Urocortins Brain CRF2 Receptors and Energy Balance

尿皮质素大脑 CRF2 受体和能量平衡

• 批准号: 7892017
• 负责人: ERIC P ZORRILLA
• 金额: $ 4.42万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892017
• 关键词: Acute; Affinity; Animals; Anorexia; Appetite Depressants; Basal metabolic rate; Behavioral; Biological; Body Composition; Body Weight; Body Weight decreased; Brain; Breeding; Carbohydrates; Cephalic; Chronic; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Desire for food; Diet; Eating; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Feeding Patterns; Food; Genetic Predisposition to Disease; Genotype; Hyperphagia; Indirect Calorimetry; Individual; Infusion procedures; Insulin; Leptin; Ligands; Long-Term Effects; Malaise; Measures; Metabolic; Metabolism; Mutant Strains Mice; Neuropeptides; Obesity; Output; Overweight; Peptides; Property; Public Health; Rattus; Receptor Activation; Recording of previous events; Resistance; Rewards; Role; Satiation; Schedule; Signal Transduction; Site; Specificity; Stress; System; Testing; Variant; Weight Gain; blood glucose regulation; energy balance; feeding; glucose tolerance; innovation; interest; medical complication; novel; obesity risk; obesity treatment; receptor; therapeutic target; tool; urocortin

DESCRIPTION (provided by applicant): Type 2 urocortins, novel ligands for corticotropin-releasing factor type 2 (CRF2) systems, retain their central anorectic properties in rats fed an energy dense "cafeteria" diet composed of palatable high fat and refined carbohydrate foods. This finding is promising because developing insensitivity to anorectics is an obstacle to obesity treatment. The present application hypothesizes that brain corticotropin- releasing factor type 2 (CRF2) systems are downstream components of the endogenous counter-regulatory system that curbs body weight gain. Acute and chronic effects of intracranial infusion of selective CRF2 ligands will be studied in rat lines selectively bred for differential vulnerability to diet-induced obesity. Neuropharmacologic studies will be performed under different dietary conditions, some of which promote obesity, to determine whether the anorectic properties of type 2 urocortins are retained despite obesity risk, high-fat diet history or manifest obesity. Indirect calorimetry and pair-feeding studies will examine metabolic components of the body weight-altering effects of CRF2 ligands in relation to genotype and diet with brain- site specificity. Long-term effects of continuous, intra-parenchymal CRF2 ligand treatment on adiposity and glucose regulation will be compared in treatment-free states. The role of CRF receptors in the energy balance-related effects of central leptin and insulin infusion will be tested using subtype-specific antagonists. Innovative forms of microstructure analysis and progressive schedules of operant responding will be used to identify the behavioral construct through which type 2 urocortins control food intake. Alternative explanations, such as malaise, will be considered. The proposed studies would identify general and brain CRF receptor- related differences in feeding patterns and metabolism that are associated with obesity and diet history. Relevance: Effective obesity treatments are few in part because obese individuals become resistant to biological signals that otherwise help regulate body weight. Brain mechanisms that can still promote weight loss in obese individuals and those with access to palatable foods are of great public health interest. The present application uses new pharmacological tools to study the role of a recently identified neuropeptide system in the control of body weight, via changes in appetite and metabolism, findings which may identify a therapeutic target for the treatment of obesity and its related medical complications.

描述（由申请人提供）：2型尿素素，用于皮质激素释放因子2型（CRF2）系统的新型配体，保留了喂食能量密集的“自助餐地”饮食的大鼠中的中心厌食特性，该特性由可紫罗兰色的高脂肪和精制碳水化合物和精制碳水化合物组成。这一发现很有希望，因为对厌食症产生不敏感是肥胖治疗的障碍。目前的应用假设脑皮质激素 - 释放因子2型（CRF2）系统是内源性反调节系统的下游组件，可抑制体重增加体重。颅内输注选择性CRF2配体的急性和慢性作用将在大鼠系中进行选择性研究，以繁殖，以使饮食诱导的肥胖症的差异差异。神经药物研究将在不同的饮食条件下进行，其中一些促进肥胖症，以确定尽​​管肥胖风险，高脂饮食史或明显的肥胖症，但仍保留了2型尿道素的厌食特性。间接的量热法和成对喂养研究将检查CRF2配体与基因型和饮食具有脑部特异性有关的改变体重的代谢成分。在无治疗状态中，将比较连续的，核内CRF2配体处理对肥胖和葡萄糖调节的长期影响。 CRF受体在中央瘦素和胰岛素输注的能量平衡相关作用中的作用将使用亚型特异性拮抗剂进行测试。微观结构分析的创新形式和操作响应的渐进时间表将用于确定行为构造，通过哪种2型尿道素控制食物的摄入。将考虑其他解释，例如不适。拟议的研究将确定与肥胖和饮食史相关的喂养模式和代谢方面的一般和脑CRF受体差异。相关性：有效的肥胖治疗很少，部分原因是肥胖个体对有助于调节体重的生物信号具有抵抗力。仍然可以促进肥胖个体体重减轻的大脑机制和获得可口食品的人具有很大的公共卫生利益。本应用使用新的药理学工具来研究最近确定的神经肽系统在控制体重，通过食欲和代谢的变化来控制体重，这些发现可能鉴定出治疗肥胖症及其相关医疗并发症的治疗靶点。