OBESITY, ADIPOGENESIS, AND LIPID LIGANDS

肥胖、脂肪生成和脂质配体

• 批准号: 7855309
• 负责人: Clay F. Semenkovich
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855309
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adipose tissue; Affect; American; Animals; Arthritis; Automobile Driving; Binding; Binding Sites; Blood Glucose; Cells; Conscious; Control Animal; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Delivery Systems; Eating; Embryo; Enzymes; Epidemic; Exercise; Fatty acid glycerol esters; Fatty-acid synthase; Fibroblasts; Genetic; Genetic Transcription; Health; Heart Diseases; Hyperlipidemia; Hypertension; Hypertrophy; Individual Differences; Inflammation; Knock-out; Lead; Lecithin; Ligands; Lipid Binding; Lipids; Liver; Luciferases; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutritional; Obesity; Obesity associated disease; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Plasmids; Predisposition; Process; Public Health; Quality of life; Receptor Activation; Reporter; Research; Resistance; Role; Serum; Signal Transduction; Sleep Apnea Syndromes; Stroke; Techniques; Testing; Thiazolidinediones; Tissues; Transcriptional Activation; United States National Institutes of Health; Vascular Diseases; Work; adipocyte differentiation; diabetes mellitus therapy; disorder risk; energy balance; feeding; glucose metabolism; improved; in vivo; innovation; lipid biosynthesis; member; novel; novel strategies; obesity risk; programs; public health relevance; receptor; receptor binding; willingness

DESCRIPTION (provided by applicant): Obesity and its sequelae including diabetes are epidemic. Manipulating fat cells could lead to new therapies for obesity-associated disease. Peroxisome proliferator-activated receptors (PPARs) are involved in obesity and diabetes. One of these receptors, PPAR, is required for adipogenesis. Identification of endogenous PPAR ligands has been elusive. We have now identified an endogenous ligand for PPAR and developed an analogous strategy for identifying endogenous PPAR ligands. This work was predicated on the finding that inactivation of fatty acid synthase (FAS) in mouse liver produces a phenotype resembling PPAR deficiency that is rescued by pharmacologic activation of PPAR. Mass spectrometry techniques identified a lipid bound to PPAR that was FAS-dependent. This application focuses on obesity-resistant animals with FAS deficiency in adipose tissue, FASKOF (Fatty Acid Synthase KnockOut in Fat) mice. FAS-deficient embryonic fibroblasts have a phenotype resembling PPAR deficiency that is rescued by pharmacologic activation of PPAR. This project will test the hypothesis that in adipose tissue and its precursors, fatty acid synthase, an enzyme required for the process of de novo lipogenesis, mediates risk for obesity and metabolic disease in part by activating the nuclear receptor PPAR. The specific aims are: 1. To determine if mice with FAS inactivation in adipose tissue (FASKOF mice) are protected from diet- induced and genetic obesity and if pharmacologic activation of PPAR reverses protection. 2. To determine if the presence of FAS is required for PPAR activation and the normal adipocyte differentiation process. 3. To use mass spectrometry analyses to identify potential endogenous PPAR ligands by comparing lipids bound to PPAR isolated from FASKOF (FAS-deficient) and control (FAS-replete) cells. This project has the potential to help clarify how endogenous ligands are generated for a nuclear receptor implicated in the modulation of adiposity, glucose metabolism and inflammation. PUBLIC HEALTH RELEVANCE: This application is relevant to public health and the mission of the NIH. Obesity shortens and diminishes the quality of life through its association with diabetes, heart disease and stroke, arthritis, sleep apnea, certain cancers, and other disorders. Identifying novel pathways for altering the function of fat cells has the potential to improve the metabolic milieu of obesity and treat obesity-associated diseases.

描述（由申请人提供）：肥胖及其后遗症，包括糖尿病是流行病。操纵脂肪细胞可能会导致肥胖相关疾病的新疗法。过氧化物酶体增殖物激活受体（PPARs）参与肥胖和糖尿病。这些受体之一，过氧化物酶体增殖物激活受体，是脂肪生成所必需的。内源性PPAR配体的鉴定一直是难以捉摸的。 我们现在已经确定了一个内源性配体的过氧化物酶体增殖物激活受体，并制定了一个类似的战略，确定内源性过氧化物酶体增殖物激活受体配体。这项工作是基于这样的发现，即小鼠肝脏中脂肪酸合酶（FAS）的失活产生了类似于PPAR缺乏症的表型，该表型可通过PPAR的药理学激活来挽救。质谱技术鉴定了与FAS依赖性的PPAR结合的脂质。本申请的重点是脂肪组织中FAS缺乏的抗肥胖动物，FASKOF（脂肪中脂肪酸合酶敲除）小鼠。FAS缺陷的胚胎成纤维细胞具有类似于通过药物激活PPAR来拯救的PPAR缺陷的表型。该项目将检验以下假设：在脂肪组织及其前体中，脂肪酸合成酶（一种从头脂肪生成过程所需的酶）部分通过激活核受体PPAR介导肥胖和代谢疾病的风险。具体目标是：1.确定脂肪组织中FAS失活的小鼠（FASKOF小鼠）是否受到饮食诱导和遗传性肥胖的保护，以及PPAR的药理学激活是否逆转保护。2.确定FAS的存在是否是PPAR活化和正常脂肪细胞分化过程所必需的。3.通过比较从FASKOF（FAS缺陷）和对照（FAS充满）细胞分离的与PPAR结合的脂质，使用质谱分析鉴定潜在的内源性PPAR配体。 这个项目有可能帮助澄清内源性配体是如何产生的核受体参与调节肥胖，葡萄糖代谢和炎症。 公共卫生相关性：此应用程序与公共卫生和NIH的使命相关。肥胖通过与糖尿病、心脏病和中风、关节炎、睡眠呼吸暂停、某些癌症和其他疾病的关联而缩短和降低生活质量。确定改变脂肪细胞功能的新途径有可能改善肥胖的代谢环境并治疗肥胖相关疾病。