A Picture is Worth 1000 Calories: The Neuroimaging of Obesity

描述(申请人提供)：肥胖相关疾病是全球第五大致死原因。肥胖是糖尿病、心血管疾病、癌症和骨关节炎的主要风险因素。越来越多的动物和人类研究表明，在肥胖的过度进食行为中，中枢多巴胺回路的放松调控。对肥胖者的神经成像研究显示，纹状体多巴胺受体水平随着体重指数的增加而降低。有趣的是，胰岛素增强了多巴胺转运体(DAT)的表面表达，而抑制了去甲肾上腺素转运体(NET)的表达。这些转运体一起分别调节纹状体和皮质中的细胞外多巴胺水平，这两个区域与奖励、习惯和认知控制密切相关。这表明，中枢胰岛素信号受损，如在肥胖饮食中观察到的那样，可能通过钝化纹状体和增强皮质多巴胺清除，导致调节食物获取和过度消费的系统的功能障碍。在这项研究中，胰岛素信号轻微受损的肥胖者，随机接受胰岛素或安慰剂治疗，将接受纵向核成像和功能成像，以检查胰岛素对肥胖患者纹状体和皮质多巴胺神经传递的正常化能力。此外，我们还将研究多巴胺神经传递与胰岛素对抑制控制前额叶皮质功能的影响之间的相互作用。这项研究的主要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去调节亚单位正常化，以服务于逐渐导致肥胖的摄食行为。这一由申请者设计的项目利用并扩展了一项更大的、正在进行的、由研究者发起的、以患者为导向的临床研究，为申请者提供了直接从事横跨神经科学、内分泌学和生物医学成像领域的转化性研究的机会。拟议的研究计划提供所有这些领域的指导和培训，来自领先的内科科学家和研究人员、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。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，目的是直接转化动物和人类研究。培训计划强调获取和发展高级神经成像研究所需的技能，包括功能和分子神经成像的教学和课外培训。外源性胰岛素是否以有益的方式调节多巴胺的神经传递和行为，这一发现最终将为当前全球肥胖症流行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.