Hyperglycemia Is Associated with Infertility and Placental Dysfunction in Obese Mice

Presentation Number: SAT 589
Date of Presentation: April 1st, 2017

Erica B Mahany*, Nicole H Bellefontaine, Xingfa Han and Carol F Elias
University of Michigan, Ann Arbor, MI


The prevalence of diabetes in the reproductive-aged population is increasing, with an estimated 10-25% of pregnant women classified as having hyperglycemia in pregnancy. These women are at increased risk for pregnancy complications, including miscarriage, congenital anomalies, preeclampsia, macrosomia, and perinatal mortality. To gain insight into the underlying mechanisms, we utilized a mouse model of obesity- and diabetes-induced miscarriage to evaluate for alterations in blood glucose in obese and diabetic mice. We selectively restored the leptin receptor in the ventral premammillary nucleus (PMV) of the hypothalamus in mice otherwise null for the leptin receptor with targeted injections of a viral vector, allowing for the improvement of fertility without altering the obese and diabetic phenotype. Of 19 “PMV hit” mice, vaginal openings were followed, and all underwent puberty. They were mated with wild type (WT) males with proven fertility. Tissue and trunk blood were harvested when the dam was noted to be pregnant, based on thrice weekly body weight measurements, and embryos corresponded to mid-gestation (E9.5-15.5). Blood samples were obtained before perfusion. Only 10 of the 19 PMV hit females became pregnant; however, 80% of pregnant mice showed embryo resorptions. When compared with pregnancies of WT control mice, the mean number of implantations was similar (7.6±0.8 vs. 6.6±0.6, p=NS), although the percentage of resorptions in the obese mice was significantly higher (32.6±10.5% vs. 6.0±2.7%, p=.008). Interestingly, serum glucose was significantly lower in the PMV hit mice that became pregnant compared with the PMV hit mice that did not become pregnant (224±20 vs. 343 ± 31 mg/dL, p=.009), which was also significantly different from the WT mice, all of which got pregnant (159±10 mg/dL, p<.05 for each). Histologically, the embryos did not have malformations, although the placentas did have increased necrosis and inflammation. RT-qPCR was performed and several genes associated with angiogenesis and cellular growth were differentially expressed in the pathologic mouse placentas (e.g., Mdk, Figf, Tlr3, Crh, Timp2, Inha, Qpct, Bhlhe40, and Hif1α). The higher glucose levels in the non-pregnant obese mice compared with the pregnant obese mice suggest that hyperglycemia may have contributed to infertility. Comparing the glucose levels of the pregnant obese mice to the pregnant WT mice, hyperglycemia may have contributed to problems with pregnancy maintenance. These data show that obesity and hyperglycemia have deleterious effects on placental function and embryo development and set the stage for poor pregnancy outcome.


Nothing to Disclose: EBM, NHB, XH, CFE