Obesity has reached epidemic proportions in the United States, and both genetic and environmental contributions to the development and maintenance of obesity have been identified in human studies and animal models. Analyses of rodent models of genetic obesity have illuminated hypothalamic signaling pathways related to the overall control of metabolism and energy balance. The majority of these have involved deficits in aspects of the leptin signaling pathway. The obese Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking CCK1 receptors is a unique genetic model of obesity in that it appears to have deficits in both a peripheral gut-brain peptide signaling pathway critical to the within meal control of food intake and in hypothalamic signaling pathways that are independent of leptin. OLETF rats are obese and hyperphagic, and we have shown that their hyperphagia, characterized by increased meal size, accounts for the obesity. Experiments under the first specific aim will characterize the contributions of vagal and dorsal medial hypothalamic (DMH) CCK-A receptors in the disordered meal patterns and overall hyperpagia and evaluate the role of DMH overexpression of NPY in their hyperphagia. In the second specific aim, we will follow up on our studies demonstrating the ability of exercise to normalize food intake and body weight in OLETF rats. These experiments will assess interactions between exercise and diet, assess a role for DMH corticotrophin releasing peptide (CRF) in mediating the effects of exercise and use microarracy techniques in an attempt to identify novel factors that contribute to both the short and long term effects of exercise. Experiments under the third specific aim will examine the role of maternal influences in the development of hyperphagia and obesity. Preliminary results demonstrate that cross fostering control Long Evans Tokushima Otsuka (LETO) pups to OLETF dams results in obesity in male offspring. Proposed experiments will investigate the basis of this phenomenon both from the standpoint of the maternal factors involved and how that experience modifies patterns of connectivity and gene expression in the brains of the developing pups. Together, results from these studies will: 1) characterize the mechanisms underlying the hyperphagia and obesity in OLETF rats, 2) identify exercise induced factors that modify the effects of disordered peripheral satiety and hypothalamic signaling, and 3) identify developmental influences that may bias towards obesity.
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