Behavioral Physiology of Body Weight Regulation

描述(申请人提供)：非内环境平衡因素对最近在美国等西方人中肥胖率上升的贡献现已得到认可。美味的高卡路里密度食物的现成供应和可负担性；调节动机和奖励的反应中枢神经系统通路的激活；内分泌肥胖信号在中枢神经系统作用的有效性的丧失，所有这些都可能导致过多的热量摄入。我们的实验室一直专注于候选肥胖信号胰岛素和瘦素在调节“食物奖励行为”方面的潜在作用。胰岛素和瘦素作用于下丘脑内侧，调节能量平衡；它们也作用于中枢神经系统，调节奖赏和动机。两者都会降低评估食物奖励的行为任务的表现。这种情况发生在影响长期能量平衡的阈值以下的剂量，这表明胰岛素和瘦素的奖赏抑制效应与它们减少食物摄入量和调节体重的慢性效应无关。我们最近的研究表明，下丘脑弓状内侧核(ARC)和腹侧被盖区(VTA)都是胰岛素和瘦素抑制食物奖赏的直接作用部位；高脂饮食背景逆转了胰岛素和瘦素的作用。这些新的见解导致了新的问题，将通过追求下面概述的具体目标来解决这些问题。这些目标将评估胰岛素和瘦素对食物奖赏调节的解剖学、行为学和发育方面。长期目标是描述与饮食或营养状态相关的调节食物奖励的行为和突触机制。目前的目标将通过评估：1)胰岛素、瘦素或细胞信号抑制物调节行为任务中表现的能力，模拟饮食复发，复发到寻求蔗糖；2)高脂饮食经历对青春期前和青春期后大鼠蔗糖自我给药的影响；以及3)响应蔗糖自我给药而激活的中枢神经系统部位，以及胰岛素、瘦素或细胞信号抑制物对这种激活的调节。这些研究将阐明调节食物奖励的关键大脑区域和细胞信号通路，并成为胰岛素和瘦素的靶标。这可能为针对非动态型“奖赏”喂养的潜在治疗干预策略提供基础，这是一种与美国成年人和儿童人口都相关的公共健康问题。

DESCRIPTION (provided by applicant): The contribution of non-homeostatic factors to the recent increase of obesity incidence in Westernized populations such as the U.S., has now come to be appreciated. Ready availability and affordability of palatable, high caloric density foods; activation of responsive CNS pathways that mediate motivation and reward; and loss of effectiveness of endocrine adiposity signals to act at the CNS, may all contribute to excess caloric intake. Our lab has focused on the potential role of the candidate adiposity signals insulin and leptin to modulate 'food reward behavior'. Insulin and leptin act at the medial hypothalamus to regulate energy homeostasis; they also act at CNS sites that mediate reward and motivation. Both decrease performance in behavioral tasks which assess food reward. This occurs at doses that are subthreshold for effects on long-term energy homeostasis, which suggests that the reward-suppressive effects of insulin and leptin are independent of their chronic effects to decrease food intake and regulate body weight. Our recent studies demonstrate that both the medial hypothalamic arcuate nucleus (ARC) and the ventral tegmental area (VTA) are direct sites of action for insulin and leptin to inhibit food reward; and that the effectiveness of insulin and leptin is reversed by high fat diet background. These new insights lead to new questions which will be addressed by pursuing the Specific Aims summarized below. These Aims will evaluate anatomical, behavioral, and developmental aspects of food reward modulation by insulin and leptin. The long-term objective is to delineate the behavioral and synaptic mechanisms that modulate food reward, in relationship to diet or nutritional status. The current Aims will build towards that objective by evaluating: 1) the ability of insulin, leptin, or cell signaling inhibitors to modulate performance in a behavioral task that models diet recidivism, relapse to sucrose-seeking; 2) the effect of high fat diet experience on sucrose self-administration in pre- and post-pubertal rats; and 3) the CNS sites activated in response to sucrose self-administration and modulation of this activation by insulin, leptin, or cell-signaling inhibitors. These studies will elucidate key brain regions and cell signaling pathways which modulate food reward and are targets for insulin and leptin. This could provide the basis for potential therapeutic intervention strategies targeting non-homeostatic, 'reward-based' feeding, a public health problem that is relevant for both adult and pediatric populations in the U.S.