A Neural Circuit of Energy Expenditure Preventing Obesity

预防肥胖的能量消耗神经回路

基本信息

批准号：
10481341
负责人：
Dong Kong
金额：
$ 32.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10481341
关键词：
Neural Circuit Energy Expenditure Preventing

项目摘要

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况和环境的变化，并将信号传递给下游目标以调节食物摄入和能量消耗，其中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仍然缺乏有效的治疗，尽管最近在剖析进食行为的神经回路方面取得了很大的成功，但了解神经回路的研究仍然缺乏。能量消耗的基础在最近的一项研究中，我们重点研究了 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），并发现了一种选择性驱动棕色的弓形电路。具体来说，我们以一种依赖于 Cre 的方式破坏了这些神经元的 GABA 能神经传递，并观察到 RIP 神经元缺乏突触 GABA 释放的小鼠能量消耗减少并变得更加肥胖。肥胖，并且由于生热作用缺陷而对高脂肪饮食引起的肥胖极其敏感，在这些动物中，通过药物遗传学 DREADD，我们敏锐地选择性地激活了弓状核中的 RIP 神经元子集。 ARC）和快速刺激的 BAT 介导的能量消耗此外，通过视紫红质通道辅助电路映射（CRACM），我们表征了 ARC RIP 神经元投射到室旁核。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。 ARC 选择性地驱动能量消耗，有助于瘦素对产热的刺激作用，并防止饮食引起的肥胖。鉴于这些神经元在维持体重和抵抗肥胖方面的重要性，全面了解它们至关重要。在目标 1 中，我们着手采用先进的光遗传学和深部脑成像方法来研究 RIP 神经元在温度调节过程中的调节，并在功能上评估它们在刺激能量消耗方面对 PVH 的投射。 PVH 中 RIP 神经元的输出信号，并识别将其信号传递至 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。总体而言，这些拟议的研究可以显着增进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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glucose Availability Predicts the Feeding Response to Ghrelin in Male Mice, an Effect Dependent on AMPK in AgRP Neurons.

葡萄糖利用率可预测雄性小鼠对 Ghrelin 的摄食反应，这种效应依赖于 AgRP 神经元中的 AMPK。

DOI：
发表时间：
2018-11-01
期刊：
影响因子：
4.8
作者：
Lockie, Sarah H;Stark, Romana;Mequinion, Mathieu;Ch'ng, Sarah;Kong, Dong;Spanswick, David C;Lawrence, Andrew J;Andrews, Zane B
通讯作者：
Andrews, Zane B

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

糖酵解抑制剂 2-脱氧葡萄糖可防止脑外伤后皮质过度兴奋。

DOI：
发表时间：
2019
期刊：
影响因子：
8
作者：
Koenig, Jenny B;Cantu, David;Low, Cho;Sommer, Mary;Noubary, Farzad;Croker, Danielle;Whalen, Michael;Kong, Dong;Dulla, Chris G
通讯作者：
Dulla, Chris G

Chemosensory modulation of neural circuits for sodium appetite.

神经回路的化学感应调节钠食欲。

DOI：
发表时间：
2019
期刊：
影响因子：
64.8
作者：
Lee, Sangjun;Augustine, Vineet;Zhao, Yuan;Ebisu, Haruka;Ho, Brittany;Kong, Dong;Oka, Yuki
通讯作者：
Oka, Yuki

Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.

前丘脑功能障碍是神经精神疾病模型子集认知缺陷的基础。

DOI：
发表时间：
2021-08-18
期刊：
影响因子：
16.2
作者：
Roy, Dheeraj S;Zhang, Ying;Aida, Tomomi;Choi, Soonwook;Chen, Qian;Hou, Yuanyuan;Lea, Nicholas E;Skaggs, Keith M;Quay, Juliana C;Liew, Min;Maisano, Hannah;Le, Vinh;Jones, Carter;Xu, Jie;Kong, Dong;Sullivan, Heather A;Saunders, Arpiar;McCar
通讯作者：
McCar

Synaptic Regulation of Metabolism.

代谢的突触调节。