Behavioral Physiology of Body Weight Regulation

描述（由申请人提供）：非稳态因素对最近西方化人群（如美国）肥胖发病率增加的贡献，现在已经得到了重视容易获得和负担得起的美味，高热量密度的食物;激活中枢神经系统的反应途径，介导的动机和奖励;和内分泌肥胖症信号的有效性丧失，在中枢神经系统，都可能导致过量的热量摄入。我们的实验室一直专注于候选肥胖信号胰岛素和瘦素调节“食物奖励行为”的潜在作用。胰岛素和瘦素作用于内侧下丘脑以调节能量稳态;它们还作用于中枢神经系统部位，介导奖励和动机。两者都降低了评估食物奖励的行为任务的表现。这发生在对长期能量稳态的影响的亚阈值剂量下，这表明胰岛素和瘦素的奖励抑制作用与其减少食物摄入和调节体重的慢性作用无关。我们最近的研究表明，内侧下丘脑弓状核（ARC）和腹侧被盖区（VTA）是胰岛素和瘦素抑制食物奖励的直接作用部位;高脂饮食背景可逆转胰岛素和瘦素的有效性。这些新的见解导致了新的问题，这些问题将通过追求下文概述的具体目标来解决。这些目标将评估胰岛素和瘦素对食物奖赏调节的解剖学、行为学和发育学方面。长期的目标是描述调节食物奖赏的行为和突触机制，与饮食或营养状态的关系。目前的目标将通过评估以下方面来实现该目标：1）胰岛素、瘦素或细胞信号传导抑制剂调节行为任务中表现的能力，该行为任务模拟饮食再犯、对蔗糖寻求的复发; 2）高脂肪饮食经历对青春期前和青春期后大鼠中蔗糖自我给药的影响;和3）响应于蔗糖自身给药而激活的CNS位点和通过胰岛素、瘦素或细胞信号传导抑制剂对该激活的调节。这些研究将阐明调节食物奖励的关键脑区和细胞信号通路，并成为胰岛素和瘦素的靶点。这可能为针对非稳态、“基于奖励”的喂养的潜在治疗干预策略提供基础，这是一个与美国成人和儿科人群相关的公共卫生问题。 公共卫生相关性：过量的卡路里摄入，基于廉价的，非常可口的食物，也恰好是高糖和高脂肪的可用性，对目前成人和儿童人群中肥胖严重程度和流行率的增加的贡献是一个巨大的公共卫生问题。我们已经确定了两种激素，可以抑制这种基于奖励的喂养的动物模型，并建议研究它们在大脑中的位置以及如何在大脑中发挥作用（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，我们正在跟踪新的试点数据，这些数据表明，在我们的实验室中，年轻的大鼠比成年大鼠更有动力使用甜味溶液，我们观察到高脂肪饮食的影响。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，并可能为处理这种过量摄入提供翻译见解。

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.