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（通过应用程序证明）：营养状态和环境中的大脑检测中的神经元可以定期食物的摄入量和能量消耗，其平衡对于维持正常的身体体重和保护大脑的复杂性至关重要。 - 因此，我仍然缺乏支出的神经基础，但在最近的研究中，此后被称为“ RIP”神经元，并发现了一个基于Arcuite的电路能量在CRE中的神经元，并且由于在这些动物中诱导了高脂肪的饮食。 CRACM）向旁牙核（PVH）投射，特别支配了PVH神经元，这些PVH神经元在脑茎中投射到孤立区（NTS）的核。鉴于这些神经元在保持体重和抵抗肥胖症的重要性，瘦素对瘦素的刺激作用有助于饮食。先进的光遗传学和深脑成像方法来研究温度调节过程中RIP神经元的法规，并且在刺激PVH的AIM 2信号中，对PVH的投影越多。终于，在AIM 3中在弧形核中的微电路中的神经元，并在调节能量消耗时进行仔细检查。

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）

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

DOI：
10.1016/j.neuron.2021.06.005
发表时间：
2021-08-18
期刊：
Neuron
影响因子：
16.2
作者：
Roy DS;Zhang Y;Aida T;Choi S;Chen Q;Hou Y;Lea NE;Skaggs KM;Quay JC;Liew M;Maisano H;Le V;Jones C;Xu J;Kong D;Sullivan HA;Saunders A;McCarroll SA;Wickersham IR;Feng G
通讯作者：
Feng G

Synaptic Regulation of Metabolism.