Metoclopramide induces preparturient, low-level hyperprolactinemia to increase milk production in primiparous sows.

Inadequate milk production by sows often limits the growth of piglets. A successful lactation requires prolactin (PRL)-induced differentiation of the alveolar epithelium within the mammary glands of sows between days 90-110 of gestation. We hypothesized that induction of late gestational hyperprolactinemia in primiparous sows by oral administration of the dopamine antagonist metoclopramide (MET) would enhance mammary epithelial differentiation, milk yield, and piglet growth rate and that these effects would carry over into a subsequent lactation. Twenty-six gilts were assigned to receive either MET (n = 13, 0.8 mg/kg) or vehicle (CON, n = 13) twice daily from days 90-110 of gestation. The same sows were followed into their second lactation without additional treatment. On day 90 of gestation, circulating PRL concentrations peaked 45 min after feeding MET (P < 0.001) and then returned to baseline 3 h later. This response occurred daily out to day 104 of gestation (P < 0.05). Compared with CON, MET-treated gilts had enlarged alveoli on gestation day 110 (P < 0.05). Treatment with MET did not affect feed intake, body weight, or body fatness during pregnancy or lactation. Piglets born to MET-treated sows had both increased body weights and average daily gain on lactation days 14 and 21 (P < 0.05). Milk intake by piglets was estimated from deuterium oxide dilution. Although milk intake by piglets nursing MET sows was not statistically different from those nursing CON sows on day 21 of lactation (P = 0.18), there was a greater increase in milk consumption by piglets born to MET-treated sows between days 9 and 21 of lactation than for those in CON litters (P < 0.001). In one group of second parity sows (n = 11) that were treated with MET during their first gestation, milk yield increased by 21% during their second lactation (P < 0.05) in association with a 14% decline in body fatness across lactation compared with a 7% decline in CON sows (P < 0.05). These findings demonstrate that MET-induced hyperprolactinemia in primiparous sows during late pregnancy can increase milk yield and piglet growth rate, setting the stage for further large-scale studies.

Effects of body condition score on direct and indirect measurements of insulin sensitivity in periparturient dairy cows.

Reductions in insulin sensitivity in periparturient dairy cows develop as a means to support lactation; however, excessive mobilization of fatty acids (FA) increases the risk for peripartal metabolic disorders. Our objectives were to investigate the effect of prepartum body condition score (BCS) on systemic glucose and insulin tolerance, and to compare direct and indirect measurements of insulin sensitivity in peripartal lean and overweight dairy cows. Fourteen multiparous Holstein cows were allocated into two groups according to their BCS at day -28 prepartum: lean (n = 7; BCS ≤ 3.0) or overweight; (n = 7; BCS ≥ 4.0). Liver biopsies were performed on day -27, -14 and 4, relative to expected parturition. Intravenous insulin or glucose tolerances tests were performed following each liver biopsy. Relative to lean cows, overweight cows exhibited lower dry matter intake, lost more BCS and displayed increased plasma FA and ß-hydroxybutyrate concentrations and elevated liver lipid content during peripartum. Glucose clearance rate was lower for all cows postpartum. Prepartum BCS had minimal effects on insulin and glucose tolerance; however, the ability of the cow to restore blood glucose levels following an insulin challenge was suppressed by increased BCS. Glucose-dependent parameters of insulin and glucose tolerance were not correlated with surrogate indices of insulin sensitivity. We conclude that prepartum BCS had minimal effect on systemic insulin sensitivity following parturition. The observed inconsistency between surrogate indices of insulin sensitivity and direct measurements of insulin and glucose tolerance adds support to growing concerns regarding their usefulness as tools to estimate systemic insulin action in periparturient cows.

Using domperidone to induce and sustain hyperprolactinemia in late-pregnant gilts.

Prolactin controls mammary development as well as the lactogenic and galactopoietic processes in sows and increasing prolactin during gestation can augment milk yield. The dopamine receptor antagonist domperidone can increase circulating prolactin concentrations in pigs, but the ideal dose to achieve sustained hyperprolactinemia remains unknown. An experiment was performed to develop a protocol for using domperidone in studies of rapid and sustained hyperprolactinemia in late-pregnant gilts. On day 90 of gestation, gilts were divided into 4 groups: (1) intramuscular (IM) injections of canola oil (3 mL, controls [CTL], n = 9), (2) IM injections with 0.1 mg/kg BW of domperidone (low [LO], n = 8), (3) IM injections with 0.5 mg/kg BW of domperidone (medium [ME], n = 11), and (4) IM injections with 1.0 mg/kg BW of domperidone (high [HI], n = 11). Injections were given daily at 8:05 from days 90 to 109 of gestation. Treated gilts also received domperidone per os (0.5 mg/kg BW) at 8:00 and 20:00 on days 89, 90, and 91 of gestation. Three jugular blood samples were collected from all gilts at 6-h intervals on days 89, 90, and 91 of gestation, then twice daily on days 92, 93, and 94. Thereafter, samples were obtained at 8:00 every other day until day 114 of gestation. Blood was sampled serially from 9 CTL and 11 HI gilts on days 89 and 94 of gestation. On day 89 of gestation, prolactin concentrations for LO, ME, and HI gilts increased within 6 h of domperidone per os (P < 0.001). From days 89 until 93 of gestation, the area under the curve (AUC) for LO, ME, and HI gilts was greater than that for CTL gilts (P < 0.001), whereas from days 89 until 114, ME and HI gilts had greater AUC than CTL and LO gilts (P < 0.05). Results demonstrate that the combination of per os treatment with IM injections of 0.5 mg/kg of domperidone in an oil emulsion leads to the rapid and sustained release of prolactin over 24 d in late-pregnant gilts. Higher doses of domperidone failed to further increase circulating prolactin levels. These findings provide a useful strategy to induce sustained hyperprolactinemia in late-pregnant gilts.

