Probing the link between sensory systems and metabolism to prevent obesity

项目摘要 代谢、饮食和嗅觉功能之间的联系机制还不清楚。上升 糖尿病和肥胖症在我国的发病率是流行病，但很少有关于慢性 代谢失衡影响感觉系统，以及这些功能障碍是否可以通过改变 饮食、药物干预或选择性基因组编辑。本提案中的工作将弥合我们在 关于嗅球（OB）活动变化如何改变能量稳态的知识。 为了测试OB兴奋性的变化如何导致体重和能量代谢的减少，我们将 操纵电压依赖性钾通道Kv1.3的贡献，仅在主要 输出神经元我们的长期研究目标是了解嗅觉和新陈代谢是如何相互关联的- 来揭示嗅觉输出神经元如何传递代谢信息。我们提出的目标是基于 以下三个假设：（1）假设1 =二尖瓣/簇状细胞中Kv1.3通道的消除将 选择性增加动作电位放电频率，降低后超极化幅度 提高葡萄糖清除率，增加总能量消耗，降低呼吸交换率 （增加脂肪利用率），这将产生体重下降或引起对饮食诱导的抵抗 肥胖（DIO）。(2)假设2：气味刺激会诱导细胞内c-fos表达的特定模式。 下丘脑和其他大脑区域。DIO将减弱对照小鼠的c-fos激活， 正常的Kv1.3传导，但在类似喂养但DIO抗性的小鼠中没有，其中Kv1.3被选择性编辑 来自二尖瓣/簇状细胞。(3)假设3 =二尖瓣/簇状细胞中选择性恢复Kv1.3活性，但 而不是在外周，或降低兴奋性将导致损失的阻力DIO作为衡量身体 体重、葡萄糖耐量和系统生理参数。我们的实验采取了多学科 使用电生理学，基因组编辑和代谢分析的方法来揭示 传递嗅觉信息以保持能量平衡从我们的研究中获得的知识 定义嗅球输出对代谢平衡的影响可以应用于减轻健康 全球肥胖和过度食品消费问题日益严重的后果。这是一个高度优先事项， 我们研究了下丘脑外脑区的协调性，以确定它们对能量的贡献。 平衡-嗅觉系统的一个新颖的和智力上具有挑战性的观点。

PROJECT SUMMARY The mechanism by which metabolism, diet, and olfactory function is linked is not well understood. The rising incidence of diabetes and obesity in our country is epidemic, yet little has been reported as to how chronic metabolic imbalance impacts sensory systems and whether these dysfunctions can be reversed via changes in diet, drug intervention, or selective genome editing. The work in this proposal will bridge gaps in our knowledge concerning how changes in activity of the olfactory bulb (OB) can modify energy homeostasis. To test how changes in OB excitability cause a reduction in body weight and energy metabolism, we will manipulate contribution from a voltage-dependent potassium channel, Kv1.3, exclusively in the major output neurons. Our long-term research goal is to understand how olfaction and metabolism are interrelated - to reveal how olfactory output neurons convey metabolic information. Our proposed aims are based upon the following three hypotheses: (1) Hypothesis 1 = Elimination of Kv1.3 channels in mitral/tufted cells will increase action potential firing frequency and decrease the after-hyperpolarization amplitude, selectively enhance glucose clearance, increase total energy expenditure, and decrease respiratory exchange ratio (increase fat utilization), which will produce a drop in body weight or cause a resistance to diet-induced obesity (DIO). (2) Hypothesis 2 = Odor stimulation will induce specific patterns of c-fos expression within the hypothalamus and other brain regions in mice. DIO will attenuate c-fos activation in control mice with normal Kv1.3 conduction, but not in similarly-fed, but DIO-resistant, mice in which Kv1.3 is selectively edited from mitral/tufted cells. (3) Hypothesis 3 = Restoration of Kv1.3 activity selectively in mitral/tufted cells, but not in the periphery, or decreased excitability will cause a loss in resistance to DIO as measured by body weight, glucose tolerance, and system physiology parameters. Our experiments take a multidisciplinary approach using electrophysiology, genome editing, and metabolic profiling to uncover the importance of relayed olfaction information for energy homeostasis. The knowledge generated from our proposed research defining the impact of olfactory bulb output on metabolic balance can be applied to lessen the health consequences of the rising global problem of obesity and excess food consumption. It is a high priority that we investigate coordination from extra-hypothalamic brain areas to determine their contribution to energy balance – a novel and intellectually challenging view of the olfactory system.