A Picture is Worth 1000 Calories: The Neuroimaging of Obesity

一张照片值 1000 卡路里：肥胖的神经影像学

基本信息

批准号：
8456802
负责人：
KRISTEN ECKSTRAND
金额：
$ 3.61万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2015-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8456802
关键词：
Animals Area Behavior Behavioral Binding Body Weight Body Weight decreased Brain Calories Cardiovascular Diseases Cause of Death Cell membrane Chronic Disease Clinical Research Complex Corpus striatum structure Cues Data Degenerative polyarthritis Development Diabetes Mellitus Diet Disinhibition Dopamine Dopamine D2 Receptor Dopamine Receptor Dorsal Down-Regulation Eating Endocrinology Epidemic Epinephrine Feeding behaviors Food Functional Imaging Functional disorder Goals Habits Human Hyperphagia Image Impairment Individual Insulin Insulin Resistance Interneurons Knowledge Lead Ligands Link Malignant Neoplasms Maps Measurable Measures Mediating Medical Medication Management Mentorship Molecular Neurosciences Neurosecretory Systems Nuclear Obesity Obesity associated disease Overweight Participant Physicians Physiology Placebos Positron-Emission Tomography Prefrontal Cortex Process Public Health Randomized Regulation Research Research Personnel Research Project Grants Resources Rewards Risk Risk Factors Role Scientist Signal Transduction Surface Synapses System Training Translating Translational Research Visit Weight Weight Gain arm bioimaging blood oxygen level dependent cognitive control design dopamine transporter executive function expectation extracellular follow-up functional disability insulin signaling meetings neural circuit neuroimaging neurotransmission noradrenaline transporter obesity treatment patient oriented peripheral blood prevent programs response reward circuitry skills trafficking

项目摘要

DESCRIPTION (provided by applicant): Obesity-associated disease is the fifth leading cause of death worldwide. Obesity is a major risk factor for the development of diabetes, cardiovascular disease, cancer and osteoarthritis. A growing body of animal and human studies implicates deregulation of central dopamine circuits in excessive feeding behavior in obesity. Neuroimaging studies of obese individuals reveal a BMI-dependent decrease in striatal dopamine receptor levels. Interestingly, insulin enhances the surface expression of the dopamine transporter (DAT) while inhibiting that of the nor epinephrine transporter (NET). Together these transporters tune extracellular dopamine levels in the striatum and cortex respectively, areas critically involved in reward, habits, and cognitive control. This suggests tha impaired central insulin signaling, such as has been observed in animals placed on an obesogenic diet could, by blunting striatal, and enhancing cortical dopamine clearance, result in functional impairments in systems mediating food acquisition and overconsumption. In this study, obese individuals with mild impaired insulin signaling, randomized to receive insulin or placebo, will undergo longitudinal nuclear and functional imaging to examine insulin's ability to normalize deregulated striatal and cortical dopamine neurotransmission in obesity. Further, the interaction between dopamine neurotransmission and the effects of insulin specifically on prefrontal cortical function of inhibitory control will be examined. The overarching aim of this study is to assess whether the resetting of central insulin tone will normalize the opposing cortical and striatal dopamine deregulation sub serving the feeding behavior that progressively leads to obesity. This applicant-designed project exploits and expands upon a larger ongoing investigator-initiated patient-oriented clinical study, providing the applicant the opportunity to engage in directly translational research spanning the fields of neuroscience, endocrinology, and biomedical imaging. The proposed research program provides mentorship and training in all of these areas from leading physician scientists and researchers, neuroscience and neuroimaging coursework, and renowned institutional resources for both biomedical imaging and diabetes research. The training plan integrates the core principles of medical and scientific knowledge surrounding the path physiology of neuroendocrine dysfunction in the clinical research setting with the aim of directly translating animal and human research. The training plan emphasizes the acquisition and development of skills required for advanced neuroimaging research, including didactic and extracurricular training in functional and molecular neuroimaging. The finding of whether exogenous insulin modulates dopamine neurotransmission and behavior in a way that is beneficial will ultimately inform the current treatment and management of the global obesity epidemic. PUBLIC HEALTH RELEVANCE: The obesity epidemic places over 1.5 billion people worldwide at risk for multiple chronic illnesses, including diabetes, cardiovascular disease, osteoarthritis, and cancer. This patient-oriented, translational research project unites molecular and functional neuroimaging to examine the role of obesity-associated impairment in insulin signaling on brain function, and will provide evidence for how optimizing pharmacologic management of obesity can prevent continued weight gain and obesity associated disease.

描述（由申请人提供）：与肥胖相关的疾病是全球死亡的第五个主要原因。肥胖是糖尿病，心血管疾病，癌症和骨关节炎的主要危险因素。越来越多的动物和人类研究的身体暗示肥胖过度喂养行为中中央多巴胺回路的放松管制。肥胖个体的神经影像学研究表明，纹状体多巴胺受体水平的BMI依赖性降低。有趣的是，胰岛素增强了多巴胺转运蛋白（DAT）的表面表达，同时抑制了Nor肾上腺素转运蛋白（NET）的表面表达。这些转运蛋白分别在纹状体和皮质中分别调节细胞外多巴胺水平，与奖励，习惯和认知控制非常重要的区域。这表明中央胰岛素信号传导受损，例如在肥胖饮食上的动物中观察到的，可以通过钝化纹状体和增强皮质多巴胺清除率，从而导致介导食物习得和过量食品的系统中的功能障碍。在这项研究中，肥胖的个体患有轻度胰岛素信号传导，随机接受胰岛素或安慰剂，将经过纵向核和功能成像，以检查胰岛素在肥胖症中胰岛素正常化的失调的纹状体和皮质多巴胺神经传递的能力。此外，将检查多巴胺神经传递与胰岛素对抑制性控制前额叶皮质功能的影响之间的相互作用。这项研究的总体目的是评估中央胰岛素张力的重置是否将相反的皮质和纹状体多巴胺放松管制范围标准化，从而逐渐导致肥胖症。该申请人设计的项目利用并扩展了一个正在进行的研究者启动的面向患者的临床研究，这为申请人提供了跨越神经科学，内分泌学和生物医学成像领域的直接转化研究的机会。拟议的研究计划提供了所有这些领域的指导和培训，这些领域的医师科学家和研究人员，神经科学和神经影像学课程以及著名的生物医学成像和糖尿病研究的机构资源。该培训计划将围绕神经内分泌功能障碍的路径生理的医学和科学知识的核心原则整合在一起，目的是直接翻译动物和人类研究。培训计划强调了高级神经成像研究所需的技能的获取和发展，包括功能和分子神经影像学中的教学和课外训练。外源胰岛素是否以有益的方式调节多巴胺神经传递和行为的发现最终将为全球肥胖症的当前治疗和管理提供信息。公共卫生相关性：肥胖流行病全球超过15亿人有多种慢性病的风险，包括糖尿病，心血管疾病，骨关节炎，和癌症。这个面向患者的转化研究项目将分子和功能性神经影像统一，以检查肥胖相关损伤在胰岛素信号传导中的作用，并将提供证据证明如何优化肥胖症的药理学管理可以防止持续的体重增加和肥胖与肥胖相关的疾病。