Activation of adipogenesis by lipocalin-type prostaglandin D synthase-generated Δ¹²-PGJ₂ acting through PPARγ-dependent and independent pathways.
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS)-produced PGD(2) accelerates adipogenesis. In this study, we investigated the molecular mechanism of PGD(2)-mediated activation of adipogenesis in mouse adipocytic 3T3-L1 cells. LC/MS analysis showed that Δ(12)-PGJ(2), one of the PGD(2) metabolites, was predominantly produced in the differentiated 3T3-L1 cells. Δ(12)-PGJ(2) enhanced the expression of adipogenic genes in a Δ(12)-PGJ(2)-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 Δ(12)-PGJ(2). Moreover, the production of adiponectin and leptin was increased by treatment with Δ(12)-PGJ(2). Furthermore, the results of a mammalian two-hybrid assay demonstrated that Δ(12)-PGJ(2) enhanced the PPARγ-mediated transcription activity. However, Δ(12)-PGJ(2)-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 Δ(12)-PGJ(2)-activated adipogenesis. These results, taken together, indicate that Δ(12)-PGJ(2) is a dominant metabolite of L-PGDS-produced PGD(2) during adipogenesis and acts as an activator for adipogenesis through both PPARγ-dependent and -independent mechanisms in 3T3-L1 cells.
Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. fujimori@gly.oups.ac.jp
Ko
K
Fujimori
Toshihiko
T
Maruyama
Shinya
S
Kamauchi
Yoshihiro
Y
Urade
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002839:Chromans; D007004:Hypoglycemic Agents; D054834:Lipocalins; D047495:PPAR gamma; D045162:Thiazolidinediones; C037112:9-deoxy-delta-9-prostaglandin D2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D000077288:Troglitazone; D015230:Prostaglandin D2