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Differential Role of Melanocortin Receptor Subtypes in Cachexia

Department of Pediatric Endocrinology (D.L.M., G.B.), Veterans Affairs Medical Center (R.T.), Vollum Institute (R.D.C.), Oregon Health and Science University, Portland, Oregon 97201; and Pennington Institute (A.A.B.), Baton Rouge, Louisiana 70808

Address all correspondence and requests for reprints to: Roger D. Cone, Vollum Institute Mailcode L474, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201. E-mail: cone{at}ohsu.edu.

Animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a sparing of lean body mass (LBM) and burning of fat, and an overall decrease in basal metabolic rate. In contrast, cachexia is a pathological state of malnutrition associated with many infections and chronic diseases, wherein appetite is diminished concomitant with an increase in metabolic rate, and a relative wasting of LBM. In previous studies, we demonstrated that anorexia and weight loss in mouse cachexia models induced by lipopolysaccharide (LPS) administration and by tumor growth are ameliorated by central melanocortin-4 (MC4) receptor (MC4-R) blockade. In contrast to the results seen with MC4 blockade, melanocortin-3 (MC3) receptor knockout (MC3-RKO) mice show illness-induced anorexia and weight loss with LPS administration and with cytokine administration, and they have similar decreases in mobility. Both MC3-RKOs and MC4-RKOs have an intact corticosterone response and fever with LPS injection. In tumor models, we show that MC4-RKO mice resist the loss of LBM brought about by tumor growth, whereas MC3-RKO animals show enhanced tissue wasting. These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia.

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