SAT-299 Chronic Treatment Of Juvenile Hypothalamic Pomc-deficient Mice With RM-493 Prevents The Development Of Obesity

Arc-Pomc knockout mice have a disruption of the two neural enhancers for the Pomc (proopiomelanocortin) gene, resulting in selective loss of Pomc gene expression in the arcuate nucleus of the hypothalamus. This gene targeting strategy leaves pituitary Pomc expression unaffected. These mice are hyperphagic starting at weaning, and develop progressive obesity, infertility and insulin resistance over their lifetime. RM-493 (setmelanotide) is a melanocortin-4 receptor agonist that has shown promise in treating humans with Pomc null mutations. In this preclinical study, we investigated the effects of chronic RM-493 treatment using subcutaneously implanted osmotic minipumps in two groups of male mice: Arc-Pomc knockout mice, fed regular chow throughout the study period, and their wildtype counterparts, fed a 45% high-fat diet. Each of these groups of mice was randomized into three treatment cohorts at weaning: one that was given RM-493 throughout the entire study period (4–24 weeks of age, “RM-493” group), one that was given RM-493 only for the first 4 weeks of the study (4–8 weeks of age, “switch” group) and then switched to vehicle, and one cohort that received vehicle for the entire study (“vehicle” group). We serially measured body weight, food intake, body composition, glucose tolerance, insulin tolerance, and several measures of metabolism using the Comprehensive Lab Animal Monitoring System, including oxygen consumption, energy expenditure, ambulatory activity and lipid and glucose oxidation. Among other results, at the end of the study (24 weeks of age), Arc-Pomc knockout mice in the RM-493 group weighed significantly less than either the switch or vehicle groups (p