CONTROL OF ADIPOGENESIS AND ENERGY METABOLISM

描述(申请人提供)：现代世界正处于肥胖症流行之中，在2003-2004年间，32%的美国成年人肥胖，50%的人超重。肥胖症的增加导致患有肥胖相关疾病的人数显著增加，其中包括2型糖尿病。人们普遍认为，脂肪细胞在导致2型糖尿病的胰岛素抵抗的发展过程中起着核心作用。因此，确定脂肪细胞调节体内胰岛素反应过程的机制是很重要的。为此，我们将注意力集中在了解成脂转录因子，尤其是C/EBPs和PPAR？，在调节脂肪细胞的形成和功能中的作用。在这些研究中，我们确定了PPAR？这有助于抑制Wnt信号通路，从而促进脂肪生成。这些研究已经产生了一系列新颖而令人兴奋的数据，这些数据代表了我们未来目标的核心。具体地说，我们已经证明了PPAR？配体结合区中的螺旋7是其对内源性配体的反应所必需的。我们还证明，Helix 7调节一组新的成脂基因的表达，包括FGF21和Ero1-La，响应依赖于NAD的脱乙酰酶SIRT1的活性。我们发现脂联素的分泌受Ero1-La调节，PPAR？和SIRT1活性。我们还鉴定了另外两组成脂基因：第3组基因编码炎症蛋白，如CCL2/MCP-1，在脂肪形成过程中以PPAR？相关的方式下调；第4组基因编码急性时相反应物，如结合珠蛋白，在脂肪生成过程中被诱导，但被胰岛素增敏剂的噻唑烷二酮家族抑制。这些研究的目标是确定PPAR通过什么机制？调节这样一个生理上重要的和多样化的成脂基因表达程序。具体目的是：1.明确SIRT1、HDAC3和PGC-1a在调节PPAR中的作用。靶基因在成脂过程和成熟脂肪细胞中的表达。2：确定与PPAR相关的转录复合体？成熟脂肪细胞中特定基因的启动子/增强子。3：定义螺旋7在PPAR的配体结合域中的作用？在控制脂肪细胞基因表达方面。4：确定PPAR翻译后修饰的作用？调节脂肪细胞基因的表达。与公共健康相关：现代世界正处于肥胖症流行之中，在2003-2004年间，32%的美国成年人肥胖，50%的人超重，这种肥胖症的增加导致患有肥胖症相关疾病的人数显著增加，包括2型糖尿病。人们普遍认为，脂肪细胞是导致2型糖尿病的胰岛素抵抗的中心参与者；因此，确定脂肪细胞调节体内胰岛素反应过程的机制是很重要的。为此，这些研究旨在确定脂肪细胞形成的“主调节器”PPAR？通过什么机制来调节特定蛋白的编码基因的表达，这些蛋白涉及代谢稳态和能量平衡，包括FGF21、Klotho和脂联素。

DESCRIPTION (provided by applicant): The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight. This increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes. It is important, therefore, to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, we have focused our attention on understanding the role of adipogenic transcription factors, most notably C/EBPs and PPAR?, in regulating the formation and function of adipocytes. During these studies, we identified a domain in PPAR? that facilitates inhibition of the Wnt signaling pathway in order to promote adipogenesis. These studies have led to a series of novel and exciting data that represent the core of our future aims. Specifically, we have demonstrated that helix 7 within the ligand-binding domain of PPAR? is required for its response to endogenous ligands. We also demonstrate that helix 7 regulates expression of a novel subset (Group 2) of adipogenic genes, including FGF21 and Ero1-La, that respond to the activity of the NAD-dependent deacetylase, SIRT1. We show that adiponectin secretion is regulated by Ero1-La and changes in PPAR? and SIRT1 activity. We have also identified two other subsets of adipogenic genes: Group 3 genes encode inflammatory proteins such as Ccl2/MCP-1 and are down-regulated during adipogenesis in a PPAR?-associated manner; Group 4 genes encode acute-phase reactants such as haptoglobin and are induced during adipogenesis, but are inhibited by the thiazolidinedione family of insulin sensitizers. The goal of these studies is to define the mechanisms by which PPAR? regulates such a physiologically important and diverse program of adipogenic gene expression. The specific aims are: 1. Define the role of SIRT1, HDAC3 and PGC-1a in regulating PPAR? target gene expression during adipogenesis and in mature adipocytes. 2: Identify the transcriptional complexes associating with PPAR? on the promoters/enhancers of select genes in mature adipocytes. 3: Define the role of helix 7 within the ligand- binding domain of PPAR? in controlling adipocyte gene expression. 4: To determine the role of posttranslational modification of PPAR? in regulating expression of adipocyte genes. PUBLIC HEALTH RELEVANCE: The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight and this increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes; consequently, it is important to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, the studies are designed to define the mechanisms by which the `master regulator' of adipocyte formation, PPAR?, regulates expression of the genes coding for select proteins involved in metabolic homeostasis and energy balance including FGF21, ¿Klotho and adiponectin.