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.

项目总结 新陈代谢、饮食和嗅觉功能之间的联系机制还不是很清楚。正在崛起的 我国糖尿病和肥胖症的发病率是流行的，但关于糖尿病和肥胖症的慢性程度的报道却很少。 代谢失衡对感觉系统的影响以及这些功能障碍是否可以通过改变来逆转 在饮食、药物干预或选择性基因组编辑方面。这项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平衡的知识。 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-- 以揭示嗅觉输出神经元是如何传递代谢信息的。我们提出的目标是基于 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的放电频率和降低超极化后的幅度 增强葡萄糖清除，增加总能量消耗，降低呼吸交换率 (增加脂肪利用率)，这将导致体重下降或对饮食诱导的抵抗 肥胖(DIO)。(2)假设2=气味刺激会诱导c-fos表达的特定模式 小鼠的下丘脑和其他脑区。Dio将减弱c-fos在对照组小鼠中的激活 Kv1.3传导正常，但在类似喂养但抗DIO的小鼠中，Kv1.3被选择性编辑 来自二尖瓣/簇状细胞。(3)假设3=在二尖瓣/簇状细胞中选择性地恢复Kv1.3的活性，但是 不在外周，或兴奋性降低将导致身体对DIO的抵抗力丧失 体重、糖耐量和系统生理参数。我们的实验需要一个多学科的 使用电生理学、基因组编辑和代谢图谱的方法来揭示 传递嗅觉信息以实现能量动态平衡。从我们提议的研究中产生的知识 确定嗅球输出对新陈代谢平衡的影响可以用来降低健康 全球日益严重的肥胖和过度食物消费问题的后果。这是一个高度优先的问题 我们研究下丘脑外脑区的协调，以确定它们对能量的贡献。 平衡--嗅觉系统的一种新颖的、具有智力挑战性的观点。