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

Alicja A. Skowronski, Michael V. Morabito, Bridget R. Mueller, Samuel Lee, Stephan Hjorth, Anders Lehmann, Kazuhisa Watanabe, Lori M. Zeltser, Yann Ravussin, Michael Rosenbaum, Charles A. Leduc, Rudolph L. Leibel

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish
Pages (from-to)1287-1295
Number of pages9
JournalObesity
Volume22
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

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