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相关性的巨大临床问题。该建议的总体目标是定义脂肪组织脂肪酸合酶（FAS）如何影响肥胖和糖尿病。我们已经产生了具有FAS（Faskof）脂肪特异性敲除的小鼠。这些小鼠似乎受到保护免受高脂肪饮食诱导的肥胖和胰岛素抵抗的保护，而FAS耗竭导致脂肪生成基因的表达降低，MyOD的表达增加（肌肉的特征）以及脂肪酸氧化基因在脂肪组织中的表达增加。我们假设脂肪组织Fas通过调节脂肪形成和肌发生之间的切换来调节脂肪。我们进一步假设，Faskof小鼠中增加的脂肪酸氧化需要激活Pparalpha，Paralpha是葡萄糖和脂质代谢的重要调节剂。我们提出了以下特定目的来检验这些假设：目标1。在肥胖和糖尿病的饮食和遗传模型中，Faskof小鼠的表征。在诱导饮食诱导的肥胖症和用DB/DB小鼠（糖尿病和肥胖症的遗传模型）穿越Faskof小鼠后，将研究葡萄糖和脂质代谢。 AIM 2。确定FAS是否调节脂肪形成和肌发生之间的切换。我们将耗尽小鼠原发性胚胎成纤维细胞中的FA，并研究对脂肪形成和肌发生的影响。由于小型G蛋白RHO是脂肪形成肌发生决定的关键决定因素，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。 AIM 3。确定FAS是否影响脂肪组织中的pParalpha激活。我们实验室的最新工作表明，肝脏和大脑中的FAS调节Paralpha的激活，Paralpha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pParalpha，我们将用PPARALPHA激活剂处理Faskof小鼠。我们还将与Paralpha敲除小鼠穿越Faskof小鼠，并评估对代谢和肥胖的影响。公共卫生相关性：肥胖及其相关的代谢疾病代表了一个主要的公共卫生问题。该应用中提出的研究的发现可能会导致治疗这些病毒的新型治疗方法。