Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

Abstract

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.

A Pegylated Leptin Antagonist Ameliorates CKD-Associated Cachexia in Mice

“…Previously, we showed that mRNA and protein content of UCP-1 and -3 in BAT were increased in CKD mice. 18 PLA treatment significantly reduced transcriptional and protein levels of BAT UCP-1, white adipose tissue UCP-2, and muscle UCP-3 in CKD mice (Figures 7 and 8).…”

Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease

“…AgRP treatment ameliorated CKDassociated cachexia. Our previous results (8) showed that administration of AgRP significantly increased the food consumption of CKD mice. To ensure that the observed effects on body mass regulation was not due to difference in nutritional intake, CKD/AgRP and Sham/AgRP mice were pair fed to CKD/V mice ( Fig.…”

“…The mixed melanocortin receptor antagonist agouti-related peptide (AgRP) is an endogenous peptide that induces hyperphagia (23). Previously, we showed that AgRP attenuated cachexia in CKD mice (8,10). Although promising, our previous studies (38,39) with AgRP have one major caveat, as we used dual energy X-ray absorptiometry (DXA) to assess the body composition in mice.…”

Melanocortin system in cancer-related cachexia

“…It has recently been demonstrated that blockade of the central MC system can prevent cachexia development in models of uremia, heart failure, and cancer [41][42][43][44].…”

“…Besides the experiments using SNT2007707 and SNT207858 in C26 adenocarcinoma mice performed by Weyermann [45], a number of other compounds with MC4R antagonist effects were investigated elsewhere -Chen et al [52] reported on a new compound from piperazine family, the name of which is yet to be attributed, Vos et al [53] investigated effects of ML00253764 in C26 adenocarcinoma mice, Nicholson et al [44] investigated ML00253764 in Lewis Lung carcinoma mice. Cheung et al [54] investigated effects of a MC4R antagonist called NBI-12i in rodent models of cachexia with 5/6 nephrectomy where 3 mg/kg of NBI-12i or saline was given to subtotally nephrectomized or sham-operated mice intraperitoneally, twice per day, for a period of 14 days. 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, moreover, NBI-12i also normalized the expression of uncoupling protein, which is normally upregulated in uremic mice which may have also beneficial effects in uremia-related cachexia.…”