Activation of adipogenesis by lipocalin-type prostaglandin D synthase-generated Δ12-PGJ2 acting through PPARγ-dependent and independent pathways

• Published in: Gene 2012-08, Vol.505 (1), p.46-52
• Main Authors: Fujimori, Ko, Maruyama, Toshihiko, Kamauchi, Shinya, Urade, Yoshihiro
• Format: Article
• Language: English
• Subjects: 3T3-L1; 3T3-L1 Cells; Adipocytes; Adipocytokines; adipogenesis; Adipogenesis - drug effects; Adipogenesis - physiology; adiponectin; Anilides - pharmacology; Animals; antagonists; Chromans - pharmacology; fatty acid-binding proteins; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; genes; HeLa Cells; Humans; Hypoglycemic Agents - pharmacology; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; L-PGDS; leptin; Lipocalins - genetics; Lipocalins - metabolism; metabolites; Mice; PPAR gamma - antagonists & inhibitors; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - biosynthesis; Prostaglandin D2 - genetics; prostaglandins; small interfering RNA; stearoyl-CoA desaturase; Thiazolidinediones - pharmacology; Δ12-PGJ2
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2012.05.052

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS)-produced PGD2 accelerates adipogenesis. In this study, we investigated the molecular mechanism of PGD2-mediated activation of adipogenesis in mouse adipocytic 3T3-L1 cells. LC/MS analysis showed that Δ12-PGJ2, one of the PGD2 metabolites, was predominantly produced in the differentiated 3T3-L1 cells. Δ12-PGJ2 enhanced the expression of adipogenic genes in a Δ12-PGJ2-concentration-dependent manner. Suppression of the expression of the adipogenic genes by L-PGDS siRNA or AT-56, an L-PGDS inhibitor, was cleared by the addition of Δ12-PGJ2. Moreover, the production of adiponectin and leptin was increased by treatment with Δ12-PGJ2. Furthermore, the results of a mammalian two-hybrid assay demonstrated that Δ12-PGJ2 enhanced the PPARγ-mediated transcription activity. However, Δ12-PGJ2-activated expression of adipogenic genes such as fatty acid binding protein 4 (aP2) and stearoyl-CoA desaturase was inhibited only at 38% and 42%, respectively, by treatment with GW9662, a PPARγ antagonist in 3T3-L1 cells, although Troglitazone-mediated activation of the expression of these adipogenic genes was completely suppressed by GW9662, suggesting the existence of a PPARγ-independent mechanism for Δ12-PGJ2-activated adipogenesis. These results, taken together, indicate that Δ12-PGJ2 is a dominant metabolite of L-PGDS-produced PGD2 during adipogenesis and acts as an activator for adipogenesis through both PPARγ-dependent and -independent mechanisms in 3T3-L1 cells. ► Δ12-PGJ2 is a major metabolite L-PGDS-produced PGD2 in adipocytes. ► Δ12-PGJ2 binds and activates PPARγ function. ► Δ12-PGJ2 activates adipogenesis through PPARγ-dependent and -independent mechanisms.