Programming of Fetal Insulin Resistance in Pregnancies with Maternal Obesity by ER Stress and Inflammation

Figure 2

Proposed model of interaction among maternal obesity, ER stress, and insulin resistance. Maternal obesity is related to ER stress response in HUVEC, involving activation of ER stress proteins PERK and ATF6. ATF6 is released from ER membranes and then processed in the Golgi by proteolytic cleavage promoting its nuclear translocation. On the other hand, PERK is autophosphorylated (grey circles) and is able to phosphorylate eIF2α, leading to induction of ATF4. Moreover, eIF2α can also be phosphorylated by PKR, which is also an ER stress-dependent protein. Hence, both ATF6 and ATF4 nuclear translocations may be able to alter insulin signaling and lead to insulin resistance in HUVEC through reduction of AKT and MAPK phosphorylation. In parallel, PKR activation may cause insulin signaling inactivation through IRS-1 inhibitory phosphorylation (red circles). Solid lines represent previously established processes; dashed lines and question marks indicate hypothetical and unknown mechanisms in our model.