Prostacyclin (PGI₂) synthase (PGIS) functions downstream of inducible cyclooxygenase COX-2 in the PGI₂ biosynthetic pathway. Although COX-2 and PGI₂ receptor (IP) are known to be involved in adipogenesis and obesity, the involvement of PGIS has not been fully elucidated. In this study, we examined the role of PGIS in adiposity by using PGIS-deficient mice. Although PGIS deficiency did not affect in vitro adipocyte differentiation, when fed a high-fat diet (HFD), PGIS knockout (KO) mice showed reductions in both body weight gain and epididymal fat mass relative to wild-type (WT) mice. PGIS deficiency might reduce HFD-induced obesity by suppressing PGI₂ production. We further found that additional gene deletion of microsomal prostaglandin (PG) E synthase-1 (mPGES-1), one of the other PG terminal synthases that also functions downstream of COX-2, emphasized the metabolic phenotypes of PGIS-deficient mice. More marked reduction in obesity and improved insulin resistance were observed in PGIS/mPGES-1 double KO (DKO) mice. Since an additive increase in PGF_2α level in epididymal fat was observed in DKO mice, mPGES-1 deficiency might affect adiposity by enhancing the production of PGF_2α. Our immunohistochemical analysis further revealed that in adipose tissues, PGIS was expressed in vascular and stromal cells but not in adipocytes. These results suggested that PGI₂ produced from PGIS-expressed stromal tissues might enhance HFD-induced obesity by acting on IP expressed in adipocytes. The balance of expressions of PG terminal synthases and the subsequent production of prostanoids might be critical for adiposity.

前列环素 (PGI ₂ ) 合酶 (PGIS) 在 PGI ₂生物合成途径中诱导型环氧合酶 COX-2 的下游发挥作用。尽管已知 COX-2 和 PGI ₂受体 (IP) 参与脂肪生成和肥胖，但 PGIS 的参与尚未完全阐明。在这项研究中，我们通过使用 PGIS 缺陷小鼠来研究 PGIS 在肥胖中的作用。尽管 PGIS 缺乏并不影响体外脂肪细胞分化，但当喂食高脂饮食 (HFD) 时，PGIS 敲除 (KO) 小鼠相对于野生型 (WT) 小鼠，体重增加和附睾脂肪量均减少。 PGIS 缺乏可能通过抑制 PGI ₂的产生来减少 HFD 引起的肥胖。我们进一步发现微粒体前列腺素 (PG) E 合酶-1 (mPGES-1) 的额外基因缺失（另一种 PG 末端合酶，也在 COX-2 下游发挥作用）强调了 PGIS 缺陷小鼠的代谢表型。在 PGIS/mPGES-1 双 KO (DKO) 小鼠中观察到肥胖更显着减少，胰岛素抵抗得到改善。由于在 DKO 小鼠中观察到附睾脂肪中 PGF _2α水平显着增加，因此 mPGES-1 缺乏可能通过增强 PGF _2α的产生来影响肥胖。我们的免疫组织化学分析进一步表明，在脂肪组织中，PGIS 在血管和基质细胞中表达，但在脂肪细胞中不表达。这些结果表明，表达 PGIS 的基质组织产生的 PGI ₂可能通过作用于脂肪细胞中表达的 IP 来增强 HFD 诱导的肥胖。 PG 末端合酶的表达平衡和随后的前列腺素类化合物的产生可能对肥胖至关重要。