Prostaglandin EP3 receptor signaling is required to prevent insulin hypersecretion and metabolic dysfunction in a non-obese mouse model of insulin resistance

摘要

When homozygous for the Leptin~(Ob) mutation (Ob), Black-and-Tan Brachyury (BTBR) mice become morbidly obese and severely insulin resistant, and by 10 wk of age, frankly diabetic. Previous work has shown prostaglandin EP3 receptor (EP3) expression and activity is upregulated in islets from BTBR-Ob mice as compared with lean controls, actively contributing to their p-cell dysfunction. In this work, we aimed to test the impact of p-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 p-cell fractional area or markers of p-cell replication ex vivo. Instead, EP3-null BTBR-lean islets had essentially uncontrolled insulin hypersecretion. The selective upregulation of constitutively active EP3 splice variants in islets from young, lean BTBR mice as compared with 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 versus Balb/c males was fully consistent with their sexually dimorphic metabolic phenotype after loss of EP3-coupled Galpha_z protein. Taken together, our findings provide a new dimension to the understanding of EP3 as a critical brake on insulin secretion.