Prenatal food restriction causes adaptive changes in the metabolic regulation of reproductive physiology

Abstract

Reproduction is the most energetically expensive undertaking that a female can perform, making energy the most important factor regulating reproduction. Reproductive physiology is sensitive to fluctuations in energy availability, and entrainment of female reproductive efforts with energy availability is especially critical because of the large amounts of energy required for gestation and lactation. To optimize reproductive fitness in an environment with reduced food availability, physiological mechanisms are needed to connect oxidizable fuel availability with reproductive physiology. When prenatal food availability is restricted, indicators of reduced maternal energy availability reach the fetus. These signals purportedly prepare the offspring for a food insecure postnatal environment. According to this idea, the energy availability in the intrauterine environment organizes the developmentally plastic mechanisms responsible for energy homeostasis, which would necessarily impact the regulation of reproduction. Therefore, we hypothesized that gestationally nutrient restricted, low birth weight (LBW) offspring would exhibit changes in energy balance and reproductive physiology that would improve survival and reproductive success in a food insecure postnatal environment. To test this hypothesis, we used a well‐characterized model of gestational nutrient restriction where pregnant rats were fed ad libitum or 50% of their normal caloric intake from embryonic day 10 to 21 and all offspring were cross‐fostered to non‐restricted dams for lactation. Consistent with previous studies, restricted female offspring were born LBW (5.6 ± 0.08 vs. 6.5 ± 0.06, p<0.01). LBW offspring also had decreased hypothalamic gonadotropin releasing hormone (GnRH) protein expression at postnatal day (PND) 1 and exhibited rapid catch‐up growth during lactation. LBW female offspring had earlier vaginal opening (33.5 ± 0.2 vs. 38.2 ± 0.2 PND, p<0.01), demonstrating early pubertal onset. AT PND 60–90, LBW female offspring had elongated estrous cycles (6.1 ± 0.4 vs. 4.7 ± 0.3, p<0.05) and significant alterations in ovarian histology. For example, ovaries from young adult LBW females were larger (3.6 ± 0.7 vs. 6.5 ± 0.6 mm2, p<0.05) due to large antral, cyst‐like follicles. By 8 months of age, 80% of LBW offspring were in persistent estrous and had stopped cycling, compared to 0% of control offspring. These data indicate that prenatal energy availability has a significant impact on the regulation of reproductive physiology. Early pubertal onset, in particular, may be an adaptive mechanism to ensure reproductive success in a food‐insecure postnatal environment, but early puberty has significant health ramifications. Therefore, a more thorough understanding of the mechanisms responsible for gestational programming of the metabolic regulation of reproduction should have a significant impact on treatment of female reproductive problems such as polycystic ovary syndrome.Support or Funding InformationNSF CAREER IOS‐1350448