The relationship between environmental factors and hypothalamic response to metabolic signals

**96*800x600*正常*0*FALSE**EN-US*JA*X-NONE****/*样式定义*/*表。MsoNormal表*{mso-style-name：“表正常”；*mso-tstyle-rowband-size：0；*mso-tstyle-colband-size：0；*mso-style-noshow：是；*mso-style-first：99；*mso-style-parent：“”；*mso-pding-alt：0 cm 5.4pt 0 cm 5.4pt；*mso-para-mark：0 cm；*mso-para-edge-Bottom：.0001pt；*mso-pagination：寡妇-孤儿；*字体大小：10.0pt；*font-Family：“New York”，“serif”；目的中枢神经系统(CNS)在调节全身新陈代谢中起着至关重要的作用。拟议研究计划的长期目标是充分理解这一规定。适应环境条件的变化对维持代谢平衡至关重要，因此对生物体的生存也很重要。环境富集物通过激活下丘脑脑源性神经营养因子(BDNF)信号来增加能量消耗和减少肥胖。然而，我假设性别和社会因素影响这种反应，小胶质细胞BDNF负责对这些因素的反应。因此，我计划调查环境因素、社会因素、性别、小胶质细胞脑源性神经营养因子和新陈代谢之间的相互作用，作为我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，环境丰富对禁食/喂养的代谢反应和下丘脑对葡萄糖的反应的影响将在雄性和雌性小鼠之间进行比较。葡萄糖是神经细胞的主要能量来源。研究2(3-5年)：为了探索社会因素和性别之间的相互作用对代谢的影响，将比较雄性和雌性小鼠的社会隔离对禁食/进食的代谢反应和下丘脑对葡萄糖的反应的影响。通过将小鼠保持在单一住所而不是集体住所的条件，将实现社会隔离。*研究3(第1-5年)：为了调查环境因素和小胶质细胞BDNF在代谢调节中的相互作用，将在对照组和小胶质细胞特异性BDNFKO小鼠中比较环境丰富对代谢反应的影响。*在所有研究中，将测量体重、食物摄入量、肥胖和能量消耗。将测定血清和组织中与代谢相关的激素、代谢物、基因和蛋白质的水平。在接下来的5年里，我将培养3名研究生(研究1 1名硕士，研究2 1名硕士，研究3 1名博士)。*意义*预计这项拟议的研究将证明：(1)环境和社会条件的变化以性别依赖的方式影响全身新陈代谢和下丘脑对葡萄糖的反应，(2)小胶质细胞中BDNF的缺失减弱了环境丰富对新陈代谢的影响。因此，拟议的计划将提供关于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的信息，并将帮助我们理解中枢神经系统调节代谢稳态的机制，代谢稳态是生物体最基本的生理功能之一。

* * 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.**