title: Effects of a novel MC4R agonist on maintenance of reduced body weight in diet-induced obese mice.
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.
authors: Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
authors: Alicja A
authors: AA
authors: Skowronski
authors: Michael V
authors: MV
authors: Morabito
authors: Bridget R
authors: BR
authors: Mueller
authors: Samuel
authors: S
authors: Lee
authors: Stephan
authors: S
authors: Hjorth
authors: Anders
authors: A
authors: Lehmann
authors: Kazuhisa
authors: K
authors: Watanabe
authors: Lori M
authors: LM
authors: Zeltser
authors: Yann
authors: Y
authors: Ravussin
authors: Michael
authors: M
authors: Rosenbaum
authors: Charles A
authors: CA
authors: LeDuc
authors: Rudolph L
authors: RL
authors: Leibel
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D001835:Body Weight / Q000187:drug effects*; D031204:Caloric Restriction; D002153:Calorimetry, Indirect; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D006728:Hormones / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D006728:Hormones; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4