Prostaglandin (PG) F2 Alpha Synthesis in Human Subcutaneous and Omental Adipose Tissue: Modulation by Inflammatory Cytokines and Role of the Human Aldose Reductase AKR1B1

Abstract

IntroductionPGF2α may be involved in the regulation of adipose tissue function.Objectives1) To examine PGF2α release by primary preadipocytes, mature adipocytes and whole tissue explants from the subcutaneous and omental fat compartments; 2) To assess which PGF synthase is the most relevant in human adipose tissue.MethodsFat samples were obtained by surgery in women. PGF2α release by preadipocytes, adipocytes and explants under stimulation by TNF-α, IL-1β or both was measured. Messenger RNA expression levels of AKR1B1 and AKR1C3 were measured by RT-PCR in whole adipose tissue and cytokine-treated preadipocytes. The effect of AKR1B1 inhibitor ponalrestat on PGF2α synthesis was investigated.ResultsPGF2α release was significantly induced in response to cytokines compared to control in omental (p = 0.01) and to a lesser extent in subcutaneous preadipocytes (p = 0.02). Messenger RNA of COX-2 was significantly higher in omental compared to subcutaneous preadipocytes in response to combined TNF-α and IL-1β (p = 0.01). Inflammatory cytokines increased AKR1B1 mRNA expression and protein levels (p≤0.05), but failed to increase expression levels of AKR1C3 in cultured preadipocytes. Accordingly, ponalrestat blunted PGF2α synthesis by preadipocytes in basal and stimulated conditions (p≤0.05). Women with the highest PGF2α release by omental adipocytes had a higher BMI (p = 0.05), waist circumference (p≤0.05) and HOMAir index (p≤0.005) as well as higher mRNA expression of AKR1B1 in omental (p<0.10) and subcutaneous (p≤0.05) adipose tissue compared to women with low omental adipocytes PGF2α release. Positive correlations were observed between mRNA expression of AKR1B1 in both compartments and BMI, waist circumference as well as HOMAir index (p≤0.05 for all).ConclusionPGF2α release by omental mature adipocytes is increased in abdominally obese women. Moreover, COX-2 expression and PGF2α release is particularly responsive to inflammatory stimulation in omental preadipocytes. Yet, blockade of PGF synthase AKR1B1 inhibits most of the PGF2α release.

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…Previous interactions of AKR1B1 with PGs have been reported. AKR1B1 has been identified as a PGF 2 synthase using PGH 2 as the substrate in the presence of NADPH (Michaud et al, 2014), whereas in its absence it may catalyze its isomerization to PGD 2 , which is a precursor for the J series of cyPGs (Nagata et al, 2011). In this context, our findings that several PGs bind to and inhibit the enzyme may be highly relevant in pathophysiological settings.…”

“…AKR1B1 has also been involved in allergic inflammation and asthma Yadav et al, 2013). Moreover, AKR1B1 participates in the metabolism of certain prostaglandins (PGs), thus regulating the generation of inflammatory or vasoactive mediators (Kabututu et al, 2009;Michaud et al, 2014).…”

Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin

“…This is of particular importance since during leukemia treatment, bone marrow exhibits substantial fat accumulation (21). Further, cancer treatment induces large increases in whole body adiposity (22), and obesity itself has been associated with higher adipose tissue expression of some of these enzymes (23,24). Together, these changes may contribute to local reduction of cytotoxic activity of chemotherapy, leading to emergence of drug resistant tumor cells and risk for treatment failure.…”

Temporal Changes in Gene Expression Profile during Mature Adipocyte Dedifferentiation

“…The number of copies for each transcript was calculated according to Luu-The et al [13] using the second derivative method and a standard curve of Cp versus logarithm of the quantity. A standard curve was established using known amounts of purified PCR products and the LightCycler 480 v1.5 program provided by the manufacturer (Roche Diagnostics, Mannheim, DE) [14]. The efficiency of PCR amplification was verified.…”