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。 与公共健康相关：基于可获得的廉价、非常美味的食物，而且恰好也是高糖和高脂肪的食物，过度摄入卡路里导致目前成年人和儿童人口肥胖严重程度和患病率的增加，这是一个巨大的公共卫生问题。我们已经确定了两种可以抑制这种基于奖励的喂养的动物模型的激素，并提议研究它们在大脑中的什么位置以及它们是如何在大脑中发挥作用的(因为使用这些激素本身作为治疗或行为干预的基础是不可行的)。重要的是，我们正在跟进新的试点数据，这些数据表明，在我们的实验室中，年轻大鼠比成年大鼠更有动力使用甜食解决方案，我们观察到了高脂肪饮食的效果。因此，我们的实验模拟了美国等西化社会中人们饮食习惯的一个方面，并可能为应对这种过量摄入提供翻译上的洞察。

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. PUBLIC HEALTH RELEVANCE: The contribution of excessive calorie intake, based on the availability of inexpensive, highly palatable food that also happens to be high in sugar and fat, to the current increase in obesity severity and prevalence among both adult and pediatric populations is an enormous public health problem. We have identified two hormones which can curb animal models of this reward-based feeding, and propose to study where in the brain and how in the brain they are having their effects (since use of these hormones themselves as the basis for therapeutic or behavioral interventions is not a viable possibility). Importantly we are following up on new pilot data that suggest that young rats are more motivated for sweet solutions than adult rats in our lab, and we observe an effect of high fat diet. Our experiments thus model one aspect of the eating habits of people in 'Westernized' societies such as the U.S. and may provide translational insight into dealing with this excessive intake.