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（由申请人提供）：肥胖是一个严重的公共卫生问题，与多种疾病（包括心血管疾病、糖尿病、肌肉骨骼疾病和癌症）的死亡率和风险增加相关。肥胖个体的体重减轻减少了许多这些风险因素，但体重减轻和维持可能非常困难。显然，开发治疗肥胖的新方法是一个重要目标，也是NIH肥胖研究战略计划的关键组成部分。治疗肥胖症的一种可能的新机制是α 7烟碱胆碱能受体的激活。尼古丁与体重减轻的关系，以及它抑制食欲、增加能量消耗和改变进食模式的能力已得到充分证实。最近的证据表明，α 7烟碱受体可能在这些效应中发挥特别突出的作用。我们小组分别研究非精神病受试者食物摄入行为的神经元机制和精神分裂症中烟碱胆碱能功能障碍的神经生物学的最新发现出人意料地收敛，表明肥胖个体中过度活跃的一些相同的大脑内在网络成分被患者中的α 7烟碱受体激动剂下调。鉴于这些作用，我们最近进行了α 7烟碱受体部分激动剂3- 2，4-二甲氧基苯亚甲基假木贼碱（DMXB-A）对患者的体重、食欲和对视觉食物线索的反应的神经元测量的作用的初步研究。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减少有关。在神经元方面，DMXB-A与我们先前发现的与肥胖倾向个体相比，瘦人群对食物摄入的反应有关的相同大脑区域的改变有关。我们还发现，DMXB-A相关的对食物线索的反应变化与体重变化有关。考虑到这些初步结果，以及动物研究中出现的证据，α 7烟碱受体的激活可能是改变一般人群中超重/肥胖个体的食物摄入行为的神经元过程并改善体重管理的新机制。本申请的总体目标是了解α 7烟碱受体部分激动剂对一般人群中肥胖的神经、生理和行为机制的影响。希望这项研究的结果将告知 我们对烟碱胆碱能参与肥胖的认识，可能导致新的治疗策略，以解决对健康和生活质量产生负面影响的关键问题。