Positive Correlation between Enhanced Expression of TLR4/MyD88/NF-κB with Insulin Resistance in Placentae of Gestational Diabetes Mellitus

Abstract

Insulin resistance (IR) is a critical factor of the pathophysiology of Gestational diabetes mellitus (GDM). Studies on key organs involved in IR, such as livers and adipose tissues, showed that Toll-like receptor 4 (TLR4) can regulate insulin sensitivity. As a maternal-fetal interface with multi-functions, placentae could contribute to the development of IR for GDM. Thus, we investigated the expressions of TLR4/Myeloid Differentiation factor 88 (MyD88)/Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) in term placentae from 33 GDM women and 36 healthy pregnant women with normal glucose tolerance, evaluated local and systemic IR and furthermore identified the association between placental TLR4 and IR. TLR4 protein was expressed in various cells of term placenta, particularly in syncytiotrophoblast of villi. Compared with normal pregnancy, the expression of TLR4/MyD88/NF-kB pathway increased in the placenta of GDM (p<0.05), and these differences were more pronounced in the maternal section of the placenta and the syncytiotrophoblast of villi. In addition, more severe IR was observed in the placenta of GDM patients than the control group, evidenced with higher pIRS-1(ser312) (p<0.001) and lower IRS-1 (p<0.05) as well as pAkt proteins (p<0.01). The expression of TLR4 in placentae is positively correlated with local IR (pIRS-1: r = 0.76, p <0.001 and pAkt: r = -0.47, p <0.001) and maternal fasting (r = 0.42, p <0.01), one-hour (r = 0.52, p <0.01) and two-hour glucose (r = 0.54, p <0.01) at OGTT. We found an that enhanced expression of the TLR4-MyD88-NF-kB pathway occurs in GDM placentae, which positively correlates with heightened local IR in placentae and higher maternal hyperglycemia. The TLR4/MyD88/NF-kB pathway may play a potential role in the development of IR in placentae of GDM.

Celastrol reverses palmitic acid (PA)‐caused TLR4‐MD2 activation‐dependent insulin resistance via disrupting MD2‐related cellular binding to PA

“…Glucose transport (GLUT-1 and GLUT-4, but not GLUT-2) and IRS-1 were decreased by PA stimulation in HepG2 cells, while increased by celastrol. Our results are consistent with previous findings that beneficial actions of Omega-3-polyunsaturated fatty acids and their bioactive lipid autacoids in preventing obesity-induced insulin resistance and hepatic steatosis through up-regulating GLUT-2/GLUT-4 and IRS-1/IRS-2 (Gonzalez-Periz et al, 2009). Celastrol expelled PA from cells, likely due to occupying the MD2 pocket to which PA binds, predicted by molecular docking (Supplementary Figure S4) as well as indicated by our results that cell pre-incubation or post-incubation with celastrol reduced the amount of PA binding in vitro.…”

“…Moreover, with high fat diet (HFD), plasma FFAs can activate the NF‐κB in target tissues, then initiate negative crosstalk between FFAs and insulin signaling. The enhanced expression of TLR4‐MyD88‐NF‐κB pathway occurs in placentae of patients with gestational diabetes mellitus, which positively correlates with heightened local insulin resistance in placentae and higher maternal hyperglycemia (Feng et al, ). FFA components such as PA can bind to TLR4, thus mediating the activation of TLR4 and NF‐κB pathways and leading to the inflammatory cascade (Sun et al, ).…”

Effects of maternal obesity on placental function and fetal development

“…Placental TLR4 expression has been reported to be elevated three to nine-fold in obese mothers and is positively correlated to maternal and placental IL-6 expression (Yang et al 2016). Similarly, in women with GDM, placental TLR4 expression is correlated with maternal hyperglycemia and insulin resistance (Feng et al 2016). In liver, expression of TLR4 constitutes an important mechanistic link between high fat diet/obesity and insulin resistance (Jia et al 2014).…”

Molecular pathways disrupted by gestational diabetes mellitus

“…The importance of the NF-κB pathway extends to GDM -increased NF-κB mRNA has been reported in the GDM placenta (Feng et al 2016). While its expression in adipose tissue or skeletal muscle of GDM pregnancies are yet to be assessed, NF-κB remains a key factor for the regulation of the inflammation in these tissues obtained from pregnant women at the time of term Caesarean section (Lappas et al 2005b).…”