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The Arcuate Nucleus: A Genetic Assessment of Function

弓状核：功能的遗传评估

基本信息

批准号：
7392810
负责人：
BRADFORD B LOWELL
金额：
$ 30.75万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392810
关键词：
Adipocytes Alleles Animals Body Weight Brain Brain region Coenzyme A Diet Disease Eating Energy Intake Energy Metabolism Epidemic Functional disorder Genes Genetic Glucose Glutamates Goals Homeostasis Hyperphagia Hypothalamic structure Insulin Interneurons Knock-out LEPR gene Leptin Ligands Lipids Localized Malonyl Coenzyme A Mediating Messenger RNA Modeling Molecular Mus Nerve Neurons Neuropeptides Neurosciences Neurotransmitters Nutrient Obesity Output POMC gene Pathway interactions Play Principal Investigator Pro-Opiomelanocortin Protein Overexpression Reagent Research Research Personnel Resistance Role Role playing therapy Signal Transduction Site Societies Structure of nucleus infundibularis hypothalami Synaptic Vesicles Testing Thinking Transgenic Mice Weight Gain anorexigenic peptide energy balance fast-acting neurotransmitter gamma-Aminobutyric Acid in vivo inhibitor/antagonist interest leptin receptor lipid metabolism long chain fatty acid loss of function malonyl-CoA decarboxylase mutant neural circuit neurotransmitter release novel novel strategies prevent programs receptor recombinase sensor tool vesicular GABA transporter

项目摘要

The brain detects alterations in diet and energy balance, and through various neural circuits, regulates energy intake and energy expenditure; Dysfunction of these homeostatic mechanisms results in obesity, an epidemic problem in affluent societies. Identification of the neural circuits, as well as the molecular effecters operating within these circuits, is a major focus of obesity research. The arcuate nucleus of the hypothalamus is hypothesized to play a major role in controlling body weight. Thus, it is critical that the key inputs to and outputs from this site be identified. Leptin, secreted by adipocytes, is thought to be an important afferent signal to the arcuate where it inhibits AGRP/NPY neurons and activates POMC neurons. Lipid is another, recently identified, potentially important afferent signal. It has been proposed that lipid metabolism within arcuate neurons, most likely AGRP/NPY neurons, serves as an important sensor for nutrient availability. Efferent signals from the arcuate include the neuropeptides, AGRP, NPY and alphaMSH. aMSH, released by POMC neurons, is the only efferent signal whose importance has been validated by genetic studies. Thus, it is likely that other important efferent signals also exist. These other important efferent signals could be classic, fast-acting neurotransmitters. AGRP/NPY neurons release GABA (inhibitory) while POMC neurons, for the most part, release glutamate (excitatory). Whereas glutamatergic and GABAergic signaling by arcuate neurons is likely to play a critical role in controlling body weight, this has not yet been evaluated. Thus, the goal of the present application is to use genetic tools (cre/lox neuron-specific gene manipulations) to test hypotheses that leptin signaling (Aim #1), "lipid sensing" (Aim #2) and neurotransmitter release (glutamate and GABA) by AGRP/NPY and POMC neurons, play important roles in preventing obesity. Novel discoveries of pathways within the arcuate nucleus that restrict body weight gain could identify new causes of obesity, as well as new therapies for this epidemic disease.

大脑检测饮食和能量平衡的变化，并通过各种神经回路调节能量摄入和能量消耗;这些稳态机制的功能障碍导致肥胖，这是富裕社会的流行病问题。神经回路的识别，以及在这些回路中操作的分子效应器，是肥胖研究的主要焦点。下丘脑的弓状核被假设在控制体重中起主要作用。因此，确定该网站的关键投入和产出至关重要。脂肪细胞分泌的瘦素被认为是弓状核的重要传入信号，在弓状核中它抑制AGRP/NPY神经元并激活POMC神经元。脂质是另一个最近发现的潜在重要的传入信号。有人提出，脂质弓状神经元（最可能是AGRP/NPY神经元）内的代谢充当营养可用性的重要传感器。从弓状神经传出的信号包括神经肽、AGRP、NPY和alphaMSH。由POMC神经元释放的aMSH是唯一的传出信号，其重要性已被遗传研究证实。因此，可能还存在其他重要的传出信号。这些其他重要的传出信号可能是经典的、快速作用的神经递质。AGRP/NPY神经元释放GABA（抑制性），而POMC神经元在大多数情况下释放谷氨酸（兴奋性）。然而弓状神经元的谷氨酸能和GABA能信号可能在控制体重中起关键作用，这尚未得到评价。因此，本申请的目标是使用遗传工具（cre/lox神经元特异性基因操作）来测试瘦素信号传导（Aim#1）、“脂质传感”（Aim#2）和AGRP/NPY和POMC神经元的神经递质释放（谷氨酸和GABA）在预防肥胖中起重要作用的假设。弓状核内限制体重增加的途径的新发现可以确定肥胖的新原因，以及这种流行病的新疗法。