OBESITY, ADIPOGENESIS, AND LIPID LIGANDS

描述（由申请人提供）：肥胖及其后遗症（包括糖尿病）是一种流行病。操纵脂肪细胞可能会带来治疗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。这些受体之一，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。 我们现已鉴定出 PPAR 的内源性配体，并开发了鉴定内源性 PPAR 配体的类似策略。这项工作的基础是发现小鼠肝脏中脂肪酸合酶 (FAS) 失活会产生类似于 PPAR 缺乏的表型，而这种表型可通过 PPAR 的药理学激活来挽救。质谱技术鉴定出与 PPAR 结合的脂质，该脂质是 FAS 依赖性的。该应用重点关注脂肪组织中存在 FAS 缺陷的抗肥胖动物，即 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 PPAR 缺陷的表型，可通过 PPAR 的药理学激活来挽救。该项目将测试以下假设：在脂肪组织及其前体中，脂肪酸合酶（一种从头脂肪生成过程所需的酶）通过激活核受体 PPAR 部分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）是否能够免受饮食引起的肥胖和遗传性肥胖的影响，以及 PPAR 的药理激活是否会逆转保护作用。 2. 确定FAS的存在是否是PPAR激活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 充足）细胞分离的 PPAR 结合的脂质，使用质谱分析来鉴定潜在的内源性 PPAR 配体。 该项目有可能帮助阐明与调节肥胖、葡萄糖代谢和炎症有关的核受体的内源配体是如何产生的。 公共卫生相关性：本申请与公共卫生和 NIH 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。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。

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.