Adiponectin ameliorates placental injury in gestational diabetes mice by correcting fatty acid oxidation/peroxide imbalance-induced ferroptosis via restoration of CPT-1 activity

Abstract

Purpose In gestational diabetes (GDM), abnormalities occur not only in glucose metabolism, but also in lipid metabolism. Adiponectin (ADPN) plays an important role in the regulation of lipid metabolism. In this paper, the role and mechanism of ADPN in GDM are discussed. Methods GDM model was formed in pregnant mice induced by high-fat diet and streptozotocin, and blood glucose level was detected after ADPN treatment. The levels of TG, TC, HDL-C, and LDL-C in blood lipid of mice were detected by biochemical apparatus. HE staining was used to detect the placenta damage in mice. The expression of oxidative stressrelated indexes in placental tissues was also detected by ELISA. Placental iron deposition was detected by Prussian blue staining. Redox capacity of placental tissue was detected by ELISA. Western blot was used to detect the expression of ferroptosis-related proteins in placental tissues. The expression of ADPN in placenta and peripheral blood was detected by ELISA, and the expression of ADPNR, downstream CPT-1, and GLUT4 of placenta were detected by RT-qPCR and western blot. Subsequently, trophoblast cells were induced by palmitic acid and glucose, and the cell activity was detected by CCK-8. The results in animal experiments were verified in cell experiments by RT-qPCR, western blot, and fluorescence labeling of iron ions. Finally, ADPN and CPT-1 inhibitor PM were given to trophoblast cells to further explore the mechanism.Results ADPN inhibited blood glucose and lipid levels in GDM mice. ADPN inhibited oxidation/peroxide imbalanceinduced ferroptosis in placental tissues of GDM mice. ADPN inhibited the expression of CPT-1 and GLUT4 in placental tissues of GDM mice. This result was also confirmed in cell experiments, and this process may be achieved by regulating CPT-1. Conclusions ADPN ameliorated placental injury in GDM by correcting fatty acid oxidation/peroxide imbalance-induced ferroptosis via restoration of CPT-1 activity.

Ferroptosis and ferritinophagy in diabetes complications

“…Adiponectin, as an adipocyte inflammatory factor, is beneficial to metabolic diseases such as diabetes [ 132 ]. Recent studies have shown that adiponectin inhibits the expression of carnitine palmityl transferase 1 (CPT1) and Glucose transporter 4 (GLUT4) in placenta tissue in order to resist the accumulation of lipid peroxides-induced ferroptosis, thereby improving placental injury in gestational diabetes mellitus (GDM) [ 133 ]. Moreover, the intervention effect of natural bioactive compounds is worthy of further exploration.…”

Role of ferroptosis in pregnancy related diseases and its therapeutic potential

“…Furthermore, it was found that HL and HG can induce GDM in pregnant rats, leading to the damage of rats’ placenta ( He et al, 2021 ). The expression of ACSL4 significantly increased in placental tissues, as well ( Zheng et al, 2022 ). Consequently, excessive FFA of GDM may cause an increase in the level of lipid peroxidation, resulting in ferroptosis.…”

“…As reported, both elevated plasma ferritin concentrations and iron supplementation in pregnant women having adequate iron stores are risk factors of GDM ( Zhang et al, 2021 ). In GDM vivo model, the levels of iron deposition significantly increased ( Zheng et al, 2022 ), inducing the production of ROS via the Fenton reaction. As a result, oxidative damage leads to the injury and ferroptosis of pancreatic β–cell in GDM ( Gautam et al, 2021 ; Du et al, 2022 ).…”

Ferroptosis in female reproductive diseases: from potential pathogenesis to therapy

“…Adiponectin, a lipid metabolism regulator, can reduce placental injury in GDM by restoring CPT-1 activity to inhibit ferroptosis. 80…”