Role of SCD1 in the Effects of Dietary Methionine Restriction on the Components o

说明(申请人提供)：肥胖与许多代谢和心血管疾病风险因素有关，包括胰岛素抵抗、高血压和脂肪和葡萄糖代谢失调。硬脂酰辅酶A去饱和酶-1(SCD1)在肥胖中增加，并催化饱和脂肪酸(16：0和18：0)转化为单不饱和脂肪酸(16：1和18：1)。SCD1已被证明在高饱和脂肪或高碳水化合物饮食后增加甘油三酯的合成和分泌。在小鼠中，SCD1基因的全局缺失导致食物摄入量增加，同时能量消耗增加，血清甘油三酯和肥胖症减少。油酸盐(18：1)是SCD1的主要产物，最近有研究表明，将油酸盐注入大脑可以减少食物摄入量，减少肝脏产生葡萄糖。药物诱导的大脑内脂肪酸前体的增加也会导致食物摄入量和葡萄糖输出的类似减少。饮食蛋氨酸限制(MR)已被用作模拟热量限制以延长啮齿动物的寿命。许多研究表明，饮食MR增加了食物的摄入量，同时矛盾地增加了能量消耗，减少了肥胖，并改善了胰岛素敏感性。我们实验室进行的初步研究表明，饮食MR还会降低大脑和肝脏下丘脑中SCD1基因的表达。由于下丘脑SCD1表达的减少预计会降低细胞内油酸水平，我们假设饮食MR可能会产生营养丰度降低的信号，从而增加食物的摄入量，并导致周围组织中一系列未解决的信号事件，从而导致能量消耗增加和体脂减少。拟议研究的目标将是确定饮食MR如何调用营养感知机制，并对碳水化合物和脂肪代谢产生组织特有的影响。这项研究的具体目的将是：1)确定相对于MR改变下丘脑和外周SCD1表达的时间，能量摄入/消耗增加发生的时间；2)确定饮食MR对SCD1表达的调节是否是MR影响能量平衡和限制脂肪沉积的机制的重要组成部分。在目标1中，将在饮食开始后立即测量食物消耗和能量消耗，以确定MR增加小鼠食物消耗和能量消耗的速度。在不同的队列中，在能量摄入/消耗开始增加之前和之后，小鼠将被安乐死，以确定SCD1降低的下丘脑特定核团。在目标2中，我们将在开始饮食后在下丘脑过度表达SCD1基因，以确定这是否逆转了饮食的代谢和生化效应。这些研究的结果将使我们更深入地了解大脑和外周组织在调节能量摄入和消耗方面的综合作用。 与公众健康相关：拟议研究的结果将有助于更彻底地了解大脑和周围组织对饮食中氨基酸和脂肪等特定营养素摄取的综合反应。这些研究还将提供对营养物质在功能上重塑脂肪组织中脂肪储存和生产能力的能力的洞察。这些研究有可能增强我们对肥胖原因的理解，并可能导致制定饮食或药物策略，以减少美国和世界各地肥胖相关疾病的体重增加和负担。 注意：下面的评论是由分配给此应用程序的评审员准备的。这些评注不一定反映审评员在小组讨论结束时的立场或小组的最后多数意见，尽管审评员被要求在讨论分配给他们的组成部分的过程中改变立场时修改他们的批评意见。摘要说明的简历和其他开头部分是小组讨论最后结果的权威表述。如果同行评审员的评论与本摘要说明页面上的优先/影响分数之间存在任何差异，则优先/影响分数应被视为最准确地代表小组讨论的最终结果。

DESCRIPTION (provided by applicant): Obesity is associated with a number of metabolic and cardiovascular disease risk factors including insulin resistance, high blood pressure and dysregulation of lipid and glucose metabolism. Stearoyl-CoA desaturase- 1 (SCD1) is increased in obesity and catalyzes the conversion of saturated fatty acids (16:0 and 18:0) to mono- unsaturated fatty acids (16:1 and 18:1). SCD1 has been shown to increase the synthesis and secretion of triglycerides following a high-saturated fat or high-carbohydrate diet. Global deletion of SCD1 in mice results in an increase in food intake accompanied by elevations in energy expenditure and reductions in serum triglycerides and adiposity. Oleate (18:1) is the primary product of SCD1 and its infusion into the brain has recently been shown to reduce food intake and decrease the production of glucose from the liver. Pharmacologically-induced increases in fatty acid precursors within the brain produce similar reductions in food intake and glucose output. Dietary methionine restriction (MR) has been used as a mimetic of caloric restriction to increase longevity in rodents. A number of studies have shown that dietary MR increases food intake while paradoxically increasing energy expenditure, reducing adiposity and improving insulin sensitivity. Preliminary studies conducted by our laboratory indicate that dietary MR also decreases SCD1 gene expression in the hypothalamus of the brain and liver. Since reductions in hypothalamic SCD1 expression would be expected to decrease intracellular oleate levels, we hypothesize that dietary MR may generate a signal of decreased nutrient abundance which increases food intake and results in a series of unresolved signaling events in peripheral tissues that lead to increased energy expenditure and decreased body-fat. The objective of the proposed studies will be to identify how dietary MR invokes nutrient sensing mechanisms and produces tissue-specific effects on carbohydrate and lipid metabolism. The Specific Aims of the study will be to 1) determine when the increase in energy intake/expenditure occurs relative to when MR alters hypothalamic and peripheral SCD1 expression and 2) determine whether modulation of SCD1 expression by dietary MR is an essential component of the mechanism used by MR to affect energy homeostasis and limit fat deposition. In Aim 1, food consumption and energy expenditure will be measured immediately following the start of the diet to determine how rapidly MR increases food consumption and energy expenditure in mice. In separate cohorts, mice will be euthanized before and after the onset of increased energy intake/expenditure to determine the specific nuclei of the hypothalamus where SCD1 is reduced. In Aim 2, we will overexpress the SCD1 gene in the hypothalamus after starting the diet to determine if this reverses the metabolic and biochemical effects of the diet. The results of these studies will provide a more thorough understanding of the integrated role of the brain and peripheral tissues in the regulation of energy intake and expenditure. PUBLIC HEALTH RELEVANCE: The results of the proposed studies will lead to a more thorough understanding of the integrated responses of the brain and peripheral tissues to the intake of specific nutrients such as amino acids and fats in the diet. These studies will also provide insight into the capacity of nutrients to functionally remodel the storage and production capacity of fat in adipose tissue. These studies have the potential to enhance our understanding of the causes of obesity and could lead to the development of dietary or pharmacological strategies to reduce the progression of weight-gain and the burden of obesity-related diseases in the United States and throughout the world. NOTE: The critiques below were prepared by the reviewers assigned to this application. These commentaries do not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their critiques if their positions changed during the discussions of the components assigned to them. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the peer reviewers' commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.