A Neural Circuit of Energy Expenditure Preventing Obesity

预防肥胖的能量消耗神经回路

• 批准号: 10469923
• 负责人: Dong Kong
• 金额: $ 15.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469923
• 关键词: Neural; Circuit; Energy; Expenditure; Preventing

 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（由申请人提供）：大脑中的神经元检测营养状态和环境的变化，并将信号传递到其下游靶点，以调节食物摄入和能量消耗，两者的平衡对于维持正常体重和防止肥胖至关重要。鉴于大脑的复杂性，这些过程背后的神经生物学机制知之甚少。因此，仍然缺乏对肥胖症的有效治疗。虽然最近在解剖摄食行为的神经回路方面取得了很大的成功，但了解能量消耗的神经基础的研究仍处于起步阶段。在最近的一项研究中，我们专注于Rip-cre转基因小鼠中一组由cre活性标记的下丘脑神经元，此后称为“RIP”神经元，并发现了一个基于谷氨酸的回路，该回路选择性地驱动棕色脂肪组织（BAT）活动和能量消耗。具体来说，我们以cre依赖性方式破坏了这些神经元的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并变得肥胖，并且由于产热缺陷对高脂饮食诱导的肥胖非常敏感。在这些动物中，瘦素刺激能量消耗的能力也减弱了。使用药物遗传学DREADD，我们急性和选择性地激活弓状核（ARC）中RIP神经元的子集，并快速刺激BAT介导的能量消耗。此外，通道视紫红质辅助电路映射（CRACM），我们的特点是ARC RIP神经元投射到室旁核（PVH），并特异性地支配PVH神经元投射到孤束核（NTS）在脑干。非常有趣的是，我们观察到RIP神经元在调节食物摄入方面没有作用。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，有助于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，我们开始采用先进的光遗传学和深部脑成像方法来研究RIP神经元在体温调节过程中的调节，并在功能上评估它们在刺激能量消耗时向PVH的投射。在目标2中，我们将关注PVH中RIP神经元的输出信号，并确定将其信号传递到BAT的神经元传出子集。最后，在目标3中，我们将调查传入输入 的RIP神经元内的微电路在弓状核，并仔细检查它们的功能，在调节能量消耗。总的来说，这些拟议的研究可以显着推进我们对能量消耗神经基础的理解，并为预防肥胖提供新的信息。