NUTRITIONAL & METABOLIC REGULATION OF BODY WEIGHT

营养

• 批准号: 2855311
• 负责人: RICHARD A. GALBRAITH
• 金额: $ 24.49万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2855311
• 关键词: anorexic agent; appetite; biological signal transduction; body weight; brain mapping; cobalt; eating; enzyme activity; fasting; fos protein; gene expression; guanylate cyclase; histochemistry /cytochemistry; hypothalamus; laboratory rat; metalloporphyrins; neuropeptide Y; neuroregulation; nitric oxide; nitric oxide synthase; nutrition related tag; second messengers

The health of the people and the economy of the United States of America remain under siege from obesity. Nutrient intake is an important variable in the control of body weight and its dysregulation can lead to obesity. Numerous afferent stimuli, including hormones both old and new, have been implicated in the nutritional and metabolic regulation of body weight, but the neurochemical basis for their integration remains elusive. A newly recognized neurotransmitter, nitric oxide, has been implicated in the neurochemical regulation of various central nervous system processes, including the ingestion of food and water. There is evidence, derived from the observation that inhibitors of nitric oxide synthase oppose the hyperphagia caused by many disparate stimuli, to suggest that the locus of action of nitric oxide may be distal to the level of many of the transmitter-receptor systems in the hypothalamus which play a role in the regulation of food intake. This grant is focused on the further evaluation of the contribution of this neurotransmitter to the control of body weight and to test the overall hypothesis that nitric oxide is a common downstream effector linking and intergrating multiple diverse stimuli with increased food intake. Specific aims are to directly inject, into the brain of rats, substances known to increase or decrease the concentration of nitric oxide and to correlate changes in food ingestion and body weight with histochemical and biochemical alterations in the levels of protein and gene expression, catalytic activity and product of the enzymes responsible for the synthesis of nitric oxide. Because nitric oxide contributes to the regulation of many central nervous system processes, specificity will be increased by focusing on the areas which are activated to express the Fos protein in response to stimuli which regulate food intake. The secondary hypothesis is that alterations in this nitric oxide-dependent pathway may account for the prolonged and marked anorectic effect of cobalt protoporphyrin, a synthetic analogue of heme, which leads to profound and sustained weight loss. Experiments to test this secondary hypothesis will be carried out in addition to experiments to examine the molecular mechanism of these actions of cobalt protoporphyrin. This approach is expected to further our understanding of the physiology of appetite and body weight regulation in the central nervous system and eventually may assist in the development of strategies to combat the epidemic of obesity in western societies.

美利坚合众国人民的健康和经济仍然受到肥胖症的困扰。 营养摄入是控制体重的重要变量，其失调可导致肥胖。 许多传入刺激，包括新旧激素，都与体重的营养和代谢调节有关，但它们整合的神经化学基础仍然难以捉摸。 一氧化氮是一种新发现的神经递质，参与了各种中枢神经系统过程的神经化学调节，包括食物和水的摄入。 一氧化氮合酶抑制剂可对抗由多种不同刺激引起的摄食过多，这一观察结果表明，一氧化氮的作用部位可能位于下丘脑中许多递质-受体系统水平的远端，这些递质-受体系统在调节食物摄入方面发挥作用。 这项资助的重点是进一步评估这种神经递质对体重控制的贡献，并测试一氧化氮是一种常见的下游效应器，将多种不同的刺激与增加的食物摄入联系起来并整合。 具体目标是将已知增加或减少一氧化氮浓度的物质直接注射到大鼠脑中，并将食物摄取和体重的变化与蛋白质和基因表达水平、催化活性和负责一氧化氮合成的酶的产物的组织化学和生物化学变化相关联。因为一氧化氮有助于调节许多中枢神经系统过程，所以通过关注响应调节食物摄入的刺激而被激活以表达Fos蛋白的区域，特异性将增加。 第二个假设是，这种一氧化氮依赖性途径的改变可能是钴原卟啉（一种血红素的合成类似物）的长期和显着的厌食作用的原因，这导致了深刻和持续的体重减轻。除了研究钴原卟啉这些作用的分子机制的实验外，还将进行实验来验证这一次要假设。 这种方法有望进一步加深我们对中枢神经系统中食欲和体重调节生理学的理解，并最终可能有助于制定对抗西方社会肥胖流行病的策略。