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：
8715798
负责人：
KRISTEN ECKSTRAND
金额：
$ 1.98万
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 2015-05-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715798
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 public health relevance 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.

描述（由申请人提供）：肥胖相关疾病是全球第五大死亡原因。肥胖是患糖尿病、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表明，中枢多巴胺回路的失调与肥胖症的过度进食行为有关。对肥胖个体的神经影像学研究揭示了纹状体多巴胺受体水平的BMI依赖性下降。有趣的是，胰岛素增强多巴胺转运蛋白（DAT）的表面表达，同时抑制去甲肾上腺素转运蛋白（NET）的表面表达。这些转运蛋白共同调节纹状体和皮层的细胞外多巴胺水平，这些区域与奖励、习惯和认知控制密切相关。这表明中枢胰岛素信号传导受损，例如在食用致胖饮食的动物中观察到的情况，可能会通过减弱纹状体和增强皮质多巴胺清除率，导致介导食物获取和过度消费的系统功能受损。在这项研究中，胰岛素信号轻度受损的肥胖个体，随机接受胰岛素或安慰剂，将接受纵向核和功能成像，以检查胰岛素使肥胖中失调的纹状体和皮质多巴胺神经传递正常化的能力。此外，还将检查多巴胺神经传递与胰岛素对抑制控制的前额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枢胰岛素张力的重置是否会使相反的皮质和纹状体多巴胺失调正常化，从而服务于逐渐导致肥胖的进食行为。该申请人设计的项目利用并扩展了正在进行的、由研究者发起的以患者为导向的更大规模的临床研究，为申请人提供了参与神经科学、内分泌学和生物医学成像领域的直接转化研究的机会。拟议的研究计划在所有这些领域提供来自领先医师科学家和研究人员、神经科学和神经影像课程以及生物医学成像和糖尿病研究的知名机构资源的指导和培训。该培训计划整合了围绕临床研究环境中神经内分泌功能障碍的路径生理学的医学和科学知识的核心原则，旨在直接转化动物和人类研究。培训计划强调先进神经影像研究所需技能的获取和发展，包括功能和分子神经影像方面的教学和课外培训。外源性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当前全球肥胖流行病的治疗和管理提供信息。