CENTRAL DOPAMINE RECEPTORS IN OBESITY

描述(由申请人提供)：中枢多巴胺被认为在肥胖中起着重要作用。为了支持这一观点，动物研究和一项人类正电子发射断层扫描(PET)研究发现，肥胖患者纹状体突触后D2样受体的可用性降低，D2受体的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。这些报道导致了这样一个概念，即多巴胺能异常(例如，D2样受体减少)会影响奖赏敏感性，导致进食行为改变，最终导致肥胖。然而，有几个关键的限制限制了他们结论的力度，从而限制了依赖于这项工作的文献中的解释和推测。首先，人类对D2样受体的估计受到内源性多巴胺释放的潜在差异的干扰，因为已知使用的PET配体(拉氯普利)可以通过内源性多巴胺取代受体。其次，未能严格筛查肥胖者的糖尿病会混淆结论，因为糖尿病与多巴胺能异常是独立相关的。最后，没有人类研究表明，D2样受体水平降低是否是肥胖的风险因素，是参与肥胖相关行为或肥胖的后果，还是以上所有因素的结果。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，与拉氯普利不同，PET配体不与内源性多巴胺竞争，从而提供D2样受体(NMB)的明确测量。肥胖和苗条的受试者将被扫描和测试被认为与多巴胺和肥胖有关的行为特征(例如，对奖励的敏感性)(时间1)。然后，肥胖的受试者将被分配到一个减肥计划中，其中包括密集的监测以及饮食和行为教育。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)D2样受体减少的明确测量有关，个体的D2样受体状态是否与多巴胺相关的个性特征和体重减轻有关。这一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是必不可少的。 与公共健康相关：这个项目将解决肥胖的神经生物学基础。我们将确定肥胖时大脑中的多巴胺受体是否减少，以及它们是否受到体重减轻的影响。此外，我们还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部影响。

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.