Sim1 Neurons and Body Weight Regulation

Sim1 神经元和体重调节

• 批准号: 8297800
• 负责人: Qingchun Tong
• 金额: $ 34.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/8297800
• 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

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. PUBLIC HEALTH RELEVANCE: Obesity is one of the greatest and the most challenging problems in medicine and is an important risk factor for type II diabetes mellitus, hypertension, and coronary heart disease. Mutations in Sim1 gene are one of important monogenic causes of obesity in both humans and rodents. Our study based on rodent models will reveal Sim1 neural pathway in body weight regulation, thus providing a framework for using Sim1 neural pathway as a therapeutic target against the current obesity epidemic.

描述(申请人提供)：编码单一基因1(Sim1)和黑素皮质素受体4(MC4Rs)的基因突变会导致人类严重肥胖。一致地，带有Sim1单倍体功能不全或PVH损害的小鼠是肥胖的。重要的是，Sim1神经元中MC4R的特异性遗传恢复可以将MC4R缺失小鼠引起的肥胖减少60%-70%，这表明Sim1神经元中的MC4Rs在体重调节中起着关键作用。然而，尽管Sim1神经元在人类和啮齿动物中的重要性已经得到证实，但我们对Sim1神经通路的了解仍然局限于Sim1神经元的水平。在Sim1神经元下游，调节其活动的神经递质的身份尚不清楚。SIM1神经元释放的神经肽(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)的作用一直是研究的重点。然而，敲除这些神经肽中的每一种在摄食或体重方面产生的缺陷很少或有限，这表明额外的神经递质起到了作用。SIM1表达区域含有丰富的囊泡状谷氨酸转运蛋白2(VGlu2，突触前谷氨酸释放所需)，表明SIM1神经元中的大多数是谷氨酸能神经元。在Sim1神经元的上游，Sim1神经元的活动是如何调节的在很大程度上仍不清楚。除了黑素皮质素的输入外，突触输入的功能尚不清楚。电生理数据表明GABA能传入PVH Sim1神经元具有重要作用。然而，GABA能输入的生理意义尚不清楚。目的1利用特异性丢失Sim1神经元释放谷氨酸的小鼠，验证谷氨酸释放介导Sim1神经元体重调节作用的假说。目的2利用MC4R缺失背景下MC4Rs的重新表达和仅限于Sim1神经元的谷氨酸释放的干扰来验证这一假设，即谷氨酸释放介导了在体重调节中Sim1神经元表达的MC4Rs的作用。目的3将利用小鼠模型确定成年Sim1神经元的GABA能输入对体重调节的作用，在该模型中，Sim1神经元中只有GABA-A受体对唑吡坦(一种模拟GABA-A激动剂的特异性苯二氮卓类药物)敏感，而所有其他脑神经元中的GABA-A受体不敏感。所有神经元中的GABA-A受体将对GABA做出正常反应，因此这些小鼠的行为将正常，但唑吡坦除外。特定激活GABA能输入对体重、食物摄入量和能量消耗的影响将通过在时间上受控和可逆的方式给药唑吡坦来检验。这些研究将揭示Sim1神经通路的重要下游调节因子谷氨酸释放和上游调节因子GABA能输入的功能，从而代表着我们对大脑神经回路对体重调节的理解迈出了重要的一步。 公共卫生相关性：肥胖是医学上最大和最具挑战性的问题之一，也是II型糖尿病、高血压和冠心病的重要风险因素。Sim1基因突变是人类和啮齿动物肥胖的重要单基因原因之一。我们基于啮齿动物模型的研究将揭示Sim1神经通路在体重调节中的作用，从而为利用Sim1神经通路作为治疗当前肥胖流行的靶点提供一个框架。