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- Title
Effects of a novel MC4R agonist on maintenance of reduced body weight in diet-induced obese mice.
- Authors
Skowronski, Alicja A.; Morabito, Michael V.; Mueller, Bridget R.; Lee, Samuel; Hjorth, Stephan; Lehmann, Anders; Watanabe, Kazuhisa; Zeltser, Lori M.; Ravussin, Yann; Rosenbaum, Michael; LeDuc, Charles A.; Leibel, Rudolph L.
- Abstract
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 (MC4R) agonist in such a paradigm. 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 4 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 (53.4 nmol/day) regained 12.4% less BW than their vehicle-treated controls since the beginning of drug treatment. In WR mice, 10.8 nmol/day of the agonist was sufficient to maintain these animals at 95.1% of initial BW versus 53.4 nmol/day required to maintain the BW of AL animals (94.5%). Conclusions In the WR state, the MC4R agonist was comparably efficacious to a five-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.
- Subjects
WEIGHT loss; HOMEOSTASIS; HIGH-fat diet; MELANOCORTIN receptors; PHYSIOLOGICAL aspects of body weight
- Publication
Obesity (19307381), 2014, Vol 22, Issue 5, p1287
- ISSN
1930-7381
- Publication type
Article
- DOI
10.1002/oby.20678