ADIPOSE TISSUE LIPOGENESIS AND METABOLIC HOMEOSTASIS

脂肪组织脂肪生成和代谢稳态

• 批准号: 7674864
• 负责人: Irfan J Lodhi
• 金额: $ 5.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674864
• 关键词: Adipose tissue; Affect; Brain; Characteristics; Clinical; Diabetes Mellitus; Diet; Embryo; Fatty acid glycerol esters; Fatty-acid synthase; Fibroblasts; Genes; Genetic Models; Glucose; Goals; Homeostasis; Insulin Resistance; Knock-out; Knockout Mice; Laboratories; Lead; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Muscle; Nuclear Receptors; Obesity; PPAR alpha; Public Health; Testing; Work; db/db mouse; fatty acid oxidation; lipid biosynthesis; lipid metabolism; myogenesis; novel therapeutic intervention; palmitoylation; public health relevance; rho

DESCRIPTION (provided by applicant): Obesity and diabetes are enormous clinical problems with global relevance. The overall goal of this proposal is to define how adipose tissue fatty acid synthase (FAS) affects obesity and diabetes. We have generated mice with fat-specific knockout of FAS (FASKOF). These mice appear to be protected from high fat diet- induced obesity and insulin resistance, and FAS depletion results in decreased expression of adipogenic genes, increased expression of MyoD (characteristic of muscle), and increased expression of fatty acid oxidation genes in adipose tissue. We hypothesize that adipose tissue FAS regulates adiposity by modulating a switch between adipogenesis and myogenesis. We further hypothesize that the increased fatty acid oxidation in FASKOF mice requires activation of PPARalpha, an important regulator of glucose and lipid metabolism. We propose the following specific aims to test these hypotheses: Aim 1. Characterization of FASKOF mice in dietary and genetic models of obesity and diabetes. Glucose and lipid metabolism will be studied after induction of diet-induced obesity and after crossing FASKOF mice with db/db mice, a genetic model of diabetes and obesity. Aim 2. Determine if FAS modulates a switch between adipogenesis and myogenesis. We will deplete FAS in mouse primary embryonic fibroblasts and study effects on adipogenesis and myogenesis. Because the small G-protein Rho is a critical determinant of the adipogenesis-myogenesis decision, we will test the possibility that FAS regulates Rho activity by mediating its palmitoylation. Aim 3. Determine if FAS affects PPARalpha activation in adipose tissue. Recent work from our laboratory suggests that FAS in liver and brain regulates activation of PPARalpha, a nuclear receptor controlling fatty acid oxidation. To determine if FAS regulates PPARalpha in adipose tissue, we will treat FASKOF mice with PPARalpha activators. We will also cross the FASKOF mice with the PPARalpha knockout mice and assess effects on metabolism and adiposity. PUBLIC HEALTH RELEVANCE: Obesity and its associated metabolic disorders represent a major public health problem. Findings from the studies proposed in this application may lead to novel therapeutic approaches to the treatment of these morbidities.

描述（由申请人提供）：肥胖和糖尿病是具有全球意义的巨大临床问题。该提案的总体目标是确定脂肪组织脂肪酸合酶（FAS）如何影响肥胖和糖尿病。我们已经培育出脂肪特异性 FAS 敲除 (FASKOF) 的小鼠。这些小鼠似乎可以免受高脂肪饮食诱导的肥胖和胰岛素抵抗的影响，并且 FAS 消耗会导致脂肪组织中脂肪形成基因表达减少、MyoD（肌肉特征）表达增加以及脂肪酸氧化基因表达增加。我们假设脂肪组织 FAS 通过调节脂肪生成和肌生成之间的转换来调节肥胖。我们进一步假设 FASKOF 小鼠中脂肪酸氧化的增加需要 PPARα 的激活，PPARα 是葡萄糖和脂质代谢的重要调节剂。我们提出以下具体目标来检验这些假设： 目标 1. 肥胖和糖尿病饮食和遗传模型中 FASKOF 小鼠的表征。在诱导饮食诱导的肥胖后以及将 FASKOF 小鼠与 db/db 小鼠（糖尿病和肥胖的遗传模型）杂交后，将研究葡萄糖和脂质代谢。目标 2. 确定 FAS 是否调节脂肪生成和肌肉生成之间的转换。我们将耗尽小鼠原代胚胎成纤维细胞中的 FAS，并研究对脂肪生成和肌肉生成的影响。由于小 G 蛋白 Rho 是脂肪生成-肌肉生成决策的关键决定因素，因此我们将测试 FAS 通过介导其棕榈酰化来调节 Rho 活性的可能性。目标 3. 确定 FAS 是否影响脂肪组织中的 PPARα 激活。我们实验室最近的研究表明，肝脏和大脑中的 FAS 调节 PPARα 的激活，PPARα 是一种控制脂肪酸氧化的核受体。为了确定 FAS 是否调节脂肪组织中的 PPARα，我们将用 PPARα 激活剂治疗 FASKOF 小鼠。我们还将 FASKOF 小鼠与 PPARalpha 敲除小鼠杂交，并评估对代谢和肥胖的影响。公共卫生相关性：肥胖及其相关代谢紊乱是一个重大的公共卫生问题。本申请中提出的研究结果可能会带来治疗这些疾病的新治疗方法。