Mechanisms Behind Illness-Induced Anorexia

Sammanfattning: Loss of appetite is together with fever and malaise hallmarks of infection. Loosing appetite during an acute infection such as influenza does not result in any longlasting effects, but loosing appetite during chronic diseases such as cancer or AIDS constitutes a risk factor for mortality. Food intake regulation during inflammation is orchestrated by the brain in response to peripheral inflammatory signals. It is known that expression of the prostaglandin synthesizing enzyme cyclooxygenase 2 (COX-2) is crucial for the mechanisms underlying inflammation-induced anorexia, and that prostaglandin E2 (PGE2) is involved in anorexia induced by interleukin-1 beta (IL-1β). In this thesis I examined the prostaglandin-pathways proposed to be involved in anorexia. We show that acute anorexia is dependent on COX-2 expression, while cancer-induced anorexia is mediated by cyclooxygenase 1 (COX-1), at least in the initial stages, suggesting that the signaling pathways for chronic- and acute anorexia are distinct. We were able to demonstrate that the pathway underlying acute anorexia is distinct from that of fever, and that taste aversion is prostaglandin independent. We could also show that both acute and chronic anorexia-cachexia is dependent on expression of myeloid differentiation primary response gene (MyD88) in hematopoietic/myeloid cells.In summary, the findings presented in this thesis suggest that anorexia is a result of many different signaling pathways, as opposed to what is the case for several other inflammatory symptoms such as fever and malaise, where the pathways have been shown to be very exclusive. This provides new insight into the diversity of the pathways underlying inflammatory symptoms, which is fundamental for the ability to present potential, symptom-specific drug targets.