Synergistic Effects of a GPR119 Agonist with Metformin on Weight Loss in Diet-Induced Obese Mice.

Abstract

G protein-coupled receptor 119 (GPR119) is a G protein-coupled receptor expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment of type 2 diabetes, with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706 [2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine], a GPR119 agonist, and metformin as monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30 mg/kg b.i.d.) or metformin at 30 and 100 mg/kg b.i.d. alone caused a 7.4%, 3.5%, and 4.4% (all P < 0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30 or 100 mg/kg resulted in a 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100 mg/kg caused a significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100 mg/kg, respectively. The combination of GSK2041706 with metformin caused greater reductions in cumulative food intake (22.2% at 30 mg/kg and 37.5% at 100 mg/kg) and higher fed plasma glucagon-like peptide 1 and peptide tyrosine tyrosine levels and decreased plasma insulin and glucose-dependent insulinotropic polypeptide levels compared with their monotherapy groups. In addition, we characterized the effect of GSK2041706 and metformin as monotherapy or in combination on neuronal activation in the appetite regulating centers in fasted DIO mice. In conclusion, our data demonstrate the beneficial effects of combining a GPR119 agonist with metformin in the regulation of body weight in DIO mice.

• Authors: Kamal Al-Barazanji, Judi McNulty, Jane Binz, Claudia Generaux, William Benson, Andrew Young, Lihong Chen
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 353 Issue 3 Pg. 496-504 (Jun 2015) ISSN: 1521-0103 [Electronic] United States
• PMID: 25770135 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 2-((1-(1-(3-(1-methylethyl)-1,2,4-oxadiazol-5-yl)-4-piperidinyl)ethyl)oxy)-5-(4-(methylsulfonyl)phenyl)pyrazine
• GPR119 protein, human
• Hypoglycemic Agents
• Insulin
• Oxadiazoles
• Proto-Oncogene Proteins c-fos
• Pyrazines
• Receptors, G-Protein-Coupled
• Gastric Inhibitory Polypeptide
• Glucagon-Like Peptide 1
• Metformin

Topics

• Animals
• Body Weight (drug effects)
• Diet, High-Fat
• Dose-Response Relationship, Drug
• Drug Synergism
• Eating (drug effects)
• Gastric Inhibitory Polypeptide (blood)
• Glucagon-Like Peptide 1 (blood)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Insulin (blood)
• Male
• Metformin (pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (drug therapy)
• Oxadiazoles (pharmacology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Pyrazines (pharmacology)
• Receptors, G-Protein-Coupled (agonists)
• Weight Loss (drug effects)