OBESITY, ADIPOGENESIS, AND LIPID LIGANDS

肥胖、脂肪生成和脂质配体

• 批准号: 8444588
• 负责人: Clay F. Semenkovich
• 金额: $ 30.46万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444588
• 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 Targeting; 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.

描述（由申请人提供）：肥胖症及其后遗症包括糖尿病是流行病的。操纵脂肪细胞可能会导致针对肥胖相关疾病的新疗法。过氧化物酶体增殖物激活受体（PPAR）参与肥胖和糖尿病。这些受体之一是脂肪形成所必需的。内源性PPAR配体的识别是难以捉摸的。 现在，我们已经确定了一种用于PPAR的内源配体，并制定了一种鉴定内源性PPAR配体的类似策略。这项工作是基于以下发现：小鼠肝脏中脂肪酸合酶（FAS）的灭活产生的表型类似于PPAR缺乏，该表型通过PPAR的药理激活而营救。质谱技术确定了与PPAR结合的脂质，该脂质依赖于FAS。该应用的重点是抗肥胖的动物，在脂肪组织中缺乏FA的动物，Faskof（脂肪酸合酶敲除脂肪）小鼠。缺乏FAS的胚胎成纤维细胞具有类似于PPAR缺乏的表型，该表型通过PPAR的药理激活而营救。该项目将检验以下假设：在脂肪组织及其前体中，脂肪酸合酶是从头脂肪生成过程所需的一种酶，介导了肥胖和代谢疾病的风险，部分通过激活核受体PPAR。具体目的是：1。确定在脂肪组织（Faskof小鼠）中fas失活的小鼠是否受到保护免受饮食诱发和遗传肥胖的保护，以及PPAR的药理激活是否会逆转保护。 2。确定PPAR激活和正常脂肪细胞分化过程是否需要FAS的存在。 3。使用质谱分析来通过比较与从Faskof（Fas缺乏剂）和对照（FAS复发）细胞分离的PPAR结合的脂质来鉴定潜在的内源性PPAR配体。 该项目有可能有助于阐明如何生成内源性配体，用于与肥胖，葡萄糖代谢和炎症的调节有关的核受体。

项目成果

The mystery of diabetes and atherosclerosis: time for a new plot.

糖尿病和动脉粥样硬化之谜：是时候开始新的情节了。

• DOI: 10.2337/diab.46.3.327
• 发表时间: 1997
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Semenkovich,CF;Heinecke,JW
• 通讯作者: Heinecke,JW

The ABCs of beta-cell dysfunction in type 2 diabetes.

2 型糖尿病 β 细胞功能障碍的基本知识。

• DOI: 10.1038/nm0307-241
• 发表时间: 2007
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Chakravarthy,ManuV;Semenkovich,ClayF
• 通讯作者: Semenkovich,ClayF