Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice.
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.
Pocai
Alessandro
A
Merck Research Laboratories, Rahway, NJ, USA.
Carrington
Paul E
PE
Adams
Jennifer R
JR
Wright
Michael
M
Eiermann
George
G
Zhu
Lan
L
Du
Xiaobing
X
Petrov
Aleksandr
A
Lassman
Michael E
ME
Jiang
Guoqiang
G
Liu
Franklin
F
Miller
Corey
C
Tota
Laurie M
LM
Zhou
Gaochao
G
Zhang
Xiaoping
X
Sountis
Michael M
MM
Santoprete
Alessia
A
Capito'
Elena
E
Chicchi
Gary G
GG
Thornberry
Nancy
N
Bianchi
Elisabetta
E
Pessi
Antonello
A
Marsh
Donald J
DJ
SinhaRoy
Ranabir
R
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
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