Nutrient restriction dynamically alters glucose tolerance and ceramide concentrations in periparturient ewes

The periparturient period in mammals is characterized by reduced insulin action, which allows nutrient partitioning to support fetal growth and milk synthesis. The sphingolipid ceramide is an established interrogator of insulin signaling in non-ruminants and accumulates during this period in dairy cows. We investigated the effects of short-term nutrient restriction (NR) on glucose tolerance and ceramide metabolism in multiparous ewes (n = 19) during this period. Ewes were fed ad libitum or subjected to two 5-d 50% NR periods in late gestation and early lactation. NR reduced circulating glucose and insulin and increased fatty acids, consistent with negative energy balance. Milk yield was lowered by lactational NR; however, production efficiency improved. Serial intravenous glucose tolerance tests revealed impaired glucose tolerance following gestational NR that was sustained across lactation, evidenced by greater glucose and fatty acid area-under-the-curves regardless of insulin secretion. Most plasma and milk ceramide subclasses were highly abundant in C24:0 and C24:1 acyl moieties; however, plasma lactosylceramide was differentially enriched with C16:0 and C20:1. NR induced biphasic shifts in plasma ceramide species and subclasses across the periparturient period, with peak ceramide and hexosylceramide species concentrations in early lactation prior to the second NR and opposite patterns in lactosylceramides. Milk ceramide and hexosylceramide profiles were distinct from plasma; however, lactosylceramide species responded similarly. Plasma lactosylceramide species also had a strong negative correlation to milk yield. Overall, NR induced coordinated endocrine, metabolic, and sphingolipid adaptations in periparturient ewes, implicating ceramides as potential mediators of metabolic regulation during this critical physiological transition.