Novel Pathways for Triglyceride Storage and Adipogenesis

甘油三酯储存和脂肪生成的新途径

• 批准号: 7898773
• 负责人: PETER J TONTONOZ
• 金额: $ 47.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898773
• 关键词: Adipocytes; Adipose tissue; Affect; Atherosclerosis; Biology; Cell Culture Techniques; Cells; Collaborations; Complementary DNA; Complex; 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维持能量稳态中发挥着核心作用。 脂肪细胞发育或功能失调导致代谢疾病的发病机制 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，这是整体目标的核心 本次 PPG 的主题。最终，对这些途径的阐明预计将为人们勾勒出新的机会 人类代谢疾病的治疗干预。 第一个具体目标是定义参与甘油三酯的新型转录因子的功能 贮存。我们利用高通量筛选方法来鉴定刺激脂质的新基因 脂肪生成细胞培养模型中的积累。我们最初的重点将是 TLE3，一种转录 之前没有发现与脂质代谢有联系的辅阻遏物。 TLE3优先表达于 脂肪组织，在肥胖/糖尿病小鼠模型中上调，在脂肪营养不良中下调 Lipinl-/-小鼠。我们假设 TLE3 通过直接调节脂肪细胞基因表达发挥作用 TLE3 活性的改变可能导致胰岛素抵抗和/或肥胖。我们建议： (a) 确定 TLE3 的靶基因，(b) 检验 TLE3 作为脂肪调节辅助因子的假设 转录因子，(c) 确定 TLE3 在体内代谢中的作用，以及 (d) 检验假设 TLE3 和脂质协同控制脂肪细胞基因表达。 第二个具体目标是确定小分子调节剂的作用机制 脂肪生成。我们利用高通量筛选来鉴定新的脂质小分子诱导剂 积累，包括一种化合物，去氢骆驼蓬碱，调节整个 PPARγ/脂质的表达 体内 1/GPIHBP1 轴。此外，去氢骆驼蓬碱对小鼠具有抗糖尿病活性，验证了我们的方法作为一种 鉴定代谢药理学调节剂的新策略。我们假设定义 小分子改变脂肪形成程序的分子机制将导致鉴定 新的信号通路。我们建议：（a）绘制介导小分子活动的顺式作用元件。 PPARy 启动子上的分子，(b) 鉴定小分子对脂肪生成作用的介质，(c) 测试 PPARγ 表达的小分子调节剂包含一类新的药理作用的假设 体内脂质和葡萄糖代谢的调节剂，(d) 确定去氢骆驼蓬碱调节的机制 GPIHBP1 表达，以及 (e) 检查目标 1 中阐明的转录途径之间的串扰 以及目标 2 中表征的小分子信号通路。