Novel Pathways for Triglyceride Storage and Adipogenesis

甘油三酯储存和脂肪形成的新途径

• 批准号: 7537504
• 负责人: PETER J TONTONOZ
• 金额: $ 52.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537504
• 关键词: Adipocytes; Adipose tissue; Affect; Atherosclerosis; Biology; Cells; Class; Collaborations; Complementary DNA; Complex; Cultured Cells; Data; Development; Diabetes Mellitus; ES01; Elements; Family member; Figs - dietary; Future; Gene Expression; Gene Expression Alteration; Gene Mutation; Gene Targeting; Genes; Genetic; Goals; Harmine; Homeostasis; Human; In Vitro; Insulin Resistance; Laboratories; Lead; Link; Lipids; Maintenance; Maps; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Principal Investigator; Regulation; Role; Screening procedure; Signal Pathway; Signal Transduction; Technology; Testing; Therapeutic Intervention; Transcription Repressor/Corepressor; Transcriptional Regulation; Triglyceride Metabolism; Triglycerides; adipocyte differentiation; base; cis acting element; cofactor; diabetic; glucose metabolism; high throughput screening; high throughput technology; in vitro Model; in vivo; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; lipine; novel; novel therapeutics; peroxisome; programs; promoter; receptor; small molecule; small molecule libraries; transcription factor

Adipose tissue plays a central role in lipid metabolism and the maintenance of energy homeostasis. Dysregulation of adipocyte development or function contributes to the pathogenesis of metabolic diseases including obesity, diabetes and atherosclerosis. The long-term goal of this Project is to understand the molecular pathways that control adipocyte differentiation and function, a goal which central to the overall theme of this PPG. Ultimately, elucidation of such pathways is expected to outline new opportunities for therapeutic intervention in human metabolic disease. The first Specific Aim is to define the function of novel transcription factors involved in triglyceride storage. We have utilized a high throughput screening approach to identify new genes that stimulate lipid accumulation in cell culture models of adipogenesis. Our initial focus will be on TLE3, a transcriptional corepressor with no previously recognized link to lipid metabolism. TLE3 is preferentially expressed in adipose tissue, is upregulated in murine models of obesity/diabetes, and is downregulated in lipodystrophic Lipinl-/- mice. We hypothesize that TLE3 acts through the direct regulation of adipocyte gene expression and that alterations in TLE3 activity may contribute to insulin resistance and/or obesity. We propose: (a) to identify target genes for TLE3, (b) to test the hypothesis that TLE3 serves as a cofactor for adipomodulatory transcription factors, (c) to determine the role of TLE3 in metabolism in vivo, and (d) to test the hypothesis that TLE3 and lipins cooperate in the control of adipocyte gene expression. The second Specific Aim is to identify the mechanism of action of small molecule regulators of adipogenesis. We have utilized high throughput screening to identify new small molecule inducers of lipid accumulation, including one compound, harmine, that regulates expression of the entire PPARy/lipin- 1/GPIHBP1 axis in vivo. Moreover, harmine has anti-diabetic activity in mice, validating our approach as a new strategy for the identification pharamcologic regulators of metabolism. We hypothesize that defining the molecular mechanism by which small molecules alter the adipogenic program will lead to the identification of new signaling pathways. We propose to: (a) map the cis-acting elements that mediate the activity of small molecules on the PPARy promoter, (b) identify mediators of small molecule action on adipogenesis, (c) test the hypothesis that small molecule regulators of PPARy expression comprise a novel class of pharmacologic regulators of lipid and glucose metabolism in vivo, (d) determine the mechanism whereby harmine regulates GPIHBP1 expression, and (e) to examine crosstalk between transcriptional pathways elucidated in Aim 1 and small molecule signaling pathways characterized in Aim 2.

脂肪组织在脂质代谢和能量稳态的维持中起着核心作用。 脂肪细胞发育或功能的失调有助于代谢疾病的发病机理 包括肥胖，糖尿病和动脉粥样硬化。该项目的长期目标是了解 控制脂肪细胞分化和功能的分子途径，这个目标与总体核心 这个PPG的主题。最终，阐明这种途径有望概述新的机会 人类代谢疾病的治疗干预。 第一个具体目的是定义甘油三酸酯中涉及的新型转录因子的功能 贮存。我们已经利用了高吞吐量筛选方法来识别刺激脂质的新基因 在脂肪生成的细胞培养模型中的积累。我们最初的重点将是TLE3，这是转录的 核压剂没有先前认识到脂质代谢的链接。 TLE3优先表示 脂肪组织在肥胖/糖尿病的鼠模型中被上调，并在脂肪营养不良中下调 Lipinl - / - 小鼠。我们假设TLE3通过脂肪细胞基因表达的直接调节起作用 TLE3活性的改变可能导致胰岛素抵抗和/或肥胖。我们建议：（a） 识别TLE3，（b）的靶基因，以测试TLE3用作脂肪调节的辅助因子的假设 转录因子，（c）确定TLE3在体内代谢中的作用，（d）检验假设 TLE3和Lipins在脂肪细胞基因表达的控制方面合作。 第二个具体目的是确定小分子调节剂的作用机理 脂肪形成。我们利用高吞吐量筛选来识别脂质的新小分子诱导剂 积累，包括一种化合物Harmine，可调节整个PPARY/LIPIN-的表达 1/gpihbp1轴体内。此外，Harmine在小鼠中具有抗糖尿病活性，证实了我们的方法 鉴定新陈代谢的识别侏罗纪研究剂的新策略。我们假设定义 小分子改变掺杂程序的分子机制将导致鉴定 新的信号通路。我们建议：（a）映射介导小的活性的顺式作用元素 PPARY启动子上的分子，（b）鉴定小分子作用对脂肪形成的介体，（c）测试 PPARY表达的小分子调节剂的假设包括一类新的药理学 脂质和葡萄糖代谢的调节剂体内，（d）确定harmine调节的机制 GPIHBP1表达和（e）检查在AIM 1中阐明的转录途径之间的串扰 AIM 2中表征的小分子信号通路。