Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice

We have recently shown that genetic or pharmacological blockade of the melanocortin-4 receptor (MC4-R) attenuates uremia-associated cachexia. However, the potential clinical utility of this approach has been limited by the need to deliver a peptide MC4-R antagonist into the ventricles of the brain. NBI-12i is a recently developed small molecule MC4-R antagonist, with high affinity and selectivity that penetrates the central nervous system after peripheral administration. We tested whether NBI-12i would also be effective in attenuating uremia-associated cachexia in a mouse model. Intraperitoneal administration of NBI-12i stimulated food intake and weight gain in uremic mice. Furthermore, NBI-12i-treated uremic mice gained lean body mass, fat mass, and had a lower basal metabolic rate compared to vehicle-treated and diet-supplemented uremic mice, which lost both lean body mass and fat mass and had an increase in basal metabolic rate. We found that NBI-12i normalizes the expression of uncoupling protein, which is normally upregulated in uremic mice, and we speculate that this may contribute to the drug's protective effect. These data underscore the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and demonstrate the potential of peripheral administration of MC4-R antagonists as a novel therapeutic approach.