Fatty acid metabolism and DGAT1 deficiency

描述(申请人提供)：肥胖是导致II型糖尿病和心脏病的一个主要因素，在美国已经达到流行的程度。肥胖是由于能量输入和输出之间的不平衡造成的，过量的卡路里以甘油三酯的形式存储。缺乏DGAT1的小鼠能量消耗增加，因此对肥胖具有抵抗力。DGAT1是一种参与三酰甘油合成的酶。能量消耗的增加可以归因于生热作用和体力活动的增加。本研究的目的是探讨DGAT1缺乏改变脂肪酸代谢的机制。我推测，DGAT1缺乏减少了脂肪酸的合成，增加了脂肪酸的氧化。我的具体目标是： 具体目标1：确定Dgatl 4-小鼠的脂肪酸合成是否减少。 目的1.1：通过测量高脂饮食中氚水在脂肪酸中的掺入来确定Dgatl 4-小鼠肝脏中的脂肪酸合成是否减少。 目的1.2：确定LXR-α活性降低是否可能是由于不饱和脂肪酸水平增加导致脂肪酸合成基因表达减少的原因。 目的1.3：用LXR-α激动剂治疗Dgatl-/-小鼠，确定SREBP-lc表达降低对肥胖抵抗表型的贡献。 特定目标2：确定Dgatl_-小鼠的脂肪酸氧化是否增加。 目标2.1：通过测量[1-1“C]棕榈酸酯生成的[1-14C]CO2和测量血清酮小体水平来确定是否存在脂肪酸氧化增加。 目的2.2：确定是否存在与脂肪酸氧化有关的基因表达增加。 目的2.3：确定Dgat1-/-小鼠肥胖抵抗表型是否需要脂肪酸氧化的主要转录调节因子PPAR_2。

DESCRIPTION (provided by applicant): Obesity, a major dsk factor for type II diabetes and heart disease, has reached epidemic proportions in the U.S. Obesity results from an imbalance between energy input and output, where excess calories are stored as triglycerides. Mice lacking DGAT1, an enzyme involved in triacylglycerol synthesis, have increased energy expenditure and are therefore obesity resistant. The increased energy expenditure can be attributed to increased thermogenesis and physical activity. The objectives of this study are to investigate the mechanisms by which DGAT1 deficiency alters fatty acid metabolism. I hypothesize that DGAT1 deficiency decreases fatty acid synthesis and increases fatty acid oxidation. My specific aims are: Specific Aim 1: To determine if fatty acid synthesis is decreased in Dgatl 4- mice. Aim 1.1: Determine if in vivofatty acid synthesis is decreased in livers of Dgatl 4- mice fed a high-fat diet by measuring the incorporation of tritiated water into fatty acids. Aim 1.2: Determine whether decreased activation of LXR-alpha, possibly due to increased levels of unsaturated fatty acids, is responsible for the decreased expression of fatty acid synthesis genes. Aim 1.3: Determine the contribution of decreased expression of SREBP-lc to the obesity-resistance phenotype by treating Dgatl -/- mice with an LXR-alpha agonist. Specific Aim 2: Determine if fatty acid oxidation is increased in Dgatl _- mice. Aim 2.1: Determine if there is increased fatty acid oxidation by measuring the formation of [1-14C] CO2 from [1-1"C] palmitate and measuring the serum levels of ketone bodies. Aim 2.2: Determine if there is increased expression of genes implicated in fatty acid oxidation. Aim 2.3: Determine if PPAR_, a master transcriptional regulator of fatty acid oxidation, is required for the obesity resistance phenotype of Dgat1-/-mice.