OBESITY, ADIPOGENESIS, AND LIPID LIGANDS

描述(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(PPAR)与肥胖和糖尿病有关。其中一种受体，PPAR，是脂肪生成所必需的。内源性PPAR配体的鉴定一直难以捉摸。我们现在已经确定了PPAR的内源性配体，并开发了一种类似的策略来识别内源性PPAR配体。这项工作的基础是发现小鼠肝脏中脂肪酸合成酶(Fas)的失活会产生一种类似于PPAR缺乏症的表型，这种表型可以通过PPAR的药物激活来挽救。质谱学技术鉴定出一种与PPAR结合的脂质是依赖于Fas的。这项应用主要针对脂肪组织中Fas缺乏的肥胖抵抗动物，FASKOF(脂肪中的脂肪酸合成酶基因敲除)小鼠。Fas缺陷的胚胎成纤维细胞具有类似于PPAR缺陷的表型，可通过PPAR的药物激活来挽救。这个项目将检验这样的假设：在脂肪组织及其前体中，脂肪酸合成酶，一种从头生成脂肪的过程中所需的酶，部分通过激活核受体PPAR来调节肥胖和代谢性疾病的风险。其具体目的是：1.确定脂肪组织中Fas失活的小鼠(FASKOF小鼠)是否对饮食诱导的和遗传性肥胖具有保护作用，以及PPAR的药物激活是否逆转了保护作用。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.通过比较FASKOF(Fas-缺失)和对照(Fas-Replete)细胞分离的PPAR结合的脂类，利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阐明核受体的内源性配体是如何产生的，核受体与肥胖、葡萄糖代谢和炎症的调节有关。 公共卫生相关性：这项申请与公共卫生和美国国立卫生研究院的使命相关。肥胖与糖尿病、心脏病和中风、关节炎、睡眠呼吸暂停、某些癌症和其他疾病有关，从而缩短和降低生活质量。寻找改变脂肪细胞功能的新途径，有可能改善肥胖的代谢环境，治疗肥胖相关疾病。

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.