This proposal will investigate the hypothesis that factors released by the immune system play a physiological role in the regulation of ingestive behavior by increasing the interval between meals. Following the establishment of baseline meal patterns for a powdered food diet in 16 rats, intravenous infusions of interleukin- 1B, interleukin-6, or tumor necrosis factor A will be administered at the end of the first meal of the night. A comparison between meal patterns will determine if the cytokines increase the length of time between meals. In addition, antibodies to the cytokines will be infused to determine if the time between meals can be shortened. Results from both experiments will demonstrate the involvement of certain cytokines in the normal, physiological maintenance of satiety between meals. These findings would provide the rationale for the possible use of these cytokines or their antibodies in two important health related areas: 1) the maintenance of feeding in anorexic patients (anorexia nervosa, as well as cachexia induced by illness or treatments such as chemotherapy) and 2) the reduction of food intake for the treatment of obesity. Positive results will provide the basis for a full investigation of the actions of cytokines in the pathophysiological and physiological maintenance of satiety. Those studies would include: 1) monitoring circulating cytokines before and after ingestion of nutrients to determine endogenous physiological levels of the cytokines released and to establish how those levels compare with levels after exogenous administration, 2) the effects of combinations of cytokines to determine the nature of interactions, 3) the effects of combinations of antibodies, 4) parametric comparisons of infusions of cytokines during the beginning, middle and end of the dark cycle to determine if their actions vary depending on the phase of the nocturnal period, 5) repeated administration of the cytokines to determine if the effects can be extinguished/habituated, 6) the effects of combinations of cytokines and putative gut peptide satiety signals.
