Maternal Obesity and Overnutrition Is Associated with Reduced Systemic Progesterone During the Estrous Cycles of Adult Female Offspring and a Marked Increase in Insulin Resistance at Midpregnancy.

Abstract

Previously published studies from our laboratory and others have demonstrated that maternal undernutrition (MU) and overnutrition (MO) alter fetal growth and development during intrauterine life, predisposing offspring to similar metabolic disturbances in postnatal life. We have recently demonstrated that MO predisposes nonpregnant female offspring to hyperphagia, increased obesity, and insulin resistance as adults. Further, we have reported that MU of ewes is associated with increased oxidative base lesions within DNA of mid-gestational (Day 78) fetal oogonia in sheep. More recently we have reported that female offspring born to MU ewes exhibited consistently reduced circulating progesterone concentrations during their estrous cycles, and reduced fertility when compared to female offspring born to ewes fed to NRC requirements. This study evaluated the impact of MO on systemic progesterone concentrations during an estrous cycle, fertility, and insulin resistance of adult female offspring at midgestation. Adult nonpregnant female offspring (2-3 years old) born to obese (OB) overnourished ewes fed 150% of NRC recommendations (n = 10), or 100% of NRC (Controls; CON, n=7) from 60 days prior to conception to term were utilized in this study. During an estrous cycle, ewes were bled daily from one estrus (Day 0) to the next, and serum collected and frozen at -80°C until analyzed for progesterone (P4) via validated RIA. At the second estrus, ewes were hand mated to an intact ram at 12hr intervals until the end of estrus. Conception rates and fetal numbers (singles and twins) were determined via real time ultrasonography, and pregnant ewes were subjected to an intravenous glucose tolerance test (IVGTT) at midgestation (75 ± 1 day). Plasma glucose and insulin was measured in triplicate by colorimetric assay and validated RIA, respectively. Estrous cycle length was reduced (P < 0.05) in the offspring of OB vs. CON ewes (17.2 ± 0.2 days vs. 18.0 ± 0.1 days). Further, serum progesterone concentrations were decreased (area under the curve, P < 0.05) during the estrous cycle of offspring from OB versus CON ewes. Baseline glucose and insulin concentrations were greater (P < 0.05) in offspring from OB vs. CON ewes, (64.03 ± 3.97 vs. 54.68 ± 1.30 mg/dL and 7.01 ± 2.18 vs. 3.43 ± 0.15 mIU/L, respectively). During the IVGTT, glucose concentrations remained greater (area under the curve; P < 0.01) than those of offspring from CON ewes during the post infusion period. Plasma insulin concentrations of OB offspring during IVGTT were also markedly increased (P < 0.03) when compared to offspring from CON ewes. These data suggest that the decrease in systemic progesterone exhibited by the OB offspring during their estrous cycles may contribute to the shortened estrous cycle lengths observed in this group. In spite of the decrease in circulating progesterone of OB offspring, however, conception rate and fecundity remained unaffected. Maternal overnutrition also resulted in a marked insulin resistance at midgestation in offspring of OB vs. CON ewes, suggesting that the F2 generation could exhibit the same metabolic alterations as their mothers resulting in a transgenerational programming effect. Supported in part by NIH INBRE #P20RR016474. (platform)