Novel suppression mechanism operating in early phase of adipogenesis by positive feedback loop for enhancement of cyclooxygenase‐2 expression through prostaglandin F_2α receptor mediated activation of MEK/ERK‐CREB cascade

Abstract

Prostaglandin (PG) F 2a suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor c. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti-adipogenic PGF 2a and PGE 2 by enhancing cyclooxygenase (COX) 2 expression through the PGF 2a -activated FP receptor ⁄ extracellular-signal-regulated kinase (ERK) ⁄ cyclic AMP response element binding protein (CREB) cascade. COX-2 expression was enhanced with a peak at 1 h for the mRNA level and at 3 h for the protein level after the addition of Fluprostenol, an FP receptor agonist. The Fluprostenol-derived elevation of COX-2 expression was suppressed by the co-treatment with an FP receptor antagonist, AL8810, with a mitogen-activated protein kinase (MEK; ERK kinase) inhibitor, PD98059. ERK was phosphorylated within 10 min after the addition of Fluprostenol, and its phosphorylation was inhibited by the co-treatment with AL8810 or PD98059. Moreover, FP receptor mediated activation of the MEK ⁄ ERK cascade and COX-2 expression increased the production of PGF 2a and PGE 2 . An FP receptor antagonist and each inhibitor for MEK and COX-2 suppressed the PGF 2a -derived induction of synthesis of these PGs. Furthermore, promoter-luciferase and chromatin immunoprecipitation assays demonstrated that PGF 2a -derived COX-2 expression was activated through binding of CREB to the promoter region of the COX-2 gene in 3T3-L1 cells. These results indicate that PGF 2a suppresses the progression of the early phase of adipogenesis by enhancing the binding of CREB to the COX-2 promoter via FP receptor activated MEK ⁄ ERK cascade. Thus, PGF 2a forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti-adipogenic PGF 2a and PGE 2 .

Anandamide-derived Prostamide F2α Negatively Regulates Adipogenesis

“…These data differ from results published previously in which it was shown that FP receptor expression increases with 3T3-L1 adipogenesis (46) and that FP receptor stimulation by fluprostenol decreases FP receptor expression in preadipocytes (52). These differences may be due to clonal differences in the 3T3-L1 cells used and the fact that activation of FP by different agonists might produce different effects.…”

“…Bimatoprost, PGF 2␣ EA, and PGF 2␣ all induced a large increase in Ptgs2 expression in 3T3-L1 cells treated with IDM adipogenic medium, as has been observed also with the FP receptor agonist fluprostenol in undifferentiated 3T3-L1 cells, resulting in increased de novo PGF 2␣ production (52). The fluprostenol-mediated induction, however, was transient, being observed for only 1 h, after which Ptgs2 transcript levels decreased significantly below base line.…”

MiR-378a-3p enhances adipogenesis by targeting mitogen-activated protein kinase 1

“…MAPK1 also reportedly regulates adipogenesis [29,30]; however, its roles in this process are complicated. On the one hand, MAPK1 up-regulates the expression of crucial adipogenic regulators such as peroxisome proliferator-activated receptor c (PPARc) and the CCAAT-enhancer-binding proteins a, b, and d at the beginning of adipogenesis [31,32].…”

Prostaglandin reductase-3 negatively modulates adipogenesis through regulation of PPARγ activity

“…Knockdown of aldo-keto reductase 1B3 (AKR1B3), a PGFS, decreased de novo PGF 2 ␣ biosynthesis in 3T3-L1 cells and then further promoted lipid accumulation ( 13 ). It has been shown that PGF 2 ␣ suppressed adipogensis by enhancing phosphorylation of PPAR ␥ via prostaglandin F receptor-activated MEK⁄ERK cascade ( 14 ). On the other hand, PGE 2 , a precursor of 15-keto-PGE 2 , is the most abundant prostaglandin produced in 3T3-L1 preadipocytes, and the highest level of PGE 2 was detected during the early phase of adipogenesis ( 15,16 ).…”