During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFa) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in non-lactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 ERK1/2 following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21 resistant state.

Neonatal calf survival and health is predominantly dependent on sufficient consumption of immunoglobulin G (IgG) and the resulting transfer of passive immunity (TPI). In this study we investigate the potential for continued IgG secretion and temporal kinetics of mammary IgG output in sequential milkings performed at 0, 4, 16, 28, 40 and 52 hours post-calving in Holstein dairy cows. For colostrum (0 hour), we also scrutinize the relationships between IgG concentration, volume, refractometer readings (˚Bx values, Brix ®) and concentration of sugars (lactose and glucose). Mammary transcripts postpartum (0 hour) indicated that active IgG secretion continues beyond the first milking (colostrum; n=4-5). IgG measurements at the different timepoints indicated that colostrum represents only 25.1% of the total IgG produced across the six sequential milking timepoints, with a substantial 48.9% being secreted into transition milk over the next three timepoints (4-, 6- and 28-hour) combined. The differences on the basis of IgG concentrations across 0-, 4- and 16-hour milking timepoints were not statistically significant (p=0.1522; n=9). For colostrum, volume remained highly variable, even with induced let-down prior to milking (n=27). Nonetheless, colostrum IgG secretion was significantly co-regulated with volume (R 2=0.915; p<0.001; n=18), an association that was stronger than that measured for lactose (R 2=0.803; p<0.001; n=18) and glucose (R 2=0.467; p=0.002; n=17). Comparing colostrum ˚Bx values to absolute IgG concentrations showed no correlation (R 2=0.127; p=0.07; n=27); biochemical separation of colostrum components indicated that both proteins and non-protein solutes could affect ˚Bx values (p<0.0001 for both; n=5). This suggests that ˚Bx values do not reasonably indicate IgG concentration to serve as a measure of “colostrum quality.” Additionally, our finding that early transition milk (4-, 6- and 28-hour) can contribute substantially more IgG than colostrum forces a rethink of existing feeding paradigms and means to maximize TPI in calves. Collectively, our results reveal the remarkable value of early transition milk and caveats to colostrum assessments that could advance application in enhancing neonatal calf health.

Maternal-offspring coevolution has introduced the biological concept of “neonatal programming,” in which soluble proteins of varying abundance in bovine colostrum can have targeted activities in the calf gut. Still, the identities and developmental programming mechanisms of the full profile of colostrum proteins on transiently expressed gut receptors/transporters, as well as the ultimate functional responses in the calf, remain to be completely elucidated. The objective of this study was to address this gap in knowledge using systems biology. First, we biopsied the mammary gland and examined the transcriptome in primiparous and multiparous Holstein cows (at parturition/day 0 contrasted to 40–50 days after parturition; n = 4–5/group; FDR< 0.05) and used a bioinformatics algorithm to delineate transcripts coding proteins destined to be secreted into colostrum. In parallel, we analyzed the neonatal small intestine (0 day-old contrasted to 7 day-old; n = 3–5/group; FDR< 0.05) to identify transcripts that code for membrane receptors/transporters precise to the period of colostrum consumption. Integrative analysis of these results highlighted 44 possible signaling circuits (cutoff: >10 nCPM) directed by colostrum in the neonatal gut, providing a consolidated predictive understanding of colostrum-mediated effects that might occur in the neonate during this crucial period in development. These findings also represent the first mechanistic insight into mammary-sourced components that target the neonatal gut to regulate aspects of postnatal development that encompass intestinal maturation, gut-based secondary signaling, and establishment of the gut microbiome, all relevant to long-term health and development. Towards applications, these results are poised to offer novel opportunities to enhance commercial supplements via biomimicry to better reflect the physiology supporting neonatal growth and development.