The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist.
Cachexia is metabolic disorder characterized by anorexia, an increased metabolic rate, and loss of lean body mass. It is a relatively common disorder, and is a pathological feature of diseases such as cancer, HIV infection, and renal failure. Recent studies have demonstrated that cachexia brought about by a variety of illnesses can be attenuated or reversed by blocking activation of the melanocortin 4 subtype receptor (MC4-R) within the central nervous system. Although the potential use of central MC4-R antagonists for the treatment of cachexia was supported by these studies, utility was limited by the need to deliver these agents intracerebroventricularly. In the current study, we present a series of experiments demonstrating that peripheral administration of a small molecule MC4-R antagonist can effectively stimulate daytime (satiated) food intake as well as decrease basal metabolic rate in normal animals. Furthermore, this compound attenuated cachexia and preserved lean body mass in a murine cancer model. These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder.
Markison
Stacy
S
Department of Pediatrics, Mailcode CDRCP, 707 Southwest Gaines Road, Portland, Oregon 97239, USA. marksd@ohsu.edu
Foster
Alan C
AC
Chen
Chen
C
Brookhart
Gregor B
GB
Hesse
Amy
A
Hoare
Sam R J
SR
Fleck
Beth A
BA
Brown
Brock T
BT
Marks
Daniel L
DL
D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D018827:Carcinoma, Lewis Lung / Q000150:complications*; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology; D008175:Lung Neoplasms / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011869:Radioligand Assay; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D007457:Iodine Radioisotopes; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-