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）：能量平衡的VMH和分子控制腹侧下丘脑（VMH）与其他大脑区域一致，可调节能量平衡。 VMH中的一组神经元以转录因子SF1（NR5A1）的表达为特征，可抵抗肥胖的发展。脂肪细胞衍生的“分解代谢”激素瘦素激发了这些SF1神经元，并在SF1神经元上删除瘦素受体（LEPR）会导致肥胖，并显着对饮食诱导的肥胖症的敏感性。因此，VMH中的SF1神经元，例如Actuate核中的POMC神经元，是瘦素的直接靶标，并促进负能量平衡。尽管对POMC神经元如何导致体重减轻的了解众所周知，但对于SF1神经元如何达到这种效果的了解相对较少。这为确定控制能量稳态的新型机制提供了独特的机会。 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在SF1神经元中，我们提出，谷氨酸能兴奋性输入（在SF1神经元的树突状刺激上突触）在控制SF1神经元的活性以及谷氨酸NMDA受体介导的这些投入的可变性，以及液能素的综合性，撰写的液态质量的综合性，从而撰写的液化性剂量，从而在控制SF1神经元的活性方面起着关键作用。为了实现这些目标，我们将利用以下最新技术：1）在体内环境中（在所有三个目标中），2）光遗传学在功能上相关的，单突触，单次神经元（在所有三个目的中）在体内环境中测试分子机制，以识别功能相关的SF1神经元（在2）和3中的启发性，并识别瞄准剂的下游靶标的功能。（在AIM 3中）。公共卫生相关性：大脑中复杂的神经通路协同控制人体脂肪储存。为了智能开发抗肥胖疗法，首先有必要破译这些电路支撑的“接线二号”。为此，我们的小组正在使用以下最新技术：1）神经元特异性基因操纵，2）光遗传学（光激活的神经元刺激），3）突触组织和可变性的功能性评估。