CNS Dopamine as Marker for Obesity Predisposition: Link to Food and Drug Reward

描述（由申请人提供）：膳食肥胖是全球范围内快速增长的流行病，解决这一公共卫生问题的有效方法是必要的。进食的享乐方面在肥胖流行中的作用尚不清楚，其研究可能揭示介导对自然和药物奖励的易感性或抗性的共同机制。该建议的重点是了解饮食肥胖倾向和涉及食物和d-安非他明奖励的中枢多巴胺系统之间的联系。我们假设（到目前为止已经证实），大鼠的近亲繁殖肥胖倾向（OP）表型的特征是低中枢多巴胺音调和减少多巴胺对食物和d-安非他明等刺激的反应。多巴胺反应的减少可能导致增加实验室食物或安非他明摄入量的补偿。下调多巴胺音调的蛋白质是肥胖易感性的潜在新标记。适当的干预可以通过微调中枢多巴胺分泌来改变OP表型对放纵刺激（如高能量饮食或精神兴奋剂）的易感性。该建议的具体目的包括考虑：1)肥胖易感性如何与体重差异出现前后以及餐前或安非他明挑战前后的多巴胺释放动力学相关；2)中枢多巴胺胞分泌的调节蛋白是否为肥胖易感性的标志物；3)改变OP表型的发育和分子干预。近亲繁殖的OP和肥胖抗性（OR）大鼠将被自始至终使用，因为它们在相同的饮食中产生体重差异，并允许与饮食历史相关的影响区分开来。通过有利于体重增加的多基因遗传，OP大鼠密切模仿人类肥胖易感性。遵循多层次的方法，我们建议描述体内多巴胺的释放和行为；急性切片和原代细胞培养的实时多巴胺胞吐多巴胺胞吐调节因子的mRNA和蛋白水平。初步结果表明，成年远交系肥胖大鼠和近交系OP大鼠的基础、食物挑战和安非他明挑战的细胞外多巴胺水平较低。成年OP大鼠的酪氨酸羟化酶mRNA水平较低，而新生OP大鼠多巴胺细胞培养的水泡单胺转运蛋白（VMAT2）蛋白水平较低。改变OP表型和相关中枢多巴胺神经传递的干预措施包括：在第PO天将OP窝与OR母鼠一起放置，OP大鼠伏隔核中VMAT2过表达，以及OP大鼠和OR大鼠配对喂养。

DESCRIPTION (provided by applicant): Dietary obesity is a fast growing epidemic worldwide and effective approaches for addressing this public health problem are necessary. The involvement of hedonic aspects of feeding in the obesity epidemic is still unclear and its study may reveal common mechanisms that mediate susceptibility or resistance to natural and drug rewards. This proposal focuses on understanding the link between dietary obesity predisposition and central dopamine systems implicated in food and d-amphetamine rewards. We hypothesize (and so far have confirmed) that the inbred obesity-prone (OP) phenotype in the rat is characterized by low central dopamine tone and reduced dopamine response to stimuli like food and d-amphetamine. The reduced dopamine response may lead to compensation with increased laboratory chow or amphetamine intake. Proteins that downregulate the dopamine tone are potential novel markers of obesity predisposition. Appropriate interventions may alter the susceptibility of the OP phenotype to indulgent stimuli (like high-energy diets or psychostimulants) by fine-tuning central dopamine exocytosis. The specific aims of this proposal include considering: 1) how obesity predisposition is linked to dopamine release kinetics before and after body weight differences arise and before and after a meal or an amphetamine challenge 2) whether regulatory proteins of central dopamine exocytosis are markers for obesity predisposition 3) developmental and molecular interventions that alter the OP phenotype. Inbred OP and obesity-resistant (OR) rats will be used throughout as they develop a weight difference while on the same diet and allow for distinction from diet history-related effects. OP rats closely model human obesity predisposition through polygenic inheritance favoring weight gain. Following a multi-level approach, we propose to profile in vivo dopamine release and behavior; real-time dopamine exocytosis in the acute slice and primary cell culture; and mRNA and protein levels of regulators of dopamine exocytosis. Preliminary results show that adult outbred obese and inbred OP rats had lower basal, meal-challenged and amphetamine-challenged extracellular dopamine levels. Tyrosine hydroxylase mRNA levels were low in OP adults, while the vesicular monoamine transporter (VMAT2) protein levels were low in OP neonatal rat dopamine cell cultures. Proposed interventions to alter the OP phenotype and associated central dopamine neurotransmission include placement of OP litters with OR dames at day PO, VMAT2 over expression in the nucleus accumbens of OP rats, and pair feeding of OP and OR rats.