Suppression of Adipocyte Differentiation by Aldo-keto Reductase 1B3 Acting as Prostaglandin F2α Synthase

Abstract

Prostaglandin (PG) F 2␣ suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferatoractivated receptor ␥. However, PGF 2␣ synthase (PGFS) in adipocytes remains to be identified. Here, we studied the expression of members of the aldo-keto reductase (AKR) 1B family acting as PGFS during adipogenesis of mouse 3T3-L1 cells. AKR1B3 mRNA was expressed in preadipocytes, and its level increased about 4-fold at day 1 after initiation of adipocyte differentiation, and then quickly decreased the following day to a level lower than that in the preadipocytes. In contrast, the mRNA levels of Akr1b8 and 1b10 were clearly lower than that level of Akr1b3 in preadipocytes and remained unchanged during adipogenesis. The transient increase in Akr1b3 during adipogenesis was also observed by Western blot analysis. The mRNA for the FP receptor, which is selective for PGF 2␣ , was also expressed in preadipocytes. Its level increased about 2-fold within 1 h after the initiation of adipocyte differentiation and was maintained at almost the same level throughout adipocyte differentiation. The small interfering RNA for Akr1b3, but not for Akr1b8 or 1b10, suppressed PGF 2␣ production and enhanced the expression of adipogenic genes such as peroxisome proliferator-activated receptor ␥, fatty acid-binding protein 4 (aP2), and stearoylCoA desaturase. Moreover, an FP receptor agonist, Fluprostenol, suppressed the expression of those adipogenic genes in 3T3-L1 cells; whereas an FP receptor antagonist, AL-8810, efficiently inhibited the suppression of adipogenesis caused by the endogenous PGF 2␣ . These results indicate that AKR1B3 acts as the PGFS in adipocytes and that AKR1B3-produced PGF 2␣ suppressed adipocyte differentiation by acting through FP receptors.

Butein is a novel anti-adipogenic compound

“…Other studies have shown that butein inhibits aldo-keto reductase 1B family members, resulting in less prostaglandin F2 ␣ production ( 38,39 ). However, knockdown and pharmacological inhibition of aldo-keto reductase induces adipogenesis and PPAR ␥ expression ( 40 ). Thus, possible inhibition of aldo-keto reductase by butein may not account for its effects on adipocyte differentiation.…”

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

“…The level of PGF 2 ␣ rapidly increased to a peak 3 h after initiation of differentiation and then declined, indicating that PGF 2 ␣ suppresses in the early phase of adipogenesis ( 13 ). 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 ).…”

“…Prostaglandin F 2 ␣ (PGF 2 ␣ ) is generated from PGH 2 by PGF 2 ␣ synthase (PGFS), and PGF 2 ␣ is reported to be an inhibitory modulator of adipocyte differentiation ( 12 ). The level of PGF 2 ␣ rapidly increased to a peak 3 h after initiation of differentiation and then declined, indicating that PGF 2 ␣ suppresses in the early phase of adipogenesis ( 13 ). 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 ).…”

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

“…On day 2, the medium was replaced with DMEM containing insulin (10 g/ml) alone and changed every 2 days. Oil red O staining was carried out as described previously (8).…”