Cachexia is a clinical
wasting syndrome that occurs in multiple disease states, and is associated with
anorexia and a progressive loss of body fat and lean mass. The development of new
therapeutics for this disorder is needed due to poor efficacy and multiple side effects of current
therapies. The pivotal role played by the central
melanocortin system in regulating
body weight has made this an attractive target for novel
cachexia therapies. The mixed
melanocortin receptor antagonist AgRP is an endogenous
peptide that induces
hyperphagia. Here, we used AgRP(83-132) to investigate the ability of
melanocortin antagonism to protect against clinical features of
cachexia in two distinct animal models. In an acute model, food intake and
body weight gain were reduced in mice exposed to radiation (300 RAD), and delivery of AgRP(83-132) into the lateral cerebral ventricle prevented these effects. In a chronic
tumor cachexia model, adult mice were injected subcutaneously with a cell line derived from murine colon-26
adenocarcinoma. Typical of
cachexia,
tumor-bearing mice progressively reduced
body weight and food intake, and gained significantly less muscle mass than controls. Administration of AgRP(83-132) into the lateral ventricles significantly increased
body weight and food intake, and changes in muscle mass were similar to the
tumor-free control mice. These findings support the idea that antagonism of the central
melanocortin system can reduce the negative impact of
cachexia and
radiation therapy.