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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：
9901506
负责人：
Dong Kong
金额：
$ 22.84万
依托单位：
TUFTS UNIVERSITY BOSTON
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 2021-02-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901506
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

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.