CONTROL OF ADIPOGENESIS AND ENERGY METABOLISM

描述（由申请人提供）：现代世界正处于肥胖流行病的中间，其增长到2003-2004年，32%的美国成年人肥胖并且>50%超重的程度。肥胖的增加导致肥胖相关疾病（包括2型糖尿病）患者数量的显著增加。众所周知，脂肪细胞是导致2型糖尿病的胰岛素抵抗发展的核心参与者。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，我们将注意力集中在了解脂肪形成转录因子的作用上，最明显的是C/EBP和PPAR？，调节脂肪细胞的形成和功能。在这些研究中，我们确定了一个领域的过氧化物酶体增殖物激活受体？促进Wnt信号通路的抑制以促进脂肪形成。这些研究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。具体而言，我们已经证明，螺旋7内的配体结合结构域的过氧化物酶体增殖物激活受体？是其对内源性配体的反应所必需的。我们还证明，螺旋7调节脂肪形成基因的一个新的子集（组2）的表达，包括FGF 21和Ero 1-La，响应NAD依赖性脱乙酰酶，SIRT 1的活性。我们发现，脂联素分泌的调节Ero 1-La和变化的过氧化物酶体增殖物激活受体？SIRT 1活性。我们还发现了另外两个成脂基因亚群：第3组基因编码炎症蛋白，如Ccl 2/MCP-1，在PPAR？联系方式;第4组基因编码急性期反应物，如触珠蛋白，并在脂肪形成过程中被诱导，但被胰岛素增敏剂噻唑烷二酮家族抑制。这些研究的目的是确定机制，通过何种PPAR？调节成脂基因表达的这种生理学上重要且多样的程序。具体目标是：1.定义SIRT 1，HDAC 3和PGC-1a在调节PPAR中的作用？在脂肪形成和成熟脂肪细胞中靶基因表达。2.识别与PPAR相关的转录复合物？在成熟脂肪细胞中选择基因的启动子/增强子上。3：确定螺旋7在过氧化物酶体增殖物激活受体配体结合结构域中的作用？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？在调节脂肪细胞基因的表达方面。公共卫生相关性：现代世界正处于肥胖流行病之中，其增长到这样的程度，在2003-2004年，32%的美国成年人肥胖，并且>50%超重，并且肥胖的这种增加导致患有肥胖相关病症（包括2型糖尿病）的个体数量显著增加。众所周知，脂肪细胞是导致2型糖尿病的胰岛素抵抗发展的核心参与者;因此，定义脂肪细胞调节体内胰岛素应答过程的机制是重要的。为此，研究旨在确定脂肪细胞形成的“主调节因子”，PPAR？，调节编码参与代谢稳态和能量平衡的选择蛋白质的基因表达，包括FGF 21、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.