BEHAVIORAL PHYSIOLOGY OF BODY WEIGHT REGULATION

体重调节的行为生理学

• 批准号: 7878213
• 负责人: DIANNE FIGLEWICZ LATTEMANN
• 金额: $ 9.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878213
• 关键词: 1-Phosphatidylinositol 3-Kinase; Antisense Oligonucleotides; Area; Attention; Behavior; Behavioral; Body Weight; Chronic; Corn Oil; Diet; Dopamine; Dose; Eating; Economics; Effectiveness; Environment; Epidemic; Exposure to; Fatty acid glycerol esters; Food; Food Intake Regulation; Functional disorder; Goals; Hormones; Hyperphagia; Hypothalamic structure; Ingestion; Injection of therapeutic agent; Insulin; Insulin Receptor; Insulin Resistance; Intake; Laboratories; Learning; Leptin; Leptin resistance; Macronutrients Nutrition; Measures; Mediating; Messenger RNA; Midbrain structure; Middle Hypothalamus; Modeling; Motivation; Neuraxis; Neurons; Neurotransmitters; Obesity; Pathway interactions; Performance; Phosphorylation; Physiology; Procedures; Property; Prosencephalon; Rattus; Regulation; Relative (related person); Research Personnel; Rewards; Role; Self Administration; Severities; Signal Transduction; Site; Societies; Solutions; Specificity; Sucrose; Testing; United States; Ventral Tegmental Area; base; density; dopaminergic neuron; environmental change; feeding; genetic regulatory protein; indexing; insulin signaling; leptin receptor; neuronal cell body; novel; preference; programs; response; reward circuitry

DESCRIPTION (provided by applicant): The current 'epidemic' of obesity in the United States has been ascribed to environmental changes that have occurred over the past two decades. Prominent in this is the ready economic availability of highly palatable, high caloric density foods. Although numerous studies have focused on hormones such as insulin and leptin, and neurotransmitters, which act at the medial hypothalamus to regulate calorie intake, little attention has focused on the potential regulation of central nervous system (CNS) circuitry which mediates the rewarding or motivating aspects of food. This circuitry includes the midbrain dopamine neurons (DA) as well as other forebrain areas with which the medial hypothalamus has extensive direct and indirect connections. Our lab has evidence that the candidate adiposity signals insulin and leptin decrease performance in behavioral tasks that assess food reward and that require DA signaling. We hypothesize that the midbrain DA neurons whose cell bodies are in the ventral tegmental area (VTA) serve as a direct target for insulin and leptin. In this proposal we will test this hypothesis in rats by studying the effects of insulin or leptin infused directly into the VTA on behavioral procedures that evaluate different aspects of food reward/motivation: a free-feeding ingestive task, the conditioned place preference, and self-administration. We will compare sweet vs. fat food reward in these tasks, to evaluate macronutrient specificity. We will infuse insulin receptor antisense oligonucleotides directly into the VTA to determine the role of endogenous insulin signaling in modulation of food reward behavior. Because VTA DA neurons express insulin and leptin receptors, we will measure insulin- and leptin-stimulation of the PI3 kinase pathway as an index of direct VTA activation at the cellular level. Comparable studies will be carried out in rats fed a defined high fat diet snack in addition to chow, a model of CNS insulin resistance that we have recently developed. We will use this model to test whether the behavioral and cellular actions of insulin and/or leptin at the VTA are blunted by high fat diet ingestion, i.e., a model of VTA insulin or leptin resistance. Together these studies will evaluate the potential regulation of reward circuitry and function in the CNS by adiposity signals. Findings from these studies will contribute to the long-term goal of learning whether altered food reward value contributes to the (relative) overeating which occurs in association with the availability of highly palatable foods, independent of caloric need.

描述（由申请人提供）：美国目前的肥胖“流行病”归因于过去二十年发生的环境变化。这方面的突出特点是，高可口、高热量密度的食物可以随时经济地获得。虽然许多研究都集中在激素，如胰岛素和瘦素，和神经递质，在内侧下丘脑，以调节热量的摄入，很少注意集中在中枢神经系统（CNS）电路的潜在调节，介导的奖励或激励方面的食物。这个回路包括中脑多巴胺神经元（DA）以及与内侧下丘脑有广泛直接和间接联系的其他前脑区域。我们的实验室有证据表明，候选肥胖信号胰岛素和瘦素降低行为任务的性能，评估食物奖励和需要DA信号。我们推测，中脑DA神经元的细胞体是在腹侧被盖区（VTA）作为胰岛素和瘦素的直接目标。在这个建议中，我们将测试这一假设在大鼠中，通过研究胰岛素或瘦素直接注入腹侧被盖区的行为程序，评估不同方面的食物奖励/动机的影响：一个自由进食摄食任务，条件性位置偏好，自我管理。我们将在这些任务中比较甜食与脂肪食物的奖励，以评估大量营养素的特异性。我们将胰岛素受体反义寡核苷酸直接注入腹侧被盖区，以确定内源性胰岛素信号在调节食物奖励行为中的作用。由于腹侧被盖区DA神经元表达胰岛素和瘦素受体，我们将测量胰岛素和瘦素刺激的PI 3激酶途径作为直接腹侧被盖区激活在细胞水平的指标。将在大鼠中进行可比研究，这些大鼠除喂食普通食物外还喂食规定的高脂肪饮食零食，这是我们最近开发的CNS胰岛素抵抗模型。我们将使用该模型来测试胰岛素和/或瘦素在腹侧被盖区的行为和细胞作用是否被高脂肪饮食摄入所减弱，即，VTA胰岛素或瘦素抵抗模型。这些研究将共同评估肥胖信号对中枢神经系统奖赏回路和功能的潜在调节作用。这些研究的结果将有助于了解改变食物奖励值是否有助于（相对）暴饮暴食的长期目标，这种暴饮暴食与高可口食物的可用性有关，而与热量需求无关。