Urocortins Brain CRF2 Receptors and Energy Balance

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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.