Sim1 Neurons and Body Weight Regulation

Sim1 神经元和体重调节

基本信息

批准号：
8450716
负责人：
Qingchun Tong
金额：
$ 32.01万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450716
关键词：
Adult Adverse effects Agonist Agreement Amygdaloid structure Benzodiazepines Body Weight Brain Brain region Cell Nucleus Coronary heart disease Corticotropin-Releasing Hormone Data Defect Development Diet Eating Energy Metabolism Epidemic Fatty acid glycerol esters Food Energy GABA-A Receptor Genes Genetic Glutamates Goals Homeostasis Hormones Human Hypertension Hypothalamic structure Knock-out Knockout Mice Lateral Lead Left Lesion Mediating Mediator of activation protein Medicine Melanocortin 4 Receptor Metabolic Mind Modeling Morbid Obesity Mus Mutation Neural Pathways Neurons Neuropeptides Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Obesity Olfactory tract Oxytocin Pathway interactions Pharmaceutical Preparations Physiological Play Predisposition Regulation Research Risk Factors Rodent Rodent Model Role Testing Therapeutic base energy balance feeding gamma-Aminobutyric Acid hypnotic mouse model neuron development neurotransmitter release novel strategies postnatal presynaptic response restoration synaptic function therapeutic development therapeutic target transcription factor vesicular glutamate transporter 2 zolpidem

项目摘要

DESCRIPTION (provided by applicant): Mutations in the genes encoding single-minded 1 (Sim1) and the melanocortin receptors 4 (MC4Rs) cause severe obesity in humans. In agreement, mice with Sim1 haploinsufficiency or PVH lesion are obese. Importantly, specific genetic restoration of MC4R in Sim1 neurons reduces obesity resulted from MC4R null mice by 60-70%, demonstrating a critical role for MC4Rs in Sim1 neurons in body weight regulation. However, despite the well established importance of Sim1 neurons in both humans and rodents, our understanding of Sim1 neural pathway is still limited to the level of Sim1 neurons. Downstream of Sim1 neurons, the identity of the neurotransmitters that mediate their action is not clear. Studies have been focused on the roles of neuropeptides released from Sim1 neurons (e.g. corticotrophin-releasing hormone, thyrotrophin-releasing hormone and oxytocin). However, knockout of each of these neuropeptides produced little or limited defects in feeding or body weight, suggesting a role for additional neurotransmitters. Sim1-expressing regions contain abundant vesicular glutamate transporter 2 (Vglut2, required for presynaptic glutamate release), indicating that the majority of Sim1 neurons are glutamatergic. Upstream of Sim1 neurons, how the activity of Sim1 neuron is regulated remains largely unknown. With the exception of the melanocortin input, the function of synaptic inputs is unknown. Electrophysiological data have suggested an important role for GABAergic input to PVH Sim1 neurons. However, the physiological significance of the GABAergic input is yet to be demonstrated. Aim 1 will test the hypothesis that glutamate release mediates the action of Sim1 neurons in body weight regulation using mice with specific loss of glutamate release from Sim1 neurons. Aim 2 will test the hypothesis that glutamate release mediates the action of MC4Rs expressed in Sim1 neurons in body weight regulation using mice with concurrent re-expression of MC4Rs and disruption of glutamate release restricted to Sim1 neurons on MC4R null background. Aim 3 will determine the function of GABAergic input to adult Sim1 neurons on body weight regulation using a mouse model in which only GABA-A receptors in Sim1 neurons will be sensitive to Zolpidem (a specific benzodiazepine mimicking GABA-A agonist), but those in all other brain neurons will not. GABA-A receptors in all neurons will respond normally to GABA, thus these mice will behave normally except for Zolpidem action. Effects of specific activation of GABAergic input on body weight, food intake and energy expenditure will be examined by administering Zolpidem in a temporally controlled and reversible fashion. These studies will reveal the function of glutamate release, an important downstream mediator, and GABAergic input, an important upstream regulator, of Sim1 neural pathway, thus representing a significant step in our understanding of brain neurocircuitry on body weight regulation.

描述（由申请人提供）：编码专一1（Sim1）和黑皮质素受体4（MC4R）的基因突变导致人类严重肥胖。一致认为，Sim1 单倍体不足或 PVH 损伤的小鼠是肥胖的。重要的是，Sim1 神经元中 MC4R 的特异性遗传恢复可将 MC4R 缺失小鼠导致的肥胖减少 60-70%，这表明 Sim1 神经元中的 MC4R 在体重调节中发挥着关键作用。然而，尽管 Sim1 神经元在人类和啮齿动物中的重要性已得到公认，但我们对 Sim1 神经通路的理解仍然仅限于 Sim1 神经元的水平。 Sim1 神经元的下游，介导其作用的神经递质的身份尚不清楚。研究重点是 Sim1 神经元释放的神经肽（例如促肾上腺皮质激素释放激素、促甲状腺激素释放激素和催产素）的作用。然而，敲除这些神经肽中的每一种都会在进食或体重方面产生很少或有限的缺陷，这表明其他神经递质的作用。 Sim1 表达区域含有丰富的囊泡谷氨酸转运蛋白 2（Vglut2，突触前谷氨酸释放所需），表明大多数 Sim1 神经元具有谷氨酸能。 Sim1 神经元的上游，Sim1 神经元的活动是如何调节的仍然很大程度上未知。除黑皮质素输入外，突触输入的功能尚不清楚。电生理数据表明 GABA 能输入对 PVH Sim1 神经元具有重要作用。然而，GABA能输入的生理意义尚未得到证实。目标 1 将使用 Sim1 神经元谷氨酸释放特定缺失的小鼠来检验谷氨酸释放介导 Sim1 神经元在体重调节中的作用这一假设。目标 2 将使用小鼠验证谷氨酸释放介导 Sim1 神经元中表达的 MC4R 在体重调节中的作用，同时在 MC4R 无效背景下重新表达 MC4R，并破坏仅限于 Sim1 神经元的谷氨酸释放。目标 3 将使用小鼠模型确定成年 Sim1 神经元的 GABA 能输入对体重调节的功能，其中只有 Sim1 神经元中的 GABA-A 受体对唑吡坦（一种特定的苯二氮卓类药物模拟 GABA-A 激动剂）敏感，但所有其他大脑神经元都不会。所有神经元中的 GABA-A 受体都会对 GABA 产生正常反应，因此这些小鼠除了唑吡坦作用外将表现正常。通过以时间控制和可逆的方式施用唑吡坦来检查特定激活 GABA 能输入对体重、食物摄入和能量消耗的影响。这些研究将揭示Sim1神经通路的谷氨酸释放（重要的下游介质）和GABA能输入（重要的上游调节器）的功能，从而代表我们在理解大脑神经回路对体重调节的理解方面迈出了重要一步。