The role of ventromedial hypothalamic steroidogenic factor-1 neurons in exercise-related metabolism

下丘脑腹内侧类固醇生成因子1神经元在运动相关代谢中的作用

基本信息

  • 批准号:
    10463197
  • 负责人:
  • 金额:
    $ 6.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-03-01 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Nearly half of the American population is classified as obese and just under one in ten suffer from type 2 diabetes mellitus (T2DM). Exercise protects against a number of deleterious metabolic changes that correspond with obesity and T2DM, including impaired glucose metabolism and altered energy balance. The ventromedial nucleus of the hypothalamus (VMH) is critical for the regulation of whole-body metabolism. Co-sponsor Dr. Joel Elmquist has shown that the expression of the transcription factor steroidogenic factor-1 (SF1) in the dorsomedial VMH (VMHdm) is required for normal energy homeostasis in response to metabolic challenges including exercise. While preliminary work in sponsor Dr. J. Nicholas Betley’s laboratory has shown that the activity of VMHdm SF1 neurons substantially increases following exercise, it remains unknown how SF1 neural activity may mediate the metabolic effects of exercise. The main goals of the proposed research are to characterize the neurophysiology of VMHdm SF1 neurons and their two major subtypes—those that express the leptin and insulin receptors (LEPR and INSR)—during exercise training; and to determine the role of SF1, LEPR, and INSR neural activity in exercise-driven changes in energy balance and glucose homeostasis. Specific Aim I experiments will use fiber photometry and endoscopic calcium imaging to monitor the neural activity of VMHdm SF1, LEPR, and INSR neurons during and immediately following both acute exercise and chronic exercise training. Specific Aim II experiments will combine optogenetic manipulation of VMHdm SF1, LEPR, and INSR neurons in in exercising and sedentary mice with metabolic chamber monitoring and glucose tolerance tests to test the necessity and sufficiency of these neural populations to drive exercise-related changes in energy balance and glucose homeostasis. Collectively, these experiments will open avenues for future research into the specific mechanisms by which VMHdm neural activity contributes to the whole-body homeostatic response to metabolic challenges such as exercise. The training plan included in this application builds upon the applicant, Dr. Ryan Post’s prior expertise in systems neuroscience, optogenetics, and fiber photometry as he develops his skills in endoscopic calcium imaging and metabolic techniques, and enters the field of metabolism. The application’s sponsor, Dr. J. Nicholas Betley, and co-sponsors, Drs. Joel Elmquist and Junhyong Kim, will be instrumental in Ryan’s completion of the proposed research and training plan. Given Dr. Betley’s expertise in the contribution of the central nervous system to metabolism, Dr. Elmquist’s experience as a leader in the field of hypothalamic research and metabolism, and Dr. Kim’s standing as a pre-eminent cell biologist and successful mentor, they will serve as invaluable resources to Ryan in his development as an independent scientist. Drs. Betley, Elmquist, and Kim will also oversee Ryan’s professional development as he attends international conferences in neuroscience and metabolism. The training and research proposed in this application will take place at the University of Pennsylvania, a world-class institution with a number of resources that will augment Dr. Post’s development.
项目摘要 近一半的美国人被归类为肥胖,不到十分之一的人患有2型糖尿病 糖尿病(T2 DM)。运动可以防止一些有害的代谢变化, 肥胖和T2 DM,包括葡萄糖代谢受损和能量平衡改变。腹内侧 下丘脑核(VMH)对于调节全身代谢至关重要。共同赞助人乔尔博士 Elmquist已经表明,转录因子类固醇生成因子-1(SF 1)在背内侧核中的表达, VMH(VMHdm)是正常能量稳态所必需的,以应对代谢挑战,包括 锻炼的虽然在赞助商J. Nicholas Betley博士实验室的初步工作表明, VMHdm SF 1神经元在运动后显著增加,但SF 1神经活动如何仍然未知。 可能介导运动的代谢影响。拟议研究的主要目标是表征 VMHdm SF 1神经元及其两种主要亚型--表达瘦素和胰岛素的神经生理学 受体(LEPR和INSR)-在运动训练中的作用;并确定SF 1,LEPR和INSR神经 在运动驱动的能量平衡和葡萄糖稳态变化中的活性。具体目标I实验将 使用纤维光度法和内窥镜钙成像监测VMHdm SF 1、LEPR和 急性运动训练和慢性运动训练期间和之后即刻的INSR神经元。具体目标 II实验将联合收割机在运动中对VMHdm SF 1、LEPR和INSR神经元进行光遗传学操作 和久坐小鼠代谢室监测和葡萄糖耐量试验,以测试的必要性和 这些神经群足以驱动能量平衡和葡萄糖的运动相关变化 体内平衡总的来说,这些实验将为未来研究特定机制开辟道路 VMHdm神经活动有助于全身对代谢挑战的稳态反应 例如锻炼。本申请中包含的培训计划是基于申请人Ryan Post博士的先前 他在发展内窥镜技术的同时,还拥有系统神经科学、光遗传学和光纤光度学方面的专业知识。 钙显像和代谢技术,进入代谢领域。该申请的发起人J. Nicholas Betley和共同赞助商Joel Elmquist博士和Junhyong Kim博士将在Ryan的 完成拟议的研究和培训计划。考虑到贝特利博士在贡献 中枢神经系统的新陈代谢,Elmquist博士的经验,在下丘脑研究领域的领导者 和新陈代谢,金博士作为一个杰出的细胞生物学家和成功的导师的地位,他们将服务于 作为宝贵的资源,瑞安在他的发展作为一个独立的科学家。贝特利,艾姆奎斯特和金博士 他还将监督瑞安的专业发展,因为他参加国际会议在神经科学和 新陈代谢.本申请中提出的培训和研究将在大学进行。 宾夕法尼亚州,一个世界级的机构与一些资源,将增加博士波斯特的发展。

项目成果

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Ryan James Post其他文献

Ryan James Post的其他文献

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{{ truncateString('Ryan James Post', 18)}}的其他基金

The role of ventromedial hypothalamic steroidogenic factor-1 neurons in exercise-related metabolism
下丘脑腹内侧类固醇生成因子1神经元在运动相关代谢中的作用
  • 批准号:
    10576275
  • 财政年份:
    2022
  • 资助金额:
    $ 6.72万
  • 项目类别:

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