When homozygous for the Leptin^Ob mutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 weeks of age, frankly diabetic. Previous work has shown Prostaglandin EP3 Receptor (EP3) expression and activity is up-regulated in islets from BTBR-Ob mice as compared to lean controls, actively contributing to their beta-cell dysfunction. In this work, we aimed to test the impact of beta-cell-specific EP3 loss on the BTBR-Ob phenotype by crossing Ptger3 floxed mice with the Rat insulin promoter (RIP)-Cre^Herr driver strain. Instead, germline recombination of the floxed allele in the founder mouse - an event whose prevalence we identified as directly associated with underlying insulin resistance of the background strain - generated a full-body knockout. Full-body EP3 loss provided no diabetes protection to BTBR-Ob mice, but, unexpectedly, significantly worsened BTBR-lean insulin resistance and glucose tolerance. This in vivo phenotype was not associated with changes in beta-cell fractional area or markers of beta-cell replication ex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective up-regulation of constitutively-active EP3 splice variants in islets from young, lean BTBR mice as compared to C57BL/6J, where no phenotype of EP3 loss has been observed, provides a potential explanation for the hypersecretion phenotype. In support of this, high islet EP3 expression in Balb/c females vs. Balb/c males was fully consistent with their sexually-dimorphic metabolic phenotype after loss of EP3-coupled Gα_z protein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion.

中文翻译：

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在非肥胖的胰岛素抵抗小鼠模型中，需要前列腺素 EP3 受体信号传导来预防胰岛素分泌过多和代谢功能障碍

当瘦素^Ob突变 (Ob) 纯合子时，黑褐色 Brachyury (BTBR) 小鼠变得病态肥胖和严重的胰岛素抵抗，并且到 10 周龄时，坦率地说是糖尿病。先前的研究表明，与瘦对照相比，BTBR-Ob 小鼠胰岛中前列腺素 EP3 受体 (EP3) 的表达和活性上调，从而导致其 β 细胞功能障碍。在这项工作中，我们旨在通过将 Ptger3 floxed 小鼠与大鼠胰岛素促进剂 (RIP)-Cre ^{Herr杂交来测试 β 细胞特异性 EP3 缺失对 BTBR-Ob 表型的影响。}司机紧张。相反，在创始人小鼠中，floxed 等位基因的种系重组——我们确定其流行与背景菌株的潜在胰岛素抵抗直接相关的事件——产生了全身敲除。全身 EP3 缺失对 BTBR-Ob 小鼠没有提供糖尿病保护，但出乎意料的是，显着恶化了 BTBR 瘦胰岛素抵抗和葡萄糖耐量。这种体内表型与 β 细胞分数面积的变化或 β 细胞离体复制的标记无关。相反，EP3-null BTBR-lean 胰岛具有基本上不受控制的胰岛素分泌过多。与未观察到 EP3 损失表型的 C57BL/6J 相比，来自年轻、瘦 BTBR 小鼠的胰岛中组成型活性 EP3 剪接变体的选择性上调，为高分泌表型提供了潜在的解释。为了支持这一点，Balb/c 雌性与 Balb/c 雄性的高胰岛 EP3 表达与其在 EP3 偶联 Gα 缺失后的性二态代谢表型完全一致_z蛋白。总之，我们的研究结果为理解 EP3 作为胰岛素分泌的关键制动器提供了一个新的维度。