CENTRAL DOPAMINE RECEPTORS IN OBESITY

描述（由申请人提供）：中枢多巴胺被认为在肥胖症中起重要作用。为了支持这一观点，动物研究和一项人体正电子发射断层扫描（PET）研究发现，肥胖症患者纹状体中突触后D2样受体的可用性降低，D2受体可用性降低与体重增加相关。此外，已知与多巴胺功能有关的奖赏敏感性也与肥胖和肥胖相关的饮食行为有关。这些报告导致了多巴胺能异常（例如D2样受体减少）影响奖赏敏感性的概念，导致饮食行为改变并最终导致肥胖。然而，有几个关键的限制，限制了他们的结论的强度，从而限制了依赖这项工作的文献中嵌入的解释和推测。首先，由于已知所用的PET配体（雷氯必利）可被内源性多巴胺从受体中置换，因此内源性多巴胺释放的潜在差异混淆了对人体D2样受体的估计。其次，由于糖尿病与多巴胺能异常独立相关，因此未能严格筛查肥胖个体的糖尿病混淆了结论。最后，没有人类研究涉及D2样受体水平降低是否是肥胖的风险因素，这是参与肥胖相关行为或肥胖或上述所有因素的结果。为了澄清这些问题，我们建议测量突触后D2样受体与PET配体的结合，与雷氯必利不同，它不与内源性多巴胺竞争，因此提供了一种无混淆的D2样受体（NMB）测量方法。将对肥胖和偏瘦受试者进行扫描，并测试被认为与多巴胺和肥胖相关的行为特征（例如，奖赏敏感性）（时间1）。然后，肥胖受试者将被分配到一个减肥计划，其中包括强化监测和饮食和行为教育。今年年底，所有受试者将再次接受扫描和测试（时间2）。结果将确定肥胖状态是否与特定大脑区域（例如腹侧纹状体和下丘脑）中减少的D2样受体的无混淆测量有关，个体的D2样受体状态是否与多巴胺相关的人格特征和体重减轻有关。这些信息对于准确定义中枢多巴胺系统在肥胖中的作用以及将该领域的动物和人类文献联系起来至关重要。 公共卫生相关性：该项目将解决肥胖的神经生物学基础。我们将确定大脑中的多巴胺受体是否在肥胖中减少，以及它们是否受到减肥的影响。此外，我们将确定多巴胺受体是否与肥胖相关的行为有关。这些信息将有助于设计新的肥胖干预措施，并了解肥胖对大脑的全面影响。

DESCRIPTION (provided by applicant): Central dopamine is thought to play a significant role in obesity. In support of this idea, animal studies and one human positron emission tomography (PET) study have found reduced postsynaptic D2-like receptor availability in the striatum in obesity, with lower D2 receptor availability associated with higher weight. In addition, reward sensitivity, known to be related to dopamine function, has also been implicated in obesity and obesity-related eating behavior. These reports have led to the concept that dopaminergic abnormalities (e.g. reduced D2-like receptors) influence reward sensitivity, leading to altered eating behaviors and eventually obesity. However, there are several critical limitations that limit the strength of their conclusions and thus the interpretations and speculations embedded in literature that relies on this work. First, estimates of D2-like receptors in humans have been confounded by potential differences in endogenous dopamine release since the PET ligand (raclopride) used is known to be displaceable from receptors by endogenous dopamine. Second, failure to rigorously screen obese individuals for diabetes confounds conclusions, since diabetes has been independently associated with dopaminergic abnormalities. Finally, no human studies have addressed whether reduced D2-like receptor levels are a risk factor for obesity, a consequence of engaging in obesity related behaviors or being obese or all of the above. To clarify these issues, we propose to measure postsynaptic D2-like receptor binding with a PET ligand that, unlike raclopride, does not compete with endogenous dopamine and thus provides an unconfounded measure of D2-like receptors (NMB). Obese and lean subjects will be scanned and tested for behavioral features thought to be associated with dopamine and obesity (e.g. reward sensitivity) (Time 1). Obese subjects then will be assigned to a weight loss program that includes intensive monitoring and dietary and behavioral education. At the end of this year, all subjects will be scanned and tested again (Time 2). Results will determine if obesity status is associated with unconfounded measurements of reduced D2-like receptors in specific brain regions (e.g. ventral striatum and hypothalamus), whether individuals' D2-like receptor status is associated with dopamine-linked personality traits and with weight loss. This information is essential for accurately defining the role of the central dopamine system in obesity and for linking animal and human literature in this field. PUBLIC HEALTH RELEVANCE: This project will address the neurobiological underpinnings of obesity. We will determine whether dopamine receptors in the brain are reduced in obesity and whether they are affected by weight loss. In addition, we will determine whether dopamine receptors are related to behaviors that are associated with obesity. This information will be useful in devising new interventions for obesity and understanding the full effect of obesity on the brain.