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Publication
The effect of the EP3 antagonist DG-041 on male mice with diet-induced obesity.
Authors Ceddia RP, Downey JD, Morrison RD, Kraemer MP, Davis SE, Wu J, Lindsley CW, Yin
H, Daniels JS, Breyer RM
Submitted By Submitted Externally on 1/17/2020
Status Published
Journal Prostaglandins & other lipid mediators
Year 2019
Date Published 10/1/2019
Volume : Pages 144 : 106353
PubMed Reference 31276827
Abstract The prostaglandin E2 (PGE2) EP3 receptor has a multifaceted role in metabolism.
Drugs targeting EP3 have been proposed as therapeutics for diabetes; however,
studies utilizing global EP3 knockout mice suggest that EP3 blockade increases
obesity and insulin resistance. The present studies attempt to determine the
effect of acute EP3 antagonist treatment on the diabetic phenotype., DG-041 was
confirmed to be a high affinity antagonist at the mouse EP3 receptor by
competition radioligand binding and by blockade of EP3-mediated responses.
DG-041 pharmacokinetic studies were performed to determine the most efficacious
route of administration. Male C57BL/6?×?BALB/c (CB6F1) mice were fed diets
containing 10%, 45%, or 60% calories from fat to induce obesity. Changes to the
metabolic phenotype in these mice were evaluated after one week treatment with
DG-041., Subcutaneous injections of DG-041 at 20?mg/kg blocked the
sulprostone-evoked rise in mean arterial pressure confirming the efficacy of
this administration regime. Seven day treatment with DG-041 had minimal effect
on body composition or glycemic control. DG-041 administration caused a
reduction in skeletal muscle triglyceride content while showing a trend toward
increased hepatic triglycerides., Short term EP3 administration of DG-041
produced effective blockade of the EP3 receptor and decreased skeletal muscle
triglyceride content but had no significant effects on the diabetic phenotype.




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