A Picture is Worth 1000 Calories: The Neuroimaging of Obesity

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，肥胖症患者的过度进食行为与中枢多巴胺回路失调有关。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依赖性降低。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。这些转运蛋白一起分别调节纹状体和皮质中细胞外多巴胺水平，这些区域与奖励，习惯和认知控制密切相关。这表明受损的中枢胰岛素信号传导，例如在接受致肥胖饮食的动物中观察到的，可以通过钝化纹状体和增强皮质多巴胺清除，导致介导食物获取和过度消费的系统的功能障碍。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，将进行纵向核和功能成像，以检查胰岛素的能力，正常化失调的纹状体和皮质多巴胺神经传递肥胖。此外，多巴胺神经传递和胰岛素的影响之间的相互作用，特别是对前额叶皮层功能的抑制控制将被检查。本研究的首要目的是评估中枢胰岛素水平的重置是否会使相反的皮质和纹状体多巴胺失调正常化，从而减少进食行为，逐渐导致肥胖。这个申请人设计的项目利用并扩展了一个更大的正在进行的由医生发起的以患者为导向的临床研究，为申请人提供了参与跨越神经科学，内分泌学和生物医学成像领域的直接转化研究的机会。拟议的研究计划为所有这些领域提供来自领先的医生科学家和研究人员的指导和培训、神经科学和神经成像课程以及生物医学成像和糖尿病研究的著名机构资源。该培训计划整合了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，旨在直接翻译动物和人类研究。培训计划强调先进的神经影像学研究所需的技能的获取和发展，包括教学和课外培训功能和分子神经影像学。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将最终为目前全球肥胖流行病的治疗和管理提供信息。

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.