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

Abstract

The progression of insulin resistance in dairy cows represents a maternal adaptation to support milk production during heightened energy demand; however, excessive adipose tissue lipolysis can develop. In diabetic non-ruminants, the mechanisms that mediate insulin resistance involve the sphingolipid ceramide. We tested the hypothesis that ceramide accumulates in dairy cows experiencing lipolysis and insulin resistance. Nine dairy cows were utilized in a replicated 3 × 3 Latin square design. Cows were ad libitum fed, nutrient-restricted (NR), or NR with nicotinic acid (NA; 5 mg of NA/h per kg BW; delivered i.v.) for 34 h. When provided access, cows were ad libitum fed a mixed ration of grass hay and ground corn to meet requirements. Intake for NR cows was limited to vitamins and minerals. Nicotinic acid was administered to suppress lipolysis. Saline was infused in cows not provided NA. At 32 and 33 h of treatment, a liver biopsy and insulin tolerance test were performed, respectively. Samples were analyzed using colorimetry, immunoassay, and mass spectrometry. Nutrient restriction increased serum fatty acids and ceramide levels, and impaired insulin sensitivity; however, NA infusion was unable to prevent these responses. We also show that NR increases hepatic ceramide accumulation, a response that was positively associated with serum ceramide supply. Our data demonstrate that circulating and hepatic 24:0-Cer are inversely associated with systemic insulin tolerance, an effect not observed for the 16:0 moiety. In conclusion, our results suggest that ceramide accrual represents a metabolic adaptation to nutrient restriction and impaired insulin action in dairy cows.

Review: Lipid biology in the periparturient dairy cow: contemporary perspectives

“…The enhanced supply of circulating and hepatic ceramide was also observed in non-pregnant and non-lactating Holstein cows intravenously infused a triglyceride emulsion, or feed-restricted to enhance circulating total FA concentrations (Davis et al, 2017;Rico et al, 2018a). In these studies, ceramide supply is positively related to circulating total FA supply, and inversely related to indirect and direct measures of systemic insulin sensitivity in cows (Rico et al, 2015 and2017a;Davis et al, 2017). These findings suggest that ceramide may antagonize insulinstimulated glucose uptake.…”

“…During the transition period, postpartum liver total and C24:0ceramide concentrations increase progressively in overconditioned dairy cows with hepatic lipid accumulation, and C16:0-ceramide concentrations increase in skeletal muscle tissue and plasma LDL fractions in all cows independent of prepartum body condition status (Rico et al, 2017a;Davis et al, 2019). The enhanced supply of circulating and hepatic ceramide was also observed in non-pregnant and non-lactating Holstein cows intravenously infused a triglyceride emulsion, or feed-restricted to enhance circulating total FA concentrations (Davis et al, 2017;Rico et al, 2018a). In these studies, ceramide supply is positively related to circulating total FA supply, and inversely related to indirect and direct measures of systemic insulin sensitivity in cows (Rico et al, 2015 and2017a;Davis et al, 2017).…”

Flaxseed Oil or n‐7 Fatty Acid‐Enhanced Fish Oil Supplementation Alters Fatty Acid Composition, Plasma Insulin and Serum Ceramide Concentrations, and Gene Expression in Lambs

“…The correlation between concentration of n‐7 fatty acids in muscle and 24:1‐MHexCer was negative (−0.46, p = 0.047); in contrast, the correlation between n‐7 concentration and 24LacCer was positive ( r = 0.24, p = 0.048). Davis et al () reported an inverse relationship between 24:0‐Cer levels and the clearance rate of glucose after an insulin challenge. Moreover, the development of maternal insulin resistance in ruminants develops with 24:0‐Cer accrual (Rico et al, , ).…”

“…Ceramides were extracted from serum using a modified Bligh and Dyer procedure and analyzed using an electrospray ionization source operating in positive ion mode that was coupled to a triple quadrupole mass spectrometer according to Davis et al (). Normalized ceramide and lactosylceramide (LacCer) concentrations were estimated by curve fitting the identified ceramide species based on acyl‐chain length.…”

Kick-starting ovarian cyclicity by using dietary glucogenic precursors in post-partum dairy cows: a review

“…Homeorhetic modifications occur PP to spare glucose and involve a decrease in insulin concentrations and tissue sensitivity to insulin [14]. Part of the mechanism is raised NEFA which reduce insulin sensitivity by provoking ceramide accumulation in plasma and liver [15,16]. When NEFA are mobilized palmitic acid increases [17] and it is a precursor of ceramides.…”