Previous work in our laboratory as part of the present program project grant has contributed significantly to our understanding of the role of central nervous system corticotropin-releasing factor (CRF) and urocortin (Ucn) peptides and their receptors in behavioral responses to stressors and energy regulation. In the previous funding period, differential effects of CRF/Ucn systems and CRF1 and CRF2 receptors both in the extended amygdala and the periphery were shown for stress-like behavior and modulation of appetite. The purpose of the experiments outlined in the present proposal are to build on these results and test the overall hypothesis that CRF/Ucn-related peptides have functional roles in the central nervous system and periphery to modulate behavioral and physiological responses to stressors in the domain of excessive energy intake. A subhypothesis is that CRF/Ucn activation, via CRF1 receptors in the extended amygdala, mediates the withdrawal-like aversive responses that contribute to binge-like eating. A second subhypothesis is that excessive, binge-like intake drives dysregulation in peripheral CRF/Ucn systems that contribute to prediabetic syndromes and obesity risk. A third subhypothesis is that rats selectively bred for vulnerability to diet-induced obesity show dysregulation of their CRF/Ucn systems that resemble those elicited by environmental models of binge eating. To test these hypotheses, in Specific Aim 1, the functional significance of alterations in the extended amygdala CRF/Ucn system for the stress-like behavior of rats withdrawn from diet-induced bingeing will be explored.
In Specific Aim 2, the functional significance of peripheral CRF/Ucn systems in the glucose regulation, whole-body metabolism and obesity risk of rats exposed to diet-induced bingeing will be explored.
In Specific Aim 3, functional alterations in central or peripheral CRF/Ucn systems produced by binge eating will be explored in rats with differential genetic vulnerability to obesity. Results of the present series of studies will provide key information regarding the roles of CRF/Ucn-related peptides in stress-like responses associated with dysregulation of appetite and energy balance. As a result, the results may provide insight into the role of CRF/Ucn systems in several stress-related pathologies of energy homeostasis, including obesity, binge-eating disorder, and diabetes.

Public Health Relevance

The proposed studies will provide key functional insight into the biological roles of the CRF/urocortin systems in the stress-like responses associated with dysregulation of appetite and energy balance. Stress contributes significantly to obesity, binge-eating disorders, and diabetes, and the proposed studies seek to identify a biological mechanism for such pathology. Results obtained will not only provide new targets for treating disorders or stress and appetite but may identify individuals vulnerable for such pathology.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Salk Institute for Biological Studies
La Jolla
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