The VMH and Molecular Control of Energy Balance

VMH 和能量平衡的分子控制

基本信息

批准号：
8233515
负责人：
BRADFORD B LOWELL
金额：
$ 36.13万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233515
关键词：
Acute Address Adipocytes Affinity Anorexia Attenuated Body Weight Body Weight decreased Body fat Brain Brain region Brain-Derived Neurotrophic Factor Cell Nucleus Complex Dendrites Dendritic Spines Development Diet Exhibits Fasting Fatty acid glycerol esters Genes Glutamates Grant Homeostasis Hormones Hypothalamic structure Imagery Leptin Leptin deficiency Light Mediating Metabolic Middle Hypothalamus Molecular Morphology Mus N-Methyl-D-Aspartate Receptors NR1 gene Neurons Neuropeptides Neurotransmitters Obesity PACAPR-1 protein Play Process Receptor Gene Regulation Role SF1 Side Site Slice Structure of nucleus infundibularis hypothalami Synapses Synaptic plasticity Technology Testing Third ventricle structure Transgenes Ursidae Family Weight Work base energy balance gamma-Aminobutyric Acid in vivo leptin receptor light effects novel optogenetics pituitary adenylate cyclase activating polypeptide pituitary adenylate cyclase-activating peptide receptor postsynaptic public health relevance receptor release factor transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): The VMH and Molecular Control of Energy Balance The ventral medial hypothalamus (VMH), in concert with other brain regions, regulates energy balance. A group of neurons within the VMH, marked by the expression of the transcription factor, SF1 (Nr5a1), resists the development of obesity. The adipocyte-derived, "catabolic" hormone leptin excites these SF1 neurons, and deletion of leptin receptors (LEPRs) on SF1 neurons results in obesity, and also marked sensitivity to diet-induced obesity. Thus, SF1 neurons in the VMH, like POMC neurons in the actuate nucleus, are direct targets of leptin and promote negative energy balance. While much is known about how POMC neurons cause weight loss, comparatively less is known about how SF1 neurons achieve this effect. This presents the unique opportunity to identify novel mechanisms controlling energy homeostasis. In this grant, we propose to determine the following: 1) the "catabolic" factor released by SF1 neurons (we propose an important role for the neuropeptide, PACAP) (Aim 1), 2) the receptor and neuron immediately downstream of SF1 neurons (we propose that the PAC1-receptor - the high affinity PACAP receptor - on POMC neurons is important) (Aim 2), and 3) on the afferent side of SF1 neurons, we propose that glutamatergic excitatory inputs, which synapse on dendritic spines of SF1 neurons, play a key role in controlling the activity of SF1 neurons, and that glutamate NMDA receptor-mediated plasticity of these inputs, and, importantly, leptin regulation of this plasticity, contributes prominently to the control of energy homeostasis. To accomplish these Aims, we will utilize the following state-of-the-art technologies: 1) neuron- specific gene manipulation to test molecular mechanisms in an in vivo context (in all three Aims), 2) optogenetics to identify functionally relevant, monosynaptic, downstream targets of SF1 neurons (in Aim 2), and 3) functional and morphologic assessments of excitatory synaptic plasticity (in Aim 3). PUBLIC HEALTH RELEVANCE: Complex neurocircuits in the brain work in concert to control body fat stores. In order to intelligently develop anti-obesity therapies, it is first necessary to decipher the "wiring-diagrams" that underpin these circuits. To accomplish this, our group is using the following state-of-the-art technologies: 1) neuron-specific gene manipulations, 2) optogenetics (light-activated neuron stimulation), and 3) functional-morphologic assessments of synaptic organization and plasticity.

描述（由申请人提供）：VMH 和能量平衡的分子控制腹侧内侧下丘脑 (VMH) 与其他大脑区域协同调节能量平衡。 VMH 内的一组神经元以转录因子 SF1 (Nr5a1) 的表达为标志，可抵抗肥胖的发展。脂肪细胞衍生的“分解代谢”激素瘦素会兴奋这些 SF1 神经元，SF1 神经元上的瘦素受体 (LEPR) 缺失会导致肥胖，并且对饮食引起的肥胖显着敏感。因此，VMH 中的 SF1 神经元与致动核中的 POMC 神经元一样，是瘦素的直接目标并促进负能量平衡。虽然人们对 POMC 神经元如何导致体重减轻了解很多，但对 SF1 神经元如何实现这种效果知之甚少。这为识别控制能量稳态的新机制提供了独特的机会。在这笔资助中，我们建议确定以下内容：1）SF1神经元释放的“分解代谢”因子（我们提出神经肽 PACAP 的重要作用）（目标 1），2）紧邻 SF1 神经元下游的受体和神经元（我们认为 POMC 神经元上的 PAC1 受体 - 高亲和力 PACAP 受体 - 很重要）（目标 2）和 3）在 SF1 神经元的传入侧，我们建议SF1 神经元树突棘上的谷氨酸兴奋性输入在控制 SF1 神经元的活动中发挥着关键作用，谷氨酸 NMDA 受体介导的这些输入的可塑性，以及重要的是，瘦素对这种可塑性的调节，发挥了显着的作用来控制能量稳态。为了实现这些目标，我们将利用以下最先进的技术：1）神经元特异性基因操作来测试体内环境中的分子机制（在所有三个目标中），2）光遗传学来识别功能相关， SF1 神经元的单突触下游靶点（目标 2），以及 3）兴奋性突触可塑性的功能和形态学评估（目标 3）。公共健康相关性：大脑中复杂的神经回路协同工作来控制体内脂肪储存。为了明智地开发抗肥胖疗法，首先有必要破译支撑这些电路的“接线图”。为了实现这一目标，我们的团队正在使用以下最先进的技术：1）神经元特异性基因操作，2）光遗传学（光激活神经元刺激），以及3）突触组织和可塑性的功能形态学评估。