title: Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice.
abstract: OBJECTIVE
  Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.
  
  
  METHODS
  We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r(-/-) and Gcgr(-/-) mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.
  
  
  RESULTS
  Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.
  
  
  CONCLUSIONS
  Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.
authors: Merck Research Laboratories, Rahway, NJ, USA.
authors: Alessandro
authors: A
authors: Pocai
authors: Paul E
authors: PE
authors: Carrington
authors: Jennifer R
authors: JR
authors: Adams
authors: Michael
authors: M
authors: Wright
authors: George
authors: G
authors: Eiermann
authors: Lan
authors: L
authors: Zhu
authors: Xiaobing
authors: X
authors: Du
authors: Aleksandr
authors: A
authors: Petrov
authors: Michael E
authors: ME
authors: Lassman
authors: Guoqiang
authors: G
authors: Jiang
authors: Franklin
authors: F
authors: Liu
authors: Corey
authors: C
authors: Miller
authors: Laurie M
authors: LM
authors: Tota
authors: Gaochao
authors: G
authors: Zhou
authors: Xiaoping
authors: X
authors: Zhang
authors: Michael M
authors: MM
authors: Sountis
authors: Alessia
authors: A
authors: Santoprete
authors: Elena
authors: E
authors: Capito'
authors: Gary G
authors: GG
authors: Chicchi
authors: Nancy
authors: N
authors: Thornberry
authors: Elisabetta
authors: E
authors: Bianchi
authors: Antonello
authors: A
authors: Pessi
authors: Donald J
authors: DJ
authors: Marsh
authors: Ranabir
authors: R
authors: SinhaRoy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000517:prevention & control; D004041:Dietary Fats / Q000494:pharmacology; D002149:Energy Intake; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000235:genetics / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D007279:Injections, Subcutaneous; D007328:Insulin / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009765:Obesity / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D053772:Oxyntomodulin / Q000008:administration & dosage / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015431:Weight Loss / Q000187:drug effects
chemical_list: D004041:Dietary Fats; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1