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.

项目摘要 尚不清楚新陈代谢，饮食和嗅觉功能的机制。复活 我国糖尿病和肥胖的发生率是流行病的，但据报道几乎没有报道 代谢影响感官系统以及是否可以通过更改逆转这些功能障碍 在饮食，药物干预或选择性基因组编辑中。该提案中的工作将弥合我们的差距 关于嗅球活动变化（OB）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 由电压依赖性钾通道KV1.3的操纵贡献，专门在专业中 输出神经元。我们的长期研究目标是了解嗅觉和代谢如何相互关联 - 揭示嗅觉输出神经元如何传达代谢信息。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KV1.3通道 提高动作电势射击频率并选择性降低后载体放大器，有选择地 提高葡萄糖清除率，增加总能量消耗并降低呼吸道交换比率 （增加脂肪利用率），这将导致体重下降或对饮食引起的抗性 肥胖（Dio）。 （2）假设2 =气味刺激将诱导C-FOS表达的特定模式 小鼠下丘脑和其他大脑区域。 DIO将通过使用 正常的KV1.3传导，但在类似喂养的情况下，但抗Dio的小鼠有选择地编辑KV1.3 来自二尖瓣/簇状细胞。 （3）假设3 =在二尖瓣/簇细胞中选择性地恢复Kv1.3活性，但 不在外围或降低兴奋性会导致对DIO的抗性损失，如人体所测量 重量，葡萄糖耐受性和系统生理学参数。我们的实验进行多学科 使用电生理学，基因组编辑和代谢分析的方法，以发现 能量稳态的传递嗅觉信息。我们拟议的研究产生的知识 定义嗅球输出对代谢平衡的影响可以降低健康状况 全球肥胖和粮食过量消耗问题的后果。重点是 我们研究了高丘脑大脑区域的协调以确定其对能量的贡献 平衡 - 嗅觉系统的新颖且聪明地具有挑战性的观点。