| Popis: |
An emerging model is that CNS fuel sensors, such as AMP kinase (AMPK) and the mammalian target of rapamycin (mTOR), integrate signals from stored and immediately available fuels, and in turn regulate food intake. The experiments described in this dissertation focus on novel CNS fuel sensing mechanisms by which fatty acid derivatives and compounds that affect fatty acid metabolism modulate food intake. Oleoylethanolamide (OEA), a derivative of oleic acid synthesized in the intestine following refeeding, reduces food intake. OEA shares similarities with other nutrient-derived hormones that signal energy status to the CNS, but its mechanisms of action remain unclear. We tested whether OEA-induced anorexia occurs through specific interactions with hormones that modulate food intake through CNS pathways involved in energy homeostasis, or is rather due to unspecific behaviors. Our results indicate that OEA suppresses feeding without causing visceral illness, and that neither ghrelin, PYY, GLP-1, apo A-IV nor CCK play a critical role in this effect. OEA is not the only fatty acid metabolism related compound that suppresses food intake. C75 is a fatty acid synthase inhibitor that inhibits food intake via direct actions in the CNS. MTOR, a member of the phosphatidylinositol kinase-related protein kinase family, plays a crucial role in nutrient sensing and the control of protein synthesis. Its inhibition stimulates food intake in rats. We hypothesized that C75-induced anorexia depends on its ability to activate the mTOR pathway in the hypothalamus. Consistent with this hypothesis, C75 increases the phosphorylation of key components of the mTOR pathway and inhibitors of mTOR reverse C75-induced anorexia. Previous work showed that C75 is ineffective when rats are on a ketogenic diet. Consistent with a role for mTOR in mediating the effects of C75, C75-induced anorexia and activation of the mTOR pathway were abolished in rats maintained on a ketogenic diet. Together, these data argue that neuronal nutrient metabolism is monitored by CNS fuel sensors and contribute to the regulation of food intake. |
