Temporal changes in sphingolipids and systemic insulin sensitivity during the transition from gestation to lactation

Abstract

Reduced insulin action develops naturally during the peripartum to ensure maternal nutrient delivery to the fetus and neonate. However, increased insulin resistance can facilitate excessive lipolysis which in turn promotes metabolic disease in overweight dairy cattle. Increased fatty acid availability favors the accumulation of the sphingolipid ceramide and is implicated in the pathogenesis of insulin resistance, however, the relationship between sphingolipid metabolism and insulin resistance during the peripartum remains largely unknown. Our objectives were to characterize temporal responses in plasma and tissue sphingolipids in lean and overweight peripartal cows and to establish the relationships between sphingolipid supply and lipolysis, hepatic lipid deposition, and systemic insulin action. Twenty-one multiparous lean and overweight Holstein cows were enrolled in a longitudinal study spanning the transition from gestation to lactation (d -21 to 21, relative to parturition). Plasma, liver, and skeletal muscle samples were obtained, and sphingolipids were profiled using LC/MS/MS. Insulin sensitivity was assessed utilizing intravenous insulin and glucose challenges. Our results demonstrated the following: first, insulin resistance develops postpartum concurrently with increased lipolysis and hepatic lipid accumulation; second, ceramides and glycosylated ceramides accumulate during the transition from gestation to lactation and are further elevated in overweight cows; third, ceramide accrual is associated with lipolysis and liver lipid accumulation, and C16:0- and C24:0-ceramide are inversely associated with systemic insulin sensitivity postpartum; fourth, plasma sphingomyelin, a potential source of ceramides reaches a nadir at parturition and is closely associated with feed intake; fifth, select sphingomyelins are lower in the plasma of overweight cows during the peripartal period. Our results demonstrate that dynamic changes occur in peripartal sphingolipids that are influenced by adiposity, and are associated with the onset of peripartal insulin resistance. These observations are in agreement with a putative potential role for sphingolipids in facilitating the physiological adaptations of peripartum.

Nutrient Restriction Increases Circulating and Hepatic Ceramide in Dairy Cows Displaying Impaired Insulin Tolerance

“…These conditions can promote fatty liver disease and ketosis which can compromise the health, fertility, and longevity of the cow. In non-ruminants, ceramide is a central mediator of insulin resistance, lipolysis, and hepatic lipid accumulation [4,7,33], and we have observed increased plasma ceramide levels in dairy cows transitioning from gestation to lactation [9,10]. In our current study, we validated previous work that demonstrated impaired insulin action in response to energy deficit [32].…”

“…3a and 4a). Consistent with previous observations in peripartal dairy cows experiencing negative energy balance [9,10], we observed a marked increase in circulating ceramide during nutrient restriction, relative to ad libitum feeding (Fig. 3b, f).…”

“…We have recently established that circulating ceramide (e.g., 24:0-Cer) is elevated in dairy cows transitioning from gestation to lactation [9,10], and in lactating cows fed supplemental palmitic acid [11]. Moreover, we demonstrated that circulating ceramide is positively related to FFA supply and inversely associated with insulin sensitivity [10][11][12]. We propose that ceramide may represent a maternal adaptation to support nutrient partitioning and milk production in dairy cattle.…”

“…As a consequence, phosphodiesterase 3B (PDE3B) is inactivated, cAMP accumulates, and the lipolytic release of unesterified fatty acids (FFA) is enhanced [7,8]. We have recently established that circulating ceramide (e.g., 24:0-Cer) is elevated in dairy cows transitioning from gestation to lactation [9,10], and in lactating cows fed supplemental palmitic acid [11]. Moreover, we demonstrated that circulating ceramide is positively related to FFA supply and inversely associated with insulin sensitivity [10][11][12].…”

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

“…2014; Rico et al. 2017). Researchers that have recently evaluated tissue ceramide supply and insulin action have proposed that C16:0 ceramide is a proapoptotic mediator of the pathophysiology of insulin resistance in response to a high saturated fat diet, and in contrast, C24:0 ceramide confers antiapoptotic and proliferative functions (Raichur et al.…”