Nicotinic Agonist Effects on BMI and Neuronal Response in Overweight/Obese Adults

烟碱激动剂对超重/肥胖成人的 BMI 和神经元反应的影响

• 批准号: 8960808
• 负责人: JASON R TREGELLAS
• 金额: $ 43.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-06 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960808
• 关键词: Address; Adult; Affinity; Agonist; Animal Model; Animals; Anterior; Behavior; Behavioral; Behavioral Mechanisms; Body Weight; Body Weight Changes; Body Weight decreased; Body fat; Brain; Brain region; Cardiovascular Diseases; Cholinergic Receptors; Cognition; Coronary heart disease; Cues; Desire for food; Diabetes Mellitus; Disease; Dopamine; Eating; Energy Intake; Energy Metabolism; Fatty acid glycerol esters; Feeding Patterns; Food; Food Intake Regulation; Functional disorder; General Population; Goals; Health; Human; Hunger; Hypothalamic structure; Individual; Insula of Reil; Knowledge; Malignant Neoplasms; Measures; Mentally Ill Persons; Metabolic; Musculoskeletal Diseases; Neuroanatomy; Neurobiology; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Obesity; Outcome; Overweight; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Placebos; Play; Process; Public Health; Quality of life; Research; Research Design; Rest; Rewards; Risk; Risk Factors; Role; Satiation; Schizophrenia; Strategic Planning; Study models; United States National Institutes of Health; Ventral Striatum; Visual; Weight; Weight Gain; Weight maintenance regimen; anabaseine; behavior measurement; cholinergic; feeding; hypertensive heart disease; improved; increased appetite; mortality; mouse model; nerve supply; novel; novel strategies; public health relevance; receptor expression; response; treatment strategy; weight maintenance

 DESCRIPTION (provided by applicant): Obesity is a profound public health issue, associated with increased mortality and risk for multiple diseases, including cardiovascular disease, diabetes, musculoskeletal disorders, and cancer. Weight loss in obese individuals reduces many of these risk factors, but weight loss and maintenance can be extremely difficult. Clearly, developing new approaches to treat obesity is an important goal, and is a key component of the Strategic Plan for NIH Obesity Research. A possible novel mechanism for treating obesity is activation of the a7 nicotinic cholinergic receptor. Nicotine's association with reduced body weight, and its ability to suppress appetite, increase energy expenditure and alter feeding patterns is well established. Recent evidence suggests that the a7 nicotinic receptor may play a particularly prominent role in these effects. Recent findings by our group separately examining the neuronal mechanisms of food intake behavior in non-mentally ill subjects and the neurobiology of nicotinic cholinergic dysfunction in schizophrenia unexpectedly have converged, showing that some of the same brain intrinsic network components that are overactive in obese individuals are down-modulated by an a7 nicotinic receptor agonist in patients. Given these effects, we recently conducted an initial study of the effect of the a7 nicotinic receptor partial agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A) on weight, appetite and neuronal measures of the response to visual food cues in patients. These measures were an add- on outcome of a study designed to examine drug effects on cognition. Compared to placebo, DMXB-A was associated with significant weight loss and a reduction in hunger and appetite. Neuronally, DMXB-A was associated with alterations in the same brain regions we previously found to be involved in the response to food intake in lean compared to obese-prone individuals. We also found that the DMXB-A-associated change in insula response to food cues was related to weight change. Considering these preliminary results, and emerging evidence from animal studies, activation of a7 nicotinic receptors may be a novel mechanism to alter neuronal processes of food intake behavior and improve weight management in overweight/obese individuals in the general population. The overall goal of this application is to understand the effects of an a7 nicotinic receptor partial agonist on neuronal, physiological, and behavioral mechanisms of obesity in the general population. It is hoped that results of this study will inform our knowledge of nicotinic cholinergic involvement in obesity, potentially leading to novel treatment strategies to address a critical problem that negatively impacts health and quality of life.

 描述(申请人提供)：肥胖是一个深刻的公共卫生问题，与死亡率和多种疾病的风险增加有关，包括心血管疾病、糖尿病、肌肉骨骼疾病和癌症。肥胖者的减肥可以减少许多这些风险因素，但减肥和维持体重可能非常困难。显然，开发治疗肥胖症的新方法是一个重要的目标，也是NIH肥胖研究战略计划的关键组成部分。治疗肥胖症的一个可能的新机制是激活A7烟碱能胆碱能受体。尼古丁与减轻体重的关系，以及它抑制食欲、增加能量消耗和改变进食模式的能力已经得到了很好的证实。最近的证据表明，A7尼古丁受体在这些效应中可能发挥着特别突出的作用。我们团队最近分别研究了非精神病患者食物摄入行为的神经机制和精神分裂症患者尼古丁胆碱能功能障碍的神经生物学研究结果出人意料地收敛，表明肥胖个体中一些过度活跃的大脑内部网络成分在患者中被一种A7尼古丁受体激动剂下调。鉴于这些效应，我们最近进行了一项关于A7尼古丁受体部分激动剂3-2，4二甲氧基亚甲基Anabaseine(DMXB-A)对患者体重、食欲和神经元对视觉食物提示反应的影响的初步研究。这些措施是一项旨在检查药物对认知影响的研究的附加结果。与安慰剂相比，DMXB-A与显著的体重减轻以及饥饿和食欲的减少有关。在神经方面，DMXB-A与我们之前发现的与肥胖倾向者相比，与瘦人对食物摄入的反应有关的大脑区域的变化有关。我们还发现，脑岛对食物暗示的反应中DMXB-A相关的变化与体重变化有关。考虑到这些初步结果和来自动物研究的新证据，A7尼古丁受体的激活可能是一种新的机制，可以改变一般人群中超重/肥胖个体的摄食行为的神经过程，并改善体重管理。这项应用的总体目标是了解A7尼古丁受体部分激动剂对普通人群肥胖的神经元、生理和行为机制的影响。希望这项研究的结果将为 我们对烟碱胆碱能参与肥胖的了解，可能会导致新的治疗策略，以解决对健康和生活质量产生负面影响的关键问题。