Increasing palmitic acid intake enhances milk production and prevents glucose-stimulated fatty acid disappearance without modifying systemic glucose tolerance in mid-lactation dairy cows.

Feeding saturated fatty acids may enhance milk yield in part by decreasing insulin sensitivity and shifting glucose utilization toward the mammary gland. Our objective was to evaluate the effects of palmitic acid (C16:0) on milk production and insulin sensitivity in cows. Twenty multiparous mid-lactation Holstein cows were enrolled in a study consisting of a 5-d covariate, 49-d treatment, and 14-d posttreatment period. All cows received a common sorghum silage-based diet and were randomly assigned to a diet containing no supplemental fat (control; n=10; 138±45d in milk) or C16:0 at 4% of ration DM (PALM; 98% C16:0; n=10; 136±44d in milk). Blood and milk were collected at routine intervals. Intravenous glucose tolerance tests (300mg/kg of body weight) were performed at d -1, 24, and 49 relative to start of treatment. Data were analyzed as repeated measures using a mixed model with fixed effects of treatment and time, and milk yield served as a covariate. The PALM treatment increased milk yield by wk 7. Furthermore, PALM increased milk fat yield and energy-corrected milk at wk 3 and 7. Changes in milk production occurred in parallel with enhanced energy intake. Increased milk fat yield during PALM treatment was due to increased C16:0 and C16:1 incorporation; PALM had no effect on concentration of milk components, BW, or body condition score. Two weeks posttreatment, energy-corrected milk and milk fat yield remained elevated in PALM-fed cows whereas yields of milk were similar between treatments. Increased milk fat yield after PALM treatment was due to increased de novo lipogenesis and uptake of preformed fatty acids. The basal concentration of nonesterified fatty acids (NEFA) in plasma increased by d 4, 6, and 8 of PALM treatment, a response not observed thereafter. Although PALM supplementation did not modify insulin, glucose, or triacylglycerol levels in plasma, total cholesterol in plasma was elevated by wk 3. Estimated insulin sensitivity was lower during the first week of PALM treatment; however, glucose disposal following glucose tolerance tests was not modified. In contrast, C16:0 feeding reduced glucose-stimulated NEFA disappearance by wk 7. Results demonstrate that increasing dietary energy from C16:0 for 7wk improves milk yield and milk composition without modifying systemic glucose tolerance. Reduced glucose-stimulated NEFA disappearance with C16:0 feeding and elevated circulating NEFA may reflect changes in adipose tissue insulin sensitivity.

Palmitic acid feeding increases ceramide supply in association with increased milk yield, circulating nonesterified fatty acids, and adipose tissue responsiveness to a glucose challenge.

Reduced insulin action is a key adaptation that facilitates glucose partitioning to the mammary gland for milk synthesis and enhances adipose tissue lipolysis during early lactation. The progressive recovery of insulin sensitivity as cows advance toward late lactation is accompanied by reductions in circulating nonesterified fatty acids (NEFA) and milk yield. Because palmitic acid can promote insulin resistance in monogastrics through sphingolipid ceramide-dependent mechanisms, palmitic acid (C16:0) feeding may enhance milk production by restoring homeorhetic responses. We hypothesized that feeding C16:0 to mid-lactation cows would enhance ceramide supply and ceramide would be positively associated with milk yield. Twenty multiparous mid-lactation Holstein cows were enrolled in a study consisting of a 5-d covariate, 49-d treatment, and 14-d posttreatment period. All cows were randomly assigned to a sorghum silage-based diet containing no supplemental fat (control; n=10; 138±45 d in milk) or C16:0 at 4% of ration dry matter (PALM; 98% C16:0; n=10; 136±44 d in milk). Blood and milk were collected at routine intervals. Liver and skeletal muscle tissue were biopsied at d 47 of treatment. Intravenous glucose tolerance tests (300mg/kg of body weight) were performed at d -1, 24, and 49 relative to start of treatment. The plasma and tissue concentrations of ceramide and glycosylated ceramide were determined using liquid chromatography coupled with tandem mass spectrometry. Data were analyzed as repeated measures using a mixed model with fixed effects of treatment and time, and milk yield served as a covariate. The PALM treatment increased milk yield, energy-corrected milk, and milk fat yield. The most abundant plasma and tissue sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide (GlcCer), and C16:0-lactosylceramide. Plasma concentrations of total ceramide and GlcCer decreased as lactation advanced, and ceramide and GlcCer were elevated in cows fed PALM. Palmitic acid feeding increased hepatic ceramide levels, a response not observed in skeletal muscle tissue. Plasma ceramides (e.g., C24:0-ceramide) were positively correlated with plasma NEFA and milk yield, and positively correlated with NEFA levels following a glucose challenge. Our data demonstrate a remodeled plasma and hepatic sphingolipidome in mid-lactation dairy cows fed PALM. The potential involvement in ceramide in homeorhetic nutrient partitioning to support lactation requires further consideration.