A Neural Circuit of Energy Expenditure Preventing Obesity

预防肥胖的能量消耗神经回路

• 批准号: 9240624
• 负责人: Dong Kong
• 金额: $ 37.13万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240624
• 关键词: Acute; Affinity Chromatography; Animals; Attenuated; Automobile Driving; Body Weight; Brain; Brain Stem; Brain imaging; Brown Fat; Calories; Cells; Chemistry; Development; Diet; Dynorphins; Eating; Energy Metabolism; Environment; Equilibrium; Feeding behaviors; Food Energy; Genetic; High Fat Diet; Hypothalamic structure; Intake; Label; Left; Leptin; Mediating; Metabolic Diseases; Modeling; Monitor; Mus; Neurons; Nucleus solitarius; Nutritional status; Obesity; Optics; Output; Pathway interactions; Pharmacogenetics; Physiologic Thermoregulation; Physiological; Process; Rabies virus; Regulation; Research; Ribosomes; Role; Signal Transduction; Structure of nucleus infundibularis hypothalami; Surveys; Synapses; Technology; Testing; Thermogenesis; Transgenic Mice; Translating; Virus; base; designer receptors exclusively activated by designer drugs; feeding; gamma-Aminobutyric Acid; imaging approach; in vivo; infancy; interest; neural circuit; neurobiological mechanism; neuromechanism; neuroregulation; neurotransmission; neurotransmitter release; novel; obesity treatment; optogenetics; paraventricular nucleus; prevent; public health relevance; relating to nervous system; success; tool

 DESCRIPTION (provided by applicant): Neurons in the brain detect changes in nutritional status and environment, and relay signals to their downstream targets to regulate food intake and energy expenditure, the balance of which is critical to maintain normal body weight and protect from obesity. Given the complexity of the brain, the neurobiological mechanisms underlying these processes are poorly understood. Efficient treatment of obesity is thus still lacking. Although a lot of success has been recently achieved in dissecting the neural circuitry of feeding behaviors, the research to understand the neural basis of energy expenditure is still in its infancy. In a recent study, we focused on a group of hypothalamic neurons labeled by cre activity in Rip-cre transgenic mice, thereafter referred to as "RIP" neurons, and uncovered an arcuate-based circuit that selectively drives brown adipose tissue (BAT) activity and energy expenditure. Specifically, we disrupted GABAergic neurotransmission from these neurons in a cre-dependent manner and observed that mice lacking synaptic GABA release from RIP neurons have reduced energy expenditure and become obese, and are extremely sensitive to high fat diet-induced obesity due to defective thermogenesis. Leptin's ability to stimulate energy expenditure is also attenuated in these animals. With pharmacogenetic DREADDs, we acutely and selectively activated the subset of RIP neurons in the arcuate nucleus (ARC) and rapidly stimulated BAT-mediated energy expenditure. Moreover, with channelrhodopsin-assisted circuit mapping (CRACM), we characterized that ARC RIP neurons project to the paraventricular nucleus (PVH) and specifically innervate the PVH neurons that project to the nucleus of solitary tract (NTS) in the brain stem. Of great interest, we observed that RIP neurons have no effects in regulating food intake. These findings demonstrate that GABAergic RIP neurons in the ARC selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity. Given the importance of these neurons in maintaining body weight and resisting obesity, it is crucial to comprehensively understand their related neural circuitry. In Aim 1, we set out to employ advanced optogenetic and deep brain imaging approaches to investigate the regulations of RIP neurons during thermoregulation and functionally assess their projection to the PVH in stimulating energy expenditure. In Aim 2, we will focus on the output signals of RIP neurons in the PVH and identify their efferent subset of neurons that convey their signals to the BAT. Finally, in Aim 3, we will survey the afferent inputs of RIP neurons within a microcircuit in the arcuate nucleus and scrutinize their functions in regulating energy expenditure. In total, these proposed studies could significantly advance our understanding of the neural basis of energy expenditure and provide novel information to prevent obesity.

 描述(申请人提供)：大脑中的神经元检测营养状态和环境的变化，并将信号传递给下游目标，以调节食物摄入量和能量消耗，两者的平衡对保持正常体重和防止肥胖至关重要。鉴于大脑的复杂性，人们对这些过程背后的神经生物学机制知之甚少。因此，仍然缺乏有效的肥胖症治疗方法。虽然最近在解剖摄食行为的神经回路方面取得了许多成功，但了解能量消耗的神经基础的研究仍处于初级阶段。在最近的一项研究中，我们专注于Rip-cre转基因小鼠中一组被cre活性标记的下丘脑神经元，此后被称为“RIP”神经元，并发现了一个基于弓状酸的回路，它选择性地驱动棕色脂肪组织(BAT)的活动和能量消耗。具体地说，我们以一种cre依赖的方式干扰了这些神经元的GABA能神经传递，并观察到缺乏RIP神经元突触GABA释放的小鼠能量消耗减少，变得肥胖，并且由于产热缺陷，对高脂饮食诱导的肥胖极其敏感。在这些动物中，瘦素刺激能量消耗的能力也会减弱。利用药物遗传学DREADDS，我们敏锐和选择性地激活了弓状核(ARC)中的RIP神经元亚群，并迅速刺激了BAT介导的能量消耗。此外，用通道视紫红质辅助的电路映射(CRACM)方法，我们发现ARC RIP神经元投射到室旁核(PVH)，并特异性地支配投射到脑干孤束核(NTS)的PVH神经元。有趣的是，我们观察到RIP神经元在调节食物摄入量方面没有任何作用。这些发现表明，ARC中的GABA能RIP神经元选择性地驱动能量消耗，参与瘦素对产热的刺激作用，并防止饮食诱导的肥胖。鉴于这些神经元在维持体重和抵抗肥胖方面的重要性，全面了解它们相关的神经回路至关重要。在目标1中，我们开始利用先进的光遗传学和脑深部成像方法来研究RIP神经元在体温调节过程中的调节，并从功能上评估它们在刺激能量消耗方面向PVH的投射。在目标2中，我们将重点关注PVH中RIP神经元的输出信号，并识别它们向蝙蝠传递信号的传出神经元子集。最后，在目标3中，我们将调查传入输入 对弓状核内微循环内的RIP神经元的研究，并仔细研究它们在调节能量消耗方面的功能。总而言之，这些拟议的研究可以显著提高我们对能量消耗的神经基础的理解，并为预防肥胖提供新的信息。