Sympathetic activation in obesity

肥胖症中的交感神经激活

• 批准号: 10412286
• 负责人: Renata Da Silva Belfort De Aguiar
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-12 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412286
• 关键词: Adipose tissue; Adrenal Glands; Animals; Area; Back; Binding; Body mass index; Brain; Brown Fat; Carbohydrates; Cardiometabolic Disease; Cardiovascular Diseases; Cervical; Data; Diabetes Mellitus; Fasting; Fatty acid glycerol esters; Food; Functional disorder; Gold; Heart; Homeostasis; Human; Hypothalamic structure; Individual; Insulin Resistance; Kidney; Liver; Measurement; Measures; Modeling; Muscle; Neuraxis; Neurons; Norepinephrine; Obesity; Organ; Pancreas; Participant; Pathogenesis; Pattern; Peripheral; Play; Positron-Emission Tomography; Process; Randomized; Rattus; Recycling; Rest; Rodent; Role; Scanning; Sex Differences; Signal Transduction; Skeletal Muscle; Source; Sprague-Dawley Rats; Stimulus; Supraclavicular; Sympathetic Nervous System; Synapses; System; Testing; Thalamic structure; Thinness; Time; Tissues; Visit; Weight; Woman; cardiometabolic risk; comorbidity; deltoid muscle; diabetes risk; food challenge; in vivo; longitudinal animal study; men; noradrenaline transporter; noradrenergic; obese person; radioligand; radiotracer; response

Project Summary Obesity is associated with an increased risk of diabetes and cardiovascular disease. Sympathetic nervous system (SNS) dysfunction has been described in individuals with obesity and may be implicated in the pathogenesis of obesity-related comorbidities. SNS regulates energy homeostasis by promoting a coordinated multi-organ response. Regionalized SNS hyperactivation of certain organs (fat, skeletal muscle and kidneys) but not others (adrenal glands, heart) has been observed in individuals with obesity. Dysfunctional coordination of SNS activation to target organs may explain the increased risk of cardiometabolic disorders in obesity. SNS activates target-organs by releasing norepinephrine (NE) which is then recycled back by pre-synaptic norepinephrine transporters (NET). Whole-body positron emission tomography (PET) with the radiotracer for norepinephrine transporters ((S,S)-11C-O- methylreboxetine ([11C]MRB) has been used to quantify NET availability in vivo in humans and rodents in: a) peripheral tissues (brown and white adipose tissues and skeletal muscle); and b) in the central nervous system. Studies using [11C]MRB PET imaging showed that NET-availability in brown adipose tissue (BAT) was reduced in women with obesity. In addition, [11C]MRB binding in skeletal muscle (deltoid) inversely correlated with body mass index (BMI) in healthy women. Therefore, to determine whether regionalized SNS activation of target organs is altered by obesity, healthy men and women with normal body mass index (BMI) and with obesity will undergo whole body [11C]MRB PET imaging and microneurography (gold standard test for assessment of muscle SNS activity). To further investigate the impact of obesity in coordinating SNS multi-organ activation, SNS activity will be also measured in response to a food challenge. Parallel animal studies will be performed to clarify the relationship between peripheral and central NET dynamics and the time course of which each of these NET sources change as obesity develops. Whole body [11C]MRB PET imaging allows simultaneous multi-organ measurements and this project will help further understand the impact of obesity in SNS activity. Dysregulated coordination of SNS activity may play a role in the pathophysiology of obesity-related cardiometabolic disorders.

项目概要 肥胖与糖尿病和心血管疾病的风险增加有关。 交感神经系统 (SNS) 功能障碍已在患有以下疾病的个体中得到描述 肥胖，并可能与肥胖相关合并症的发病机制有关。社交网络服务 通过促进协调的多器官反应来调节能量稳态。 某些器官（脂肪、骨骼肌和肾脏）局部 SNS 过度激活，但 在肥胖个体中没有观察到其他（肾上腺、心脏）。 SNS 激活与靶器官的功能失调可能解释了 肥胖导致心脏代谢紊乱的风险。 SNS 通过释放去甲肾上腺素 (NE) 激活靶器官，然后再循环利用 由突触前去甲肾上腺素转运蛋白（NET）返回。全身正电子发射 使用去甲肾上腺素转运蛋白放射性示踪剂 ((S,S)-11C-O- 甲基瑞波西汀 ([11C]MRB) 已用于量化人类体内 NET 的可用性 和啮齿类动物：a) 外周组织（棕色和白色脂肪组织和骨骼 肌肉）; b) 在中枢神经系统中。使用 [11C]MRB PET 成像的研究 研究表明，患有以下疾病的女性棕色脂肪组织 (BAT) 中的 NET-可用性降低 肥胖。此外，[11C]MRB 在骨骼肌（三角肌）中的结合与 健康女性的体重指数（BMI）。因此，要判断是否区域化 肥胖、正常的健康男性和女性会改变目标器官的 SNS 激活 体重指数 (BMI) 和肥胖者将接受全身 [11C]MRB PET 成像 和显微神经造影（评估肌肉 SNS 活动的金标准测试）。到 进一步研究肥胖对协调SNS多器官激活、SNS的影响 还将测量针对食物挑战的活动。平行动物研究将 澄清外围和中央 NET 动态之间的关系 以及随着肥胖的发展，这些 NET 来源中的每一个发生变化的时间过程。 全身 [11C]MRB PET 成像可同时进行多器官测量 该项目将有助于进一步了解肥胖对 SNS 活动的影响。失调 SNS 活动的协调可能在肥胖相关的病理生理学中发挥作用 心脏代谢紊乱。