Probing the link between sensory systems and metabolism to prevent obesity

探索感觉系统和新陈代谢之间的联系以预防肥胖

• 批准号: 10659964
• 负责人: DEBRA Ann FADOOL
• 金额: $ 47.4万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-25 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659964
• 关键词: Acceleration; Action Potentials; American; Anosmia; Area; Attenuated; Blood Glucose; Body Weight; Body Weight decreased; Body Weights and Measures; Body fat; Brain; Brain region; CRISPR/Cas technology; Cell Nucleus; Cells; Chronic; Circulation; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Consumption; Country; Cre lox recombination system; Diabetes Mellitus; Diet; Drops; Educational workshop; Electrophysiology (science); Energy Metabolism; Epidemic; Equilibrium; Excision; Exercise; FOS gene; Fatty acid glycerol esters; Frequencies; Functional disorder; Genes; Genetic; Glucose; Goals; Health; Heart; Homeostasis; Hypothalamic structure; Incidence; Insulin Resistance; Intervention; Knockout Mice; Knowledge; Kv1.3 potassium channel; Lead; Link; Maps; Metabolic; Metabolic dysfunction; Metabolism; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Deafness and Other Communication Disorders; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Odors; Olfactory Pathways; Output; Overweight; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Play; Potassium Channel; Property; Quantum Dots; Reporting; Research; Resistance; Role; Sensory; Serology; Signal Transduction; Slice; Smell Perception; Synapses; System; Testing; Therapeutic Intervention; Vestibule; Viral; Washington; Weight Gain; Work; Workload; biophysical properties; diet-induced obesity; energy balance; experimental study; food consumption; genome editing; glucose tolerance; improved; inhibitor; interdisciplinary approach; metabolic phenotype; mouse model; nanoparticle; neural; neuronal excitability; novel; nutrition; obesity prevention; olfactory bulb; olfactory sensory neurons; prevent; respiratory; restoration; sensory system; total energy expenditure; voltage

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.

项目概要 新陈代谢、饮食和嗅觉功能之间的联系机制尚不清楚。 我国糖尿病和肥胖症的发病率呈流行趋势，但其慢性程度却鲜有报道。 代谢失衡会影响感觉系统以及这些功能障碍是否可以通过改变来逆转 该提案中的工作将弥补我们在饮食、药物干预或选择性基因组编辑方面的差距。 有关嗅球 (OB) 活动的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 我们的长期研究目标是了解嗅觉和新陈代谢如何相互关联 - 揭示嗅觉输出神经元如何传递代谢信息。 以下三个假设： (1) 假设 1 = 消除二尖瓣/簇状细胞中的 Kv1.3 通道将 选择性地增加动作电位放电频率并降低后超极化幅度 增强葡萄糖清除率，增加总能量消耗，降低呼吸交换率 （增加脂肪利用率），这会导致体重下降或对饮食引起的抵抗力 (2) 假设 2 = 气味刺激会诱导体内 c-fos 表达的特定模式。 小鼠下丘脑和其他大脑区域的 DIO 会减弱对照小鼠的 c-fos 激活。 Kv1.3 传导正常，但在类似喂养但具有 DIO 抗性的 Kv1.3 被选择性编辑的小鼠中则不然 (3) 假设 3 = 在二尖瓣/簇状细胞中选择性恢复 Kv1.3 活性，但是 不在外周，或者兴奋性下降会导致身体对 DIO 的抵抗力下降 我们的实验采用了多学科的方法。 使用电生理学、基因组编辑和代谢分析的方法来揭示 传递能量稳态的嗅觉信息。 定义嗅球输出对代谢平衡的影响可用于减轻健康状况 日益严重的全球肥胖和过量食物消费问题的后果是一个高度优先事项。 我们研究下丘脑外大脑区域的协调以确定它们对能量的贡献 平衡——对嗅觉系统的一种新颖且具有智力挑战性的观点。