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: 9307811
• 负责人: JASON R TREGELLAS
• 金额: $ 35.42万
• 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/9307811
• 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; 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; Thinness; United States National Institutes of Health; Ventral Striatum; Visual; Weight; Weight Gain; Weight maintenance regimen; anabaseine; behavior measurement; cholinergic; feeding; hypertensive heart disease; improved; 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.