Effects of a novel MC4R agonist on maintenance of reduced body weight in diet induced obese mice

OBJECTIVE: The physiology of the weight reduced (WR) state suggests that pharmacologic agents affecting energy homeostasis may have greater efficacy in WR individuals. Our aim was to establish a protocol that allows for evaluation of efficacy of weight maintenance agents and to assess the effectiveness of AZD2820, a novel melanocortin 4 receptor agonist in such a paradigm. DESIGN AND METHODS: MC4R agonist was administered in stratified doses to mice who were either fed high fat diet ad libitum (AL) throughout the study; or stabilized at a 20% reduced body weight (BW), administered the drug for four weeks, and thereafter released from caloric restriction while continuing to receive the drug (WR). RESULTS: After release of WR mice to AL feeding, the high-dose group (53.4nmol/day) regained 12.4% less BW than their vehicle-treated controls. In WR mice, 10.8nmol/day of the agonist was sufficient to maintain these animals at 95.1% of initial BW vs 53.4nmol/day required to maintain the BW of AL animals (94.5%). CONCLUSIONS: In the WR state, the MC4R agonist was comparably efficacious to a 5-fold higher dose in the AL state. This protocol provides a model for evaluating the mechanisms and quantitative efficacy of weight-maintenance strategies and agents.