Urocortins Brain CRF2 Receptors and Energy Balance

尿皮质素大脑 CRF2 受体和能量平衡

• 批准号: 8007028
• 负责人: ERIC P ZORRILLA
• 金额: $ 9.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007028
• 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型尿皮质素，促肾上腺皮质激素释放因子2型（CRF2）系统的新型配体，在喂食由可口的高脂肪和精制碳水化合物食物组成的能量密集“自助餐厅”饮食的大鼠中保留其中枢厌食特性。这一发现是有希望的，因为发展对减食欲药的不敏感性是肥胖治疗的障碍。本申请假设脑促肾上腺皮质激素释放因子2型（CRF2）系统是抑制体重增加的内源性反调节系统的下游组分。选择性CRF2配体颅内输注的急性和慢性效应将在选择性饲养的大鼠品系中进行研究，以区分对饮食诱导的肥胖的易感性。神经药理学研究将在不同的饮食条件下进行，其中一些促进肥胖，以确定2型尿皮质素的厌食特性是否保留，尽管肥胖风险，高脂饮食史或明显肥胖。间接量热法和配对喂养研究将检查CRF2配体的体重改变效应的代谢组分与基因型和饮食的关系，具有脑部位特异性。将在无治疗状态下比较连续脑实质内CRF2配体治疗对肥胖和血糖调节的长期影响。CRF受体在中枢瘦素和胰岛素输注的能量平衡相关效应中的作用将使用亚型特异性拮抗剂进行测试。创新形式的微观结构分析和渐进的时间表的操作性反应将被用来确定的行为结构，通过2型尿皮质素控制食物的摄入。将考虑其他解释，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的一般和大脑CRF受体相关差异。相关性：有效的肥胖治疗方法很少，部分原因是肥胖个体对生物信号产生了抵抗力，而这些信号原本有助于调节体重。仍然可以促进肥胖个体和那些能够获得可口食物的人减肥的大脑机制具有巨大的公共卫生利益。本申请使用新的药理学工具来研究最近鉴定的神经肽系统在通过食欲和代谢的变化控制体重中的作用，这些发现可以鉴定用于治疗肥胖症及其相关医学并发症的治疗靶标。