Somatotropin increases plasma ceramide in relation to enhanced milk yield in cows

https://doi.org/10.1016/j.domaniend.2020.106480Get rights and content

Highlights

  • Recombinant bovine somatotropin modifies the plasma lipidome in cows.

  • Somatotropin increases plasma total and very-long-chain ceramides.

  • Plasma ceramides were positively related to free fatty acids and milk production.

  • During somatotropin-induced increases in ceramides, insulin action appeared reduced.

Abstract

Recombinant bovine somatotropin (rBST) changes metabolism to spare glucose for milk synthesis in cows. Ceramides inhibit insulin responsiveness in bovine adipocytes and are associated with insulin resistance and milk production in cows. The mechanisms by which rBST supports lactation may involve ceramide. Eight multiparous lactating Holstein cows were enrolled in a 2 × 2 replicated Latin square design with 14-d periods. Cows received a single rBST injection (Posilac; Elanco Animal Health, Indianapolis, IN; 0.062 mg/kg BW) or no injection (CON). An epinephrine challenge, insulin tolerance test, and liver biopsy were performed. Somatotropin enhanced the conversion of feed nutrients into milk components and increased plasma free fatty acid (FFA) concentrations (P < 0.01). Area-under-the-curves for FFA in response to epinephrine and insulin were greater in rBST-treated cows. In response to insulin, glucose concentrations (20- and 30-min post-challenge) and insulin area-under-the-curve were higher with rBST treatment (P < 0.05, <0.10, and <0.01), suggesting insulin resistance. Somatotropin modified the plasma lipidome. For example, rBST decreased plasma di- and triacylglycerol levels (eg, DG-50:1 and TG-18:0/16:0/16:1), phosphatidylcholines and sphingomyelins (P < 0.05). Somatotropin increased plasma total and very-long-chain (C22:0-, C24:0-, C26:0-) ceramide concentrations (P < 0.01). Liver ceramide concentrations were not modified. Plasma ceramides were positively correlated with circulating FFA (r ~ 0.57; P < 0.05) and milk yield (r ~ 0.63; P < 0.05). We conclude that rBST administration modifies the bovine lipidome and increases plasma ceramide concentrations in association with increased milk production in cows.

Introduction

In dairy cows experiencing positive energy balance, somatotropin (ST) is released from the anterior pituitary and stimulates insulin-like growth factor 1 (IGF-1) production from the liver. Insulin-like growth factor 1 inhibits further ST release [1,2] and acts as an insulin-sensitizer to facilitate glucose uptake by peripheral tissues [3]. In periparturient cows experiencing negative energy balance, the ST-IGF-1 axis becomes uncoupled, likely due to the reduction in GH receptor 1A mRNA in the liver [[4], [5], [6]]. This uncoupling leads to an increase in circulating ST, while IGF-1 and insulin concentrations decrease [5,7,8]. The reduction of these hormones decreases anabolism and increases catabolism in peripheral tissues [4]. The elevation in ST develops with the downregulation of insulin signaling in the skeletal muscle and favors partitioning of nutrients (eg, glucose and free fatty acids [FFAs]) to the mammary gland to support milk synthesis [9,10]. Effects of ST on insulin-stimulated glucose uptake in adipose tissue is less clear.

Administration of recombinant bovine somatotropin (rBST) to mid- and late-lactation cows restores homeorhetic mechanisms to increase milk yield. For instance, rBST decreases insulin-stimulated glucose uptake into peripheral tissues, and inhibits insulin's ability to promote lipogenesis [9,11,12]. Administration of rBST also increases responsiveness to catecholamines, which promotes mobilization of fuel reserves to meet short-term energy demands [11]. The mechanisms by which rBST inhibits peripheral glucose utilization is not completely understood. It is important to define these mechanisms to develop nutrition-based strategies aimed at enhancing milk production efficiency.

