The purpose of this application is to define the central mechanisms that lead to decreased appetite and weight loss in conditions of pathologic anorexia. Our previous work supports the hypothesis that tumors and other inflammatory stimuli cause anorexia via a mechanism dependent on signaling by melanocortins, brain peptides that regulate food intake under physiologic conditions. Signals elaborated by the tumor cells are proposed to increase melanocortin receptor signaling, an inappropriate 'satiety' signal which causing negative energy balance, and leading to inexorable weight loss. The potency of the effect of cancer on energy homeostasis through the melanocortin system is highlighted by the fact that compensatory changes engendered by weight loss, such as decreases in serum leptin, are unable to effect the normal hypothalamic responses that stimulate a return to the baseline body weight. The first major objective of this application is to identify the components of the melanocortin system that are up-regulated in rodent models of cancer anorexia. This will be accomplished by 1) testing if pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) is both necessary and sufficient for cancer anorexia to occur, using both gene knock-out model and adenoviral gene therapy models, respectively; 2) determining if signaling by agouti-related peptide (Agrp), the endogenous melanocortin antagonist, is reduced, through in situ hybridization studies; and 3) determining if down-regulation of melanin concentrating hormone (MCH) is a consequence of melanocortin signaling and mediates anorexia, using in situ hybridization as well as adenoviral gene therapy studies. The second major objective is to investigate whether anorexia induced by an inflammatory stimulus, lipopolysaccharide (LPS) injection, involves the same melanocortin-dependent mechanism involved in cancer anorexia by using experimental strategies similar to the ones outlined above. By improving our understanding of the mechanism of cancer anorexia, these studies will help to identify potential central targets for the treatment of obesity as well as characterizing strategies for the treatment of anorexia in chronic disease states. This research will prepare the applicant for an academic career as an independent investigator in the field of energy homeostasis. The transition to independence will be facilitated by the rich training environment afforded by Dr. Schwartz and the Harborview Medical Center Energy Metabolism Laboratory, and by joining a large community of productive researchers in the field of energy homeostasis across the University of Washington campus.
