Novel Pathways for Triglyceride Storage and Adipogenesis

项目3的目标是定义控制脂肪细胞分化和 功能。阐明调控脂肪细胞分化和甘油三酯储存的信号通路 脂肪组织通路有望为人类治疗干预发现新的机会 代谢性疾病。在目前的资助期间，我们发现了三种以前没有特征的蛋白质 控制脂肪细胞中脂肪代谢的物质(TLE3、PSPC1和Idol)。在我们当前工作的基础上 在授权期内，我们提出了一系列分子、细胞生物学和小鼠研究来研究假说 关于这些新的调节因子在生理和疾病中的作用。具体目标1是澄清 TLE3在白色和棕色脂肪组织表型规范中的作用机制。我们有 发现在脂肪组织中过度表达TLE3的小鼠表现出脂肪细胞功能的深刻变化， 包括从棕色脂肪组织到白色脂肪组织的表型转变。将白色脂肪组织移向 棕色特征越多，新陈代谢越好，对糖尿病的抵抗力越强。更好的 了解控制脂肪细胞表型的分子途径将具有非常重要的意义 可能具有治疗意义。具体目标2是确定的功能和作用机制 脂肪细胞分化过程中可能的RNA结合蛋白PSPC1。PSPC1和TLE3被鉴定为 在我们最初的高通量筛选中，发现了一种新的脂肪细胞分化启动子。破译 这一新的因子的作用机制可能揭示调控因子在 脂肪细胞基因表达的调控。具体目标3是定义LXR-Idol轴在 甘油三酯代谢和脂肪储存。对偶像基因敲除小鼠的初步分析指出了一种意想不到的结果 在控制甘油三酯代谢和脂肪储存方面的作用。我们假设LXR依赖于 脂肪组织中Idol的调节是外周脂肪蛋白受体活性的重要决定因素 而美国偶像提供了一种机制，将饮食和类固醇代谢的变化与脂肪摄取和 这些组织中的新陈代谢。 相关性(请参阅说明)： 脂肪组织功能或质量改变与心血管代谢疾病有关，强调 脂肪细胞在新陈代谢中的基本重要性。阐明调控的信号通路 脂肪组织途径中脂肪细胞分化和甘油三酯储存有望发现新的 人类代谢性疾病(如肥胖、糖尿病)的治疗干预机会。

The objective of Project 3 is to define novel molecular pathways that controi adipocyte differentiation and function. Elucidating signaling pathways that govern adipocyte differentiation and triglyceride storage in adipose tissue pathways is expected to uncover new opportunities for therapeutic intervention in human metabolic disease. During the current grant period, we discovered three previously uncharacterized proteins that control lipid metabolism in adipocytes (TLE3, PSPC1, and IDOL). Building on our work in the current grant period, we propose a series of molecular, cell biological, and mouse studies to investigate hypotheses regarding the roles of these novel regulatory factors in physiology and disease. Specific Aim 1 is to elucidate the mechanism of action of TLE3 in white versus brown adipose tissue phenotypic specification. We have discovered that mice overexpressing TLE3 in adipose tissue show profound alterations in adipocyte function, including a phenotypic shift from brown to white adipose tissue. Shifting white adipose tissue towards a more brown character is associated with improved metabolism and resistance to diabetes. A better understanding ofthe molecular pathways that control adipocyte phenotype would be highly significant and may have therapeutic implications. Specific Aim 2 is to determine the function and mechanism of action of the putative RNA-binding protein PSPC1 in adipocyte differentiation. PSPC1 was identified along with TLE3 in our initial high-throughput cDNA screen as a new promoter of adipocyte differentiation. Deciphering the mechanism of action of this novel factor is likely to uncover new modes of action for regulatory factors in the control of adipocyte gene expression. Specific Aim 3 is to define the role of the LXR-IDOL axis in triglyceride metabolism and lipid storage. Preliminary analysis of Idol knockout mice points to an unexpected function in the control of triglyceride metabolism and lipid storage. We hypothesize that LXR-dependent regulation of IDOL in adipose tissue is an important determinant of peripheral lipoprotein receptor activity and that IDOL provides a mechanism to link alterations in diet and sterol metabolism to lipid uptake and metabolism in these tissues. RELEVANCE (See instructions): Altered adipose tissue function or mass is associated with cardiovascular metabolic disease, underscoring the fundamental importance of adipocytes in metabolism. Elucidating signaling pathways that govern adipocyte differentiation and triglyceride storage in adipose tissue pathways is expected to uncover new opportunities for therapeutic intervention in human metabolic diseases (e.g., obesity, diabetes mellitus).