EFFECTS OF A POTENT MELANOCORTIN AGONIST ON THE DIABETIC OBESE PHENOTYPE IN YELLOW MICE/

OBJECTIVE: To test the hypothesis that a melanocortin agonist can reve rse obesity and insulin resistance in mice overexpressing the agouti p rotein. EXPERIMENTAL MODEL: Mice overexpressing the agouti protein eit her by transgene introduction (beta-actin promotor) or by mutation (A( y)). DESIGN: NDPMSH was tested for pharmacokinetic suitability. NDPMSH at various doses was administered subcutaneously twice a day for 2-3 weeks. MEASUREMENTS: Fur pigmentation, various fatness parameters (cor e temperature, fat pad weight and body weight), blood glucose and horm ones, fatty acid synthase measurement. RESULTS: NDPMSH caused fur pigm entation and core temperature changes, but failed to affect any metabo lic parameters in agouti-dependent manner. CONCLUSION: NDPMSH, as a re presentation melanocortin agonist, does not compete with agouti in rev ersing agouti-dependent metabolic effects. This suggests that 1) agout i works via a receptor other than a melanocortin receptor to mediate i ts metabolic effects, 2) agouti-dependent metabolic effects are mediat ed through melanocortin receptors but not via antagonism of these rece ptors, or 3) NDPMSH is pharmacodynamically an inappropriate molecule f or these types of studies.