| dc.description.abstract | Chronic consumption of a high-fat diet leads to development of diet-inducedobesity (DIO) with significant variability in humans and rodents. This variability is associated with individual differences in intrinsic levels of spontaneous physical activity (SPA). The neurobiological basis of SPA is distributed across multiple brain regions and involves multiple neuropeptides, including the orexins. The orexin peptides and their two receptors are involved in multiple physiologicalprocesses, including energy homeostasis, arousal, stress and reward. Highersignaling of the orexin peptides at the orexin receptors protects against obesity, probably through increases in SPA, but it is less clear how orexin signaling through individual brain sites contributes to individual sensitivity to diet-induced obesity. In a polygenic model of obesity, the obesity-prone (OP) and obesity-resistant (OR) rats, the OR phenotype correlates with higher SPA1NT and SPA induced by injection of OXA in the rostral lateral hypothalamus, RLH. Also, the higher levels of SPA1NT in OR rats are predictive of lower fat mass gain throughout their lifetime. These data suggest that a decrease in SPA1NT and changes in orexin function are related to higher DIO sensitivity. However, studies of DIO in nonselectivelybred rodents are inconclusive about effects of DIO in SPA1NT The studies conducted in this thesis aimed at testing two hypotheses: (1) sensitivity to DIO is mediated by decreased SPA and activity of the orexins in the rostral lateral hypothalamus (2) intrinsic variability in SPA is related to orexin signaling and predicts DIO sensitivity. The first part of this present work shows that that variability in DIO sensitivity is mediated through adaptations in theactivity of the orexin peptides and their receptors. First, resistance to DIO isassociated with an increase in SPA. Analysis of orexin receptors expressionshowed that DIO resistance is associated with increased receptor expression insites that mediate orexin's effect on SPA, including the RLH. Furthermore, daily injections of orexin peptide in RLH prevent DIO development, probably throughshort-term SPA increase. The second part of the work presentad in this thesis focused the analysis of orexin activity and sensitivity to diet-induced obesity in non-manipulated male Sprague Dawley rats selected for differences in intrinsic SPA. This work defined a new model of differential DIO sensitivity; the high-activity and low activity-rats.These results suggest that naturally occurring variations in intrinsic SPA aremediated by differences in orexin signaling in RLH, which affect DIO sensitivity. In summary, the work conducted in this thesis shows that individual sensitivity to DIO depends on specific adaptations of orexin signaling in the RLH. These results illustrate the complexity surrounding the brain adaptations following development of DIO. | |
