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

Obesity (Silver Spring). 2014 May;22(5):1287-95. doi: 10.1002/oby.20678. Epub 2014 Jan 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Composition
  • Body Weight / drug effects*
  • Caloric Restriction
  • Calorimetry, Indirect
  • Diet, High-Fat / adverse effects
  • Energy Metabolism
  • Hormones / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / drug therapy*
  • Receptor, Melanocortin, Type 4 / agonists*
  • Weight Loss

Substances

  • Blood Glucose
  • Hormones
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4