A Genetic-Neuroanatomic Dissection of MC4R function

MC4R 功能的遗传神经解剖学剖析

• 批准号: 7128354
• 负责人: BRADFORD B LOWELL
• 金额: $ 33.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128354
• 关键词: amygdala; bioenergetics; brain mapping; cell surface receptors; gamma aminobutyrate; gene expression; genetically modified animals; glutamates; hypothalamus; laboratory mouse; lenticular nucleus; neural transmission; neuroanatomy; nutrient intake activity; overeating; paraventricular nucleus; receptor expression

DESCRIPTION (provided by applicant): 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 last decade has seen the discovery of a number of proteins that are critical components of this system. 1 such protein is the meIanocortin-4-receptor (MC4R), a G-protein-coupled receptor expressed by a number of neurons in the brain. The essential role of MC4Rs is evident from the presence of severe obesity in both gene knockout mice and in humans with naturally occurring mutations. In the case of Mc4r null mice, in which energy balance has been studied in great detail, obesity has been found to be caused by the combined effects of increased food intake (hyperphagia) and decreased energy expenditure. While the importance of MC4R signaling is clear, the neural substrate responsible for MC4R-mediated regulation of food intake and energy expenditure is presently unknown. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB-Mc4r) that can be re-activated by Cre-recombinase (Balthasar et al., Cell, IN PRESS). Mice homozygous for the loxTB-Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that there is disassociation in pathways controlling energy balance and that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. In work proposed in the present application, we will use loxTB-Mc4r mice, as well as Iox-Mc4r mice, in combination with various transgenic mice expressing Cre-recombinase in different, potentially important groups of neurons, to identify the specific neurons that mediate MC4R's effects on food intake and energy expenditure. This information will facilitate the construction of a wiring diagram of energy homeostasis.

描述（申请人提供）：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。这些体内平衡机制的功能障碍导致肥胖，这是富裕社会的一个普遍问题。识别神经回路，以及在这些回路中运作的分子效应，是肥胖研究的主要焦点。在过去的十年里，我们发现了许多蛋白质，它们是这个系统的关键组成部分。这种蛋白是meanocortin -4受体（MC4R），一种g蛋白偶联受体，由大脑中的许多神经元表达。MC4Rs的重要作用从基因敲除小鼠和自然发生突变的人类中存在的严重肥胖中可以明显看出。在Mc4r缺失小鼠的情况下，对能量平衡进行了非常详细的研究，发现肥胖是由食物摄入增加（嗜食）和能量消耗减少的综合作用引起的。虽然MC4R信号的重要性是明确的，但负责MC4R介导的食物摄入和能量消耗调节的神经底物目前尚不清楚。为了确定MC4R表达的功能相关位点，我们生成了一个loxp修饰的空MC4R等位基因（loxTB-Mc4r），该等位基因可以被Cre-recombinase重新激活（Balthasar等人，Cell, IN PRESS）。loxTB-Mc4r等位基因纯合的小鼠不表达MC4Rs，并且明显肥胖。使用Sim1-Cre转基因小鼠，恢复室旁下丘脑（PVH）和杏仁核神经元亚群中MC4R的表达，可以防止60%的肥胖。值得注意的是，增加的食物摄入量（典型的Mc4r缺失小鼠）完全获救，而减少的能量消耗不受影响。这些发现表明，在控制能量平衡的途径中存在分离，PVH和/或杏仁核中的MC4Rs控制食物摄入，但其他地方的MC4Rs控制能量消耗。在本申请中提出的工作中，我们将使用loxTB-Mc4r小鼠以及Iox-Mc4r小鼠，与各种在不同的潜在重要神经元组中表达Cre-recombinase的转基因小鼠结合，以确定介导MC4R对食物摄入和能量消耗影响的特定神经元。这些信息将有助于构建能量稳态接线图。