Placental programming mediates the vicious cycle between maternal gestational diabetes and offspring type 2 diabetes in a novel mouse model

Abstract

Accumulating evidence from human epidemiological studies indicates that there is a vicious cycle between maternal gestational diabetes (GDM) and offspring type 2 diabetes (T2D). However, the underlying mechanisms remain unclear. A handful of studies found that mitochondrial defects occur in the GDM placenta, including excess accumulation of destroyed mitochondria, reduced ATP and enhanced ROS production, which indicates that mitophagy, a specific process to remove destroyed mitochondria, may be impaired in the GDM placenta. Our recent study suggested that BNIP3 plays a critical role in maintaining mitochondria homeostasis in human trophoblast cells. Therefore, in this study, we hypothesized that conditional knockout of BNIP3 specifically in mouse trophoblast cells will recapitulate the typical symptoms of GDM in maternal pregnancy and T2D in offspring. First, we made male mice with double homozygous Cre and LoxP by breeding Cyp19-Cre and Bnip3-LoxP mice, which was used to mate females with homozygous LoxP, forming a cKO group. On the other hand, wild-type female mice were bred by males with homozygous Cre, forming a control group (CT). Second, offspring from cKO and CT mothers were allowed to grow up. On Day 18 of pregnancy, glucose tolerance test was conducted in pregnant cKO or CT mice. The placental tissues were collected and mRNA and protein levels of BNIP3 were measured by qPCR and Western blotting, respectively. In male offspring at the age of eight months, glucose tolerance test was conducted, and metabolic rate was measured by CaloBox Indirect Calorimetry. All numerical parameters between the cKO and CT pregnant mice, and between their male offspring were analyzed by ANOVA (n=5). The main findings include: 1) On Day 18 of pregnancy, BNIP3 mRNA and protein levels in the placental tissue were reduced by 47% and by 40% in cKO compared to CT mice (p<0.05), respectively (p<0.05); 2) Pregnant cKO mice demonstrated enhanced glucose intolerance compared to those control mice; 3) At the age of 8 months, the body weight of male offspring from cKO mothers was increased by 1.16-fold (p<0.05) compared to those from CT mothers; 4) Male offspring from cKO mothers demonstrated enhanced glucose intolerance compared to those from CT mothers; 5) The metabolic rates was lower in male offspring from cKO mothers compared to those from CT mothers, with decreased oxygen consumption and carbon dioxide production by 1.18- and 1.19-fold, respectively (p<0.05). These results suggest that placental programming possibly via the disrupted functions of BNIP3 in trophoblast cells mediates the occurrence of maternal GDM and offspring T2D, therefore, placental BNIP3 may play a critical role in the vicious cycle of maternal GDM and offspring T2D and thus, being a potential target in treatment of GDM and prevention of T2D. NIH research grants R03HD095417, U54MD007597. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.