNK1/JNK2-deficiency profoundly up-regulates a subset of PPAR-¿-target genes including pepck, a key gene involved in glyceroneogenesis and NEFA re-esterification. These data provoke three pivotal questions. First, how does JNK1/JNK2 deficiency increase the transcription of PPAR-¿-target genes? Second, what mechanisms underlie JNK1/JNK2-deficiency-stimulated lipolysis and NEFA re-esterification? Third, is JNK1/JNK2-deficiency sufficient to override TNF-¿-stimulated NEFA release? The Aims are: 1) using co-immunoprecipitation and interaction cloning strategy to test the hypothesis that the JNK pathway inhibits PPAR-¿ activity in adipocytes through activation of c-Jun and/or through regulation of the activities of PAPR-¿ co-factors; 2) to test the hypothesis that removal of JNK1 and JNK2 stimulates the expression and/or activities of proteins involved in triglyceride turnover by characterizing the phenotypes of JNK1/JNK2-deficient adipocytes; and 3) to test the hypothesis that JNK1/JNK2-deficiency-mediated increase in NEFA utilization is sufficient to delay or prevent TNF-¿-stimulated NEFA release in adipocytes.

主要研究者：阮红 项目摘要 尽管有大量证据表明，过量的循环非酯化脂肪酸（NEFA）， 诱导全身性胰岛素抵抗，血浆NEFA水平升高的潜在机制仍然存在 不清楚脂肪组织是NEFA最大的储存库。从脂肪细胞释放的NEFA的量， 主要由脂肪分解和脂肪细胞内NEFA再酯化之间的平衡决定，呈线性 与血浆NEFA水平有关。因此，确定控制脂肪细胞NEFA的调节机制， 这一版本应该为胰岛素抵抗的新疗法提供指导。JNK 1和JNK 2通路具有 与肥胖相关的2型糖尿病有关。我们最近证明了1）去除JNK 1和 JNK 2刺激基线脂解的动力学和幅度，同时减少NEFA释放超过24 h; 2）JNK 1/JNK 2缺乏增加NEFA再酯化和氧化;和3）JNK 1/JNK 2缺乏 深刻上调了一组PPAR-â靶基因，包括pepck，这是一个参与的关键基因 甘油生成和NEFA再酯化。这些数据引发了三个关键问题。一、如何 JNK 1/JNK 2缺陷增加了PPAR-γ靶基因的转录？第二， JNK 1/JNK 2缺陷刺激的脂解和NEFA再酯化？第三，JNK 1/JNK 2缺陷 足以抵消TNF-α刺激的NEFA释放吗目的是：1）使用免疫共沉淀， 相互作用克隆策略，以检验JNK途径抑制脂肪细胞中的PPAR-γ活性的假设 通过激活c-Jun和/或通过调节PAPR辅因子的活性; 2）测试 假设JNK 1和JNK 2的去除刺激了参与JNK 1和JNK 2的蛋白质的表达和/或活性， 通过表征JNK 1/JNK 2缺陷型脂肪细胞的表型来检测甘油三酯周转;和3）检测甘油三酯周转， 假设JNK 1/JNK 2缺陷介导NEFA利用增加足以延迟或预防 TNF-α刺激脂肪细胞中NEFA的释放。