In nonruminants, ceramides are elevated during states of FFA oversupply (ie, obesity and type 2 diabetes) and are correlated with the degree of insulin resistance [13]. When pharmacologic approaches are used to decrease circulating ceramides in diabetic models, insulin sensitivity is restored [14]. In cows, plasma ceramides are elevated during early lactation, more-so for cattle experiencing increased lipolysis and insulin resistance [15,16]. Furthermore, ceramide concentrations increase in the plasma, liver, and muscle during nutritional interventions that increase FFA supply [[17], [18], [19]]. We have also observed that circulating ceramide concentrations are inversely related to insulin sensitivity and positively associated with milk yield [16,17,20]. An increase in ceramide production may modulate insulin sensitivity in cows to spare glucose for milk production. Since ceramides are synthesized de novo from FFA and acute administration of rBST can increase circulating FFA levels in cows, the potential exists that rBST increases milk production through ceramide-dependent mechanisms.

The primary objective of this study was to determine if rBST-induced increases in milk production involve an increase in circulating ceramides. We hypothesized that administration of rBST would increase plasma FFA and ceramide concentrations, as well as liver ceramide concentrations. We also expected an increase in ceramide supply to be in positive association with circulating FFA concentrations and milk yield. Considering rBST induces major shifts in lipid metabolism to support milk production, a secondary objective was to characterize the plasma lipidome in response to rBST. We hypothesized that rBST would decrease the concentrations of complex plasma lipids, such as acylglycerols (di- and triacylglycerols [DGs and TGs, respectively]), phosphatidylcholines (PCs), and sphingomyelins (SMs).

Section snippets

Experimental design

Experimental procedures were approved by the Cornell University Institutional Animal Care and Use Committee (protocol #2017–0077). The experiment was completed at the Cornell University Dairy Research Center (Hartford, NY). Eight multiparous, Holstein dairy cows (195 ± 34.1 d in milk [DIM]; 2.50 ± 0.53 parity; 2.99 ± 0.21 BCS [5-point scale; Wildman et al, 1982]; 706 ± 19.9 kg BW) were enrolled in a 2 × 2 replicated Latin square design with 14-d periods and a 7-d washout period. Cows received a

Effects of recombinant bovine somatotropin on milk, efficiency, and energy balance

Cows were fed a lactation diet primarily composed of corn silage, mixed legume haylage, and concentrates (Supplemental Table 1). Recombinant bovine somatotropin increased milk yields compared with CON by d 3 (Fig. 1A; P < 0.01), an effect that was sustained for the remainder of the experimental period. The maximum difference in milk yield between the groups was 7.93 kg on d 9 of the period (Fig. 1A; P < 0.01). Milk fat yield and percent, and milk protein and lactose yields were increased in

Discussion

Previous studies have reported that rBST administration improves the efficiency to produce milk due to increased nutrient partitioning to the mammary gland [28]. We observed that acute administration of rBST increased milk yield, milk components, 3.5% FCM, and ECM, while DMI remained unchanged, resulting in an improvement in the efficiency of nutrient use for lactation. The increase in milk fat content and yield can be explained by elevations in adipose tissue lipolysis, which would result in a

Conclusions

We conclude that rBST administration increases circulating ceramide concentrations in dairy cattle, which suggests a role for these sphingolipids in rBST-induced increases in milk production. During the ITT, we observed elevated glucose concentrations, a tendency for reduced glucose clearance (20 min), and elevated insulin AUC, suggesting that insulin-stimulated glucose disposal was likely impaired. Considering plasma FFA were elevated and correlated with VLC ceramides in rBST-treated cows, we

CRediT authorship contribution statement

A.N. Davis: Writing - original draft, Conceptualization, Methodology, Visualization, Formal analysis, Investigation. W.A. Myers: Investigation. C. Chang: Investigation. B.N. Tate: Investigation. J.E. Rico: Methodology, Investigation. M. Moniruzzaman: Resources. N.J. Haughey: Resources. J.W. McFadden: Funding acquisition, Supervision, Conceptualization, Methodology.

Acknowledgments

The authors gratefully acknowledge M. Elena Diaz and the BRC Metabolomics Facility at Cornell's Institute of Biotechnology for lipidomics analysis, as well as the Cornell University Ruminant Center staff for their assistance with this project. This work was supported by the United States Department of Agriculture (USDA-2016–67015–24582) and the National Science Foundation Graduate Research Fellowship Program (DGE-1650441). The funding bodies did not have any role in the study design, data

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