Role of SCD1 and Dietary Methionine Restriction on Energy Homeostasis

SCD1 和饮食蛋氨酸限制对能量稳态的作用

• 批准号: 8162815
• 负责人: Eric Paul Plaisance
• 金额: $ 4.71万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8162815
• 关键词: Address; Adipose tissue; Affect; Amino Acids; Animals; Biochemical; Body fat; Brain; Caloric Restriction; Carbohydrates; Cell Nucleus; Commit; Complement; Critiques; Deposition; Development; Diet; Eating; Energy Intake; Energy Metabolism; Event; Expenditure; Face; Fatty Acids; Fatty acid glycerol esters; Feeding behaviors; Food Energy; Gene Expression; Genes; Genetic; Hepatic; Homeostasis; Hyperphagia; Hypertension; Hypothalamic structure; Infusion procedures; Insulin; Insulin Resistance; Intake; Knockout Mice; Laboratories; Lead; Link; Liver; Longevity; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methionine; Molecular; Mono-S; Mus; Mutation; Neurons; Nutrient; Obesity; Obesity associated disease; Outcome; Peripheral; Phenotype; Physiological; Play; Positioning Attribute; Process; Production; Proteins; Published Comment; Regulation; Relative (related person); Research; Risk Factors; Rodent; Role; Saturated Fatty Acids; Secondary to; Series; Serum; Signal Transduction; Site; Stearates; Stearoyl-CoA Desaturase; System; Time; Tissues; Transgenic Mice; Transgenic Organisms; Triglycerides; United States; Unsaturated Fatty Acids; Very low density lipoprotein; Weight Gain; Work; carbohydrate metabolism; cardiovascular disorder risk; cohort; detection of nutrient; fascinate; food consumption; glucose metabolism; glucose output; glucose production; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; lipid metabolism; loss of function; mimetics; mouse model; overexpression; peer; public health relevance; response; saturated fat; sensor; tool

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.

描述（由申请人提供）：肥胖与许多代谢和心血管疾病风险因素相关，包括胰岛素抵抗、高血压以及脂质和葡萄糖代谢失调。硬脂酰辅酶A去饱和酶-1（SCD 1）在肥胖症中增加，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）。SCD 1已被证明可以增加高饱和脂肪或高碳水化合物饮食后甘油三酯的合成和分泌。在小鼠中，SCD 1的整体缺失导致食物摄入增加，伴随着能量消耗的升高以及血清甘油三酯和肥胖的降低。油酸（18：1）是SCD 1的主要产物，最近已证明其输注到大脑中可减少食物摄入量并减少肝脏葡萄糖的产生。药理学诱导的脑内脂肪酸前体的增加产生类似的食物摄入和葡萄糖输出的减少。饮食蛋氨酸限制（MR）已被用作热量限制的模拟物，以增加啮齿动物的寿命。许多研究表明，饮食MR增加食物摄入，同时矛盾地增加能量消耗，减少肥胖和改善胰岛素敏感性。我们实验室进行的初步研究表明，饮食MR也降低了大脑和肝脏下丘脑中SCD 1基因的表达。由于下丘脑SCD 1表达的减少预计会降低细胞内油酸水平，我们假设饮食MR可能会产生营养丰富度降低的信号，从而增加食物摄入量，并导致外周组织中一系列未解决的信号传导事件，导致能量消耗增加和体脂减少。拟议研究的目的是确定饮食MR如何调用营养感应机制，并对碳水化合物和脂质代谢产生组织特异性影响。本研究的具体目的是：1）确定相对于MR改变下丘脑和外周SCD 1表达的时间，何时发生能量摄入/消耗增加; 2）确定饮食MR对SCD 1表达的调节是否是MR影响能量稳态和限制脂肪沉积的机制的重要组成部分。在目标1中，在饮食开始后立即测量食物消耗和能量消耗，以确定MR如何快速增加小鼠的食物消耗和能量消耗。在单独的组群中，将在能量摄入/消耗增加开始之前和之后对小鼠实施安乐死，以确定SCD 1减少的下丘脑的特定核。在目标2中，我们将在开始饮食后在下丘脑中过表达SCD 1基因，以确定这是否逆转饮食的代谢和生化作用。这些研究的结果将提供一个更全面的了解大脑和外周组织在调节能量摄入和消耗的综合作用。 公共卫生相关性：拟议研究的结果将导致更全面地了解大脑和外周组织对饮食中特定营养素（如氨基酸和脂肪）摄入的综合反应。这些研究还将提供对营养素在功能上重塑脂肪组织中脂肪储存和生产能力的能力的深入了解。这些研究有可能提高我们对肥胖原因的理解，并可能导致饮食或药理学策略的发展，以减少美国和世界各地体重增加的进展和肥胖相关疾病的负担。 注：以下评论由分配给此应用程序的评审员编写。这些评论不一定反映小组讨论结束时审查人员的立场或小组的最后多数意见，但如果审查人员在讨论分配给他们的组成部分期间立场发生变化，则要求他们修改其评论。简历和简要说明的其他开头部分是小组讨论最终结果的权威表述。如果同行评审员的评论与本概要说明首页上的优先级/影响力评分之间存在任何差异，优先级/影响力评分应被视为最准确地反映小组讨论的最终结果。