Insulin and CNS Contol of Body Weight and Food Intake

胰岛素和中枢神经系统控制体重和食物摄入量

• 批准号: 7667364
• 负责人: STEPHEN C WOODS
• 金额: $ 31.3万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667364
• 关键词: Address; Adipose tissue; Amino Acids; Behavior; Blood; Body Weight; Brain; Brain region; Cells; Clinical; Eating; Eating Disorders; Endocrine system; Energy Intake; Energy Metabolism; Environment; Expenditure; Fatty Acids; Female; Food; Glucose; Goals; Homeostasis; Hormones; Hypothalamic structure; Individual; Insulin; Laboratory Rat; Leptin; Life; Maintenance; Metabolic; Molecular; Neurons; Neuropeptides; Nutrient; Obesity; Pancreatic Hormones; Research; Sex Characteristics; Signal Transduction; Technology; Translations; insulin signaling; male; novel therapeutics; public health relevance; relating to nervous system; research study; response

DESCRIPTION (provided by applicant): Multiple inputs and controls participate in the maintenance of energy homeostasis, and numerous neural and endocrine systems are involved in the integrated responses that maintain energy stores in the body at a level. Since most stored energy is in the form of adipose tissue (fat), and since the brain is the major controller of energy homeostasis, a fundamental requirement is that the brain receive accurate and timely information about the amount and distribution of body fat. This information is then integrated with other factors to determine whether an individual seeks and eats food (i.e., energy intake), as well as the efficiency with which the ingested food is utilized (energy expenditure) or stored. Information regarding the amount of fat stored in the body reaches the brain via the circulating signals insulin and leptin. Each is secreted into the blood in direct proportion to total body fat, and each is transported from the blood into the brain where it interacts with neurons situated to influence energy intake and expenditure. Hence, insulin and leptin are considered to be adiposity signals, and the long-term goal of this project is to elucidate how adiposity signals interact with other factors to influence energy homeostasis. We anticipate that the coming decade will see considerable progress in this arena, as well as the translation of the new-found information into potential novel therapeutic strategies to tackle clinical problems of dysregulation of energy homeostasis (i.e., obesity, eating disorders). With this as an ultimate end point, the present proposal has three specific aims that address critical and as yet unanswered questions regarding the actions of adiposity signals in the brain. The first assesses the hypothesis that insulin and leptin act in the hypothalamus by enhancing the signal provided by local levels of nutrients, including glucose and fatty acids. The second assesses several hypotheses following from our observation that there are important gender differences in the actions of insulin and leptin in the central control of energy homeostasis, and that males and females utilize different strategies to regulate energy homeostasis and defend their body fat stores. The final aim assesses hypotheses regarding the effect of reducing insulin signaling in specific brain regions on food intake and body weight, and upon related levels of metabolic hormones and neuropeptides, utilizing lentiviral technology. PUBLIC HEALTH RELEVANCE: Hormones such as insulin and leptin that are secreted in direct proportion to body fat interact in the brain with nutrients such as glucose, fatty acids and amino acids to determine food intake and energy expenditure. Proposed research will determine how these signals interact within neurons in the hypothalamus and intervene by manipulating the ability of the brain of laboratory rats to detect and respond to insulin or leptin. Experiments will assess behavior as well as molecular signals within cells.

描述（由申请人提供）：多个输入和控制参与能量体内平衡的维持，许多神经和内分泌系统参与了使体内能量存储保持在一个水平的综合响应。由于大多数存储的能量是以脂肪组织（脂肪）的形式，并且由于大脑是能量稳态的主要控制器，因此基本要求是大脑会收到有关体内脂肪的数量和分布的准确，及时的信息。然后将这些信息与其他因素集成在一起，以确定个人是否寻求和食用食物（即能量摄入量），以及利用摄入的食物（能量消耗）或存储的效率。有关体内脂肪量的信息通过循环信号胰岛素和瘦素到达大脑。每个人都直接与总体内脂肪成比例地分泌到血液中，每个人都会从血液转移到大脑中，并与该神经元相互作用以影响能量摄入和支出。因此，胰岛素和瘦素被认为是肥胖信号，该项目的长期目标是阐明肥胖信号如何与其他因素相互作用以影响能量稳态。我们预计，未来十年将在该领域取得很大的进步，以及将新发现的信息转化为潜在的新型治疗策略，以解决能量稳态失调（即肥胖症，饮食障碍）的临床问题。以此为最终的终点，目前的提案具有三个具体目标，可以解决有关大脑中肥胖信号的行为的关键问题，尚未解决问题。第一个评估了以下假设：胰岛素和瘦素通过增强局部营养水平（包括葡萄糖和脂肪酸）提供的信号来在下丘脑中起作用。第二个评估了我们的观察结果，即胰岛素和瘦素在能量稳态的中央控制中的作用存在重要的性别差异，并且男性和女性利用不同的策略来调节能量稳态并捍卫其体内脂肪储存。最终目的评估了有关使用慢病毒技术减少特定大脑区域中胰岛素信号传导对食物摄入和体重的影响以及代谢激素和神经肽的相关水平的假设。公共卫生相关性：与人体脂肪直接分泌的激素，例如胰岛素和瘦素，与葡萄糖，脂肪酸和氨基酸等营养中的人体相互作用，以确定食物摄入和能量消耗。拟议的研究将确定这些信号在下丘脑中如何在神经元内相互作用，并通过操纵实验室大鼠大脑检测和对胰岛素或瘦素做出反应的能力来进行干预。实验将评估细胞内的行为以及分子信号。