RESUMEN
Poor maternal nutrition during gestation can negatively affect offspring growth, development, and health pre- and post-natally. Overfeeding during gestation or maternal obesity (MO) results in altered metabolism and imbalanced endocrine hormones in animals and humans which will have long-lasting and detrimental effects on offspring growth and health. In this study, we examined the effects of overnutrition during gestation on autophagy associated pathways in offspring heart muscles at two gestational and one early postnatal time point (n = 5 for treated and untreated male and female heart respectively at each time point). Two-way ANOVA was used to analyze the interaction between treatment and sex at each time point. Our results revealed significant interactions of maternal diet by developmental stages for offspring autophagy signaling. Overfeeding did not affect the autophagy signaling at mid-gestation day 90 (GD90) in both male and female offspring while the inflammatory cytokines were increased in GD90 MO male offsrping; however, overfeeding during gestation significantly increased autophagy signaling, but not inflammation level at a later developmental stage (GD135 and day 1 after birth) in both males and females. We also identified a sexual dimorphic response in which female progeny were more profoundly influenced by maternal diet than male progeny regardless of developmental stages. We also determined the cortisol concentrations in male and female hearts at three developmental stages. We did not observe cortisol changes between males and females or between overfeeding and control groups. Our exploratory studies imply that MO alters autophagy associated pathways in both male and female at later developmental stages with more profound effects in female. This finding need be confirmed with larger sample numbers in the future. Our results suggest that targeting on autophagy pathway could be a strategy for correction of adverse effects in offspring of over-fed ewes.
RESUMEN
BACKGROUND: Understanding the mechanisms of N utilization for lactation can lead to improved requirement estimates and increased efficiency, which modern dairy diets currently fail to maximize. The mechanistic target of rapamycin complex 1 (mTORC1) is a central hub of translation regulation, processing extra- and intra-cellular signals of nutrient availability and physiological state, such as amino acids and energy. We hypothesized that dietary amino acids regulate lactation through mTORC1, such that inhibition of mTORC1 will lead to decreased lactation performance when amino acids are not limiting. Our objectives were to assess lactation performance in lactating mice undergoing dietary and pharmacologic interventions designed to alter mTORC1 activity. METHODS: First lactation mice (N = 18; n = 6/treatment) were fed an adequate protein diet (18% crude protein), or an isocaloric protein-restricted diet (9% crude protein) from the day after parturition until lactation day 13. A third group of mice was fed an adequate protein diet and treated with the mTORC1 inhibitor rapamycin (4 mg/kg every other day) intraperitoneally, with the first two groups treated with vehicle as control. Dams and pups were weighed daily, and feed intake was recorded every other day. Milk production was measured every other day beginning on lactation day 4 by the weigh-suckle-weigh method. Tissues were collected after fasting and refeeding. RESULTS: Milk production and pup weight were similarly decreased by both protein restriction and rapamycin treatment, with final production at 50% of control (P = 0.008) and final pup weight at 85% of control (P < 0.001). Mammary phosphorylation of mTORC1's downstream targets were decreased by protein restriction and rapamycin treatment (P < 0.05), while very little effect was observed in the liver of rapamycin treated mice, and none by protein restriction. CONCLUSIONS: Overall, sufficient supply of dietary amino acids was unable to maintain lactation performance status in mice with pharmacologically reduced mammary mTORC1 activity, as evidenced by diminished pup growth and milk production, supporting the concept that mTORC1 activation rather than substrate supply is the primary route by which amino acids regulate synthesis of milk components.