Regulative effect of maternal serum fatty acid-binding protein 4 on insulin resistance and the development of gestational diabetes mellitus

Abstract

Fatty acid binding protein 4 (FABP4) was found to be closely correlated with gestational diabetes mellitus (GDM), a severe pregnancy syndrome. However, safe and efficient treatment for GDM is limited. We aimed to investigate whether inhibition of FABP4 could ameliorate GDM and the underlying mechanism. An evaluation of blood samples from a total of 109 patients showed significantly positive correlations between serum FABP4 and biochemical parameters known to associate with GDM. This correlation was subsequently explored in vitro. FABP4 inhibition was achieved using BMS309403 in GDM mice. GDM related symptoms, including insulin resistance and macrophage infiltration in the adipose tissues, were measured. Lipid metabolism in 3T3-L1 adipocytes was tested. We firstly confirmed the positive correlations between serum FABP4, insulin resistance and inflammation cytokines, including tumor necrosis factor-α (TNF) and interleukin-6 (IL-6), in GDM patients. Surprisingly, inhibition of FABP4 by BMS309403 resulted in significant alleviation of GDM symptoms in GDM mouse model. BMS309403 improved glucose and insulin tolerance and transcriptionally repressed the levels of TNF-α and IL-6, suggesting a role of FABP4 in inflammation. Furthermore, macrophage infiltration into the adipose tissues was dramatically decreased in the BMS309403-treated GDM mice compared to untreated GDM mice. Interestingly, incubation of 3T3-L1 adipocytes with FABP4 protein decreased the mRNA and protein levels of peroxisome proliferator-activated receptor γ (PPARγ), which was absent when BMS309403 was used. However, lipid accumulation was promoted in FABP4-treated 3T3-L1 adipocytes which showed no change in the presence of BMS309403. In conclusion, inhibition of FABP4 by BMS309403 could be an effective treatment to alleviate GDM.