The relationship between environmental factors and hypothalamic response to metabolic signals

环境因素与下丘脑对代谢信号反应的关系

• 批准号: RGPIN-2017-05937
• 负责人: Mizuno, Tooru
• 金额: $ 1.82万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659924
• 关键词: relationship; between; environmental; factors; hypothalamic

* * 96* 800x600* *** * Normal* 0* * * * * false* false* false* * EN-US* JA* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Table Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin:0cm;* mso-para-margin-bottom:.0001pt;* mso-pagination:widow-orphan;* font-size:10.0pt;* font-family:"New York","serif";}****Objectives***The central nervous system (CNS) plays a critical role in the regulation of whole-body metabolism. The long-term goal of the proposed research program is to fully understand this regulation. Adaptation to changes in environmental conditions is essential to maintain metabolic homeostasis and therefore important for survival of organisms. Environmental enrichment increases energy expenditure and reduces adiposity through the activation of the hypothalamic brain-derived neurotrophic factor (BDNF) signaling. However, I am hypothesizing that sex and social factors affect this response and that microglial BDNF is responsible for the response to these factors. Consequently, I plan to investigate the interaction between environmental factors, social factors, sex, microglial BDNF and metabolism as one component of my long-term program goals. ******Scientific approach***Study 1 (year 1-3): To determine the interaction between environmental factors and sex on metabolism, the effect of environmental enrichment on metabolic response to fasting/feeding and hypothalamic response to glucose, a major energy source for neuronal cells will be compared between male and female mice. Environment enrichment will be achieved by housing mice in groups supplemented with physical objects such as toys.***Study 2 (year 3-5): To explore the interaction between social factors and sex on metabolism, the effect of social isolation on metabolic response to fasting/feeding and hypothalamic response to glucose will be compared between male and female mice. Social isolation will be achieved by maintaining mice in a single-housing condition instead of group-housing condition.***Study 3 (year 1-5): To investigate the interaction between environmental factors and microglial BDNF in the regulation of metabolism, the effect of environmental enrichment on metabolic response to fasting/feeding will be compared between control and microglia-specific BDNF KO mice.***In all studies, body weight, food intake, adiposity and energy expenditure will be measured. Levels of metabolism-related hormones, metabolites, genes and proteins in serum and tissues will be determined. I will train 3 graduate students (1 MSc in study 1, 1 MSc in study 2 and 1 PhD in study 3) during the next 5 years. ******Significance***It is expected that the proposed research will demonstrate that (1) changes in environmental and social conditions affect whole-body metabolism and hypothalamic response to glucose in a sex-dependent manner and (2) deletion of BDNF from microglia attenuates the effect of environmental enrichment on metabolism. Thus, the proposed program will provide powerful information on how animals maintain metabolic homeostasis by adapting to environmental and social changes and will help us understand the mechanism of the CNS regulation of metabolic homeostasis, one of the most fundamental physiological functions of living organisms.**

* * 96* 800 x600 * 正常 * 0* * false * false* * EN-US* JA* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** * /* 样式定义 */*table.MsoNormalTable* {mso-style-name：“Table Normal”;* mso-tstyle-rowband-size：0;* mso-tstyle-colband-size：0;* mso-style-noshow：yes;* mso-style-priority：99;* mso-style-parent：“";* mso-padding-alt：0cm 5.4pt 0cm 5.4pt;* mso-para-margin：0cm;* mso-para-margin-bottom：.0001pt;* mso-pagination：widow-orphan;* font-size：10.0pt;* font-family：“纽约”，“serif”;* 目的 * 中枢神经系统（CNS）在全身代谢的调节中起着关键作用。拟议研究计划的长期目标是充分了解这一规定。适应环境条件的变化是维持代谢稳态的必要条件，因此对生物体的生存至关重要。丰富的环境通过激活下丘脑脑源性神经营养因子（BDNF）信号增加能量消耗并减少肥胖。然而，我假设性别和社会因素会影响这种反应，而小胶质细胞BDNF负责对这些因素的反应。因此，我计划研究环境因素，社会因素，性别，小胶质细胞BDNF和代谢之间的相互作用，作为我的长期计划目标的一个组成部分。** 科学方法 * 研究1（第1-3年）：为了确定环境因素和性别对代谢的相互作用，将在雄性和雌性小鼠之间比较环境富集对禁食/进食的代谢反应和下丘脑对葡萄糖（神经元细胞的主要能量来源）的反应的影响。通过将小鼠分组饲养并辅以实物（如玩具）来实现环境富集。*研究2（3-5年）：为了探索社会因素和性别对代谢的相互作用，将在雄性和雌性小鼠之间比较社会隔离对禁食/进食的代谢反应和下丘脑对葡萄糖的反应的影响。将通过将小鼠维持在单一饲养条件而不是群体饲养条件下实现社会隔离。*研究3（1-5年）：为了研究环境因素和小胶质细胞BDNF在代谢调节中的相互作用，将在对照和小胶质细胞特异性BDNF KO小鼠之间比较环境富集对禁食/进食的代谢反应的影响。在所有研究中，将测量体重、摄食量、肥胖和能量消耗。将测定血清和组织中代谢相关激素、代谢物、基因和蛋白质的水平。我将在未来5年内培养3名研究生（1名研究1的硕士，1名研究2的硕士和1名研究3的博士）。** 重要性 * 预计拟议的研究将证明（1）环境和社会条件的变化以性别依赖的方式影响全身代谢和下丘脑对葡萄糖的反应，以及（2）从小胶质细胞中删除BDNF减弱了环境富集对代谢的影响。因此，拟议的计划将提供有关动物如何通过适应环境和社会变化来维持代谢稳态的强有力信息，并将帮助我们了解CNS调节代谢稳态的机制，这是生物体最基本的生理功能之一。