ADIPOSE TISSUE LIPOGENESIS AND METABOLIC HOMEOSTASIS

描述(申请人提供)：肥胖和糖尿病是与全球相关的巨大临床问题。这项提案的总体目标是定义脂肪组织脂肪酸合成酶(FAS)如何影响肥胖和糖尿病。我们已经产生了脂肪特异性Fas基因敲除(FASKOF)的小鼠。这些小鼠似乎可以免受高脂饮食诱导的肥胖和胰岛素抵抗的影响，Fas缺失会导致脂肪组织中成脂基因表达减少，MyoD(肌肉特征)表达增加，脂肪组织中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肉生成之间的转换来调节肥胖。我们进一步假设，FASKOF小鼠脂肪酸氧化增加需要激活PPARpha，PPARpha是糖和脂代谢的重要调节因子。我们提出以下具体目标来验证这些假说：目的1.FASKOF小鼠在肥胖和糖尿病的饮食和遗传模型中的特征。在诱导饮食诱导的肥胖以及将FASKOF小鼠与糖尿病和肥胖症的遗传模型db/db小鼠杂交后，将研究葡萄糖和脂肪代谢。目的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，并研究其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-肌肉发生决策的关键决定因素，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。目的3.确定Fas是否影响脂肪组织中PPARα的激活。我们实验室最近的工作表明，肝脏和大脑中的Fas调节PPARpha的激活，PPARpha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PPARpha，我们将用PPARpha激活剂治疗FASKOF小鼠。我们还将把FASKOF小鼠与PPARpha基因敲除小鼠进行杂交，评估它们对新陈代谢和肥胖的影响。公共卫生相关性：肥胖及其相关的代谢紊乱是一个重大的公共卫生问题。在本申请中提出的研究结果可能导致治疗这些疾病的新的治疗方法。

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.