BACKGROUND/AIMS 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. METHODS 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. RESULTS 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. CONCLUSION 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.

中文翻译：

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EP3拮抗剂DG-041对饮食诱发的肥胖雄性小鼠的影响。

背景/目的前列腺素E2（PGE2）EP3受体在代谢中具有多方面的作用。已经提出了靶向EP3的药物作为糖尿病的治疗剂。但是，利用全球EP3基因敲除小鼠的研究表明，EP3阻滞剂会增加肥胖和胰岛素抵抗。本研究试图确定急性EP3拮抗剂治疗对糖尿病表型的影响。方法DG-041通过竞争性放射性配体结合和阻断EP3介导的反应，被证实是对小鼠EP3受体的高亲和力拮抗剂。进行了DG-041药代动力学研究，以确定最有效的给药途径。给雄性C57BL / 6×BALB / c（CB6F1）小鼠喂食含有10％，45％或60％卡路里的脂肪饮食，以诱导肥胖。用DG-041治疗一周后，评估这些小鼠的代谢表型的变化。结果皮下注射DG-041的剂量为20 mg / kg，阻止了sulprostone引起的平均动脉压升高，证实了该给药方案的有效性。DG-041治疗7天对人体成分或血糖控制的影响很小。施用DG-041导致骨骼肌甘油三酸酯含量降低，而肝甘油三酸酯却呈增加趋势。结论短期给予EP3 DG-041可有效阻断EP3受体并降低骨骼肌甘油三酸酯含量，但对糖尿病表型无明显影响。结果皮下注射DG-041的剂量为20 mg / kg，阻止了sulprostone引起的平均动脉压升高，证实了该给药方案的有效性。DG-041治疗7天对人体成分或血糖控制的影响很小。施用DG-041导致骨骼肌甘油三酸酯含量降低，而肝甘油三酸酯却呈增加趋势。结论短期给予EP3 DG-041可有效阻断EP3受体并降低骨骼肌甘油三酸酯含量，但对糖尿病表型无明显影响。结果皮下注射DG-041的剂量为20 mg / kg，阻止了sulprostone引起的平均动脉压升高，证实了该给药方案的有效性。DG-041治疗7天对人体成分或血糖控制的影响很小。施用DG-041导致骨骼肌甘油三酸酯含量降低，而肝甘油三酸酯却呈增加趋势。结论短期给予EP3 DG-041可有效阻断EP3受体并降低骨骼肌甘油三酸酯含量，但对糖尿病表型无明显影响。施用DG-041导致骨骼肌甘油三酸酯含量降低，而肝甘油三酸酯却呈增加趋势。结论短期给予EP3 DG-041可有效阻断EP3受体并降低骨骼肌甘油三酸酯含量，但对糖尿病表型无明显影响。施用DG-041导致骨骼肌甘油三酸酯含量降低，而肝甘油三酸酯却呈增加趋势。结论短期给予EP3 DG-041可有效阻断EP3受体并降低骨骼肌甘油三酸酯含量，但对糖尿病表型无明显影响。