Alan W. Bell

Adaptations of Glucose Metabolism During Pregnancy and Lactation

Increased glucose requirements of the gravid uterus during late pregnancy and even greater requirements of the lactating mammary glands necessitate major adjustments in glucose production and utilization in maternal liver, adipose tissue, skeletal muscle, and other tissues. In ruminants, which at all times rely principally on hepatic gluconeogenesis for their glucose supply, hepatic glucose synthesis during late pregnancy and early lactation is increased to accommodate uterine or mammary demands even when the supply of dietary substrate is inadequate. At the same time, glucose utilization by adipose tissue and muscle is reduced. In pregnant animals, these responses are exaggerated by moderate undernutrition and are mediated by reduced tissue sensitivity and responsiveness to insulin, associated with decreased tissue expression of the insulin-responsive facilitative glucose transporter, GLUT4. Peripheral tissue responses to insulin remain severely attenuated during early lactation but recover as the animal progresses through mid lactation. Specific homeorhetic effectors of decreased insulin-mediated glucose metabolism during late pregnancy have yet to be conclusively identified. In contrast, somatotropin is almost certainly a predominant homeorhetic influence during lactation because its exogenous administration causes specific changes in glucose metabolism (and many other functions) of various nonmammary tissues which faithfully mimic normal adaptations to early lactation.

Protein nutrition in late pregnancy, maternal protein reserves and lactation performance in dairy cows.

Empirical evidence suggests that prolonged underfeeding of protein to late-pregnant dry cows can have modest negative carry-over effects on milk volume and/or protein yield during early lactation, and may also cause increased incidence of metabolic diseases associated with fatty liver. However, assessment of requirements is hampered by lack of information on relationships between dietary intake of crude protein (N x 6.25) and metabolizable protein supply during late pregnancy, and by incomplete understanding of the quantitative metabolism of amino acids in maternal and conceptus tissues. Inability of the postparturient cow to consume sufficient protein to meet mammary and extra-mammary amino acid requirements, including a significant demand for hepatic gluconeogenesis, necessitates a substantial, albeit transient, mobilization of tissue protein during the first 2 weeks of lactation. Ultimately, much of this mobilized protein appears to be derived from peripheral tissues, especially skeletal muscle and, to a lesser extent, skin, through suppression of tissue protein synthesis, and possibly increased proteolysis. In the shorter term, soon after calving, it is likely that amino acids required for hepatic glucose synthesis are diverted from high rates of synthesis of splanchnic tissue and export proteins, including serum albumin. The prevailing endocrine milieu of the periparturient cow, including major reductions in plasma levels of insulin and insulin-like growth factor-I, together with insulin resistance in peripheral tissues, must permissively facilitate, if not actively promote, net mobilization of amino acids from these tissues.

THE STRUCTURE AND PHYSIOLOGY OF GASTROINTESTINAL MUCUS

The primary function of gastrointestinal mucus is considered to be protection of the surface mucosal cells (Hollander, 1954; Florey, 1955). Mucus forms a gel which, throughout the gut, protects the mucosal surfaces from the vigorous shear forces that attend digestion (Fig. 1). The mucus gel provides a slimy lubricant for the passage of solid material through the gat while some of the gel layer remains firmly stuck to the mucosa to protect it from the next round of mechanical abuse. Mucus has particular physical properties which allow it to flow and if sectioned, anneal. Such properties, which show mucus to be a weaker gel than a rigid gel such as agar, facilitate the spread of the mucus over the mucosal surface. However, mucus will not dissolve with infinite dilution and is quite distinct from a viscous liquid.

Maternal leptin is elevated during pregnancy in sheep

Maternal plasma leptin is elevated during pregnancy in several species, but it is unclear to what extent this elevation reflects changes in adiposity or energy balance. Therefore, Karakul ewes (n = 8) were fed to minimize changes in maternal energy status over the pregnancy-lactation cycle. They were studied 20-40 d before breeding and during mid pregnancy (d 50-60 post coitus [PC]), late pregnancy (d 125-135 PC) and early lactation (d 15-22 post partum). Consistent with the maintenance of near energy equilibrium in nongravid maternal tissues, maternal body weight was increased only during late pregnancy when the weight of the conceptus became significant and plasma concentrations of insulin, NEFA and glucose did not vary with physiological state. In contrast, maternal plasma leptin concentration rose from 5.3 to 9.5 ng/mL between prebreeding and mid pregnancy and then declined progressively through late pregnancy and early lactation. Leptin gene expression increased 2.3 fold in maternal white adipose tissue (WAT) from prebreeding to mid pregnancy and declined to prebreeding levels during early lactation. To determine whether tissue response to insulin was involved in this effect, insulin tolerance tests were performed. The maternal plasma glucose response declined from prebreeding to early lactation, but was not correlated with either plasma leptin concentration or WAT leptin mRNA abundance. In conclusion, pregnancy causes an increase in the synthesis of leptin in sheep. This stimulation does not require increases in adiposity or energy balance and is unrelated to the ability of insulin to promote glucose utilization.

Regulation of placental nutrient transport and implications for fetal growth

Fetal macronutrient requirements for oxidative metabolism and growth are met by placental transport of glucose, amino acids, and, to a lesser extent that varies with species, fatty acids. It is becoming possible to relate the maternal-fetal transport kinetics of these molecules in vivo to the expression and distribution of specific transporters among placental cell types and subcellular membrane fractions. This is most true for glucose transport, although apparent inconsistencies among data on the roles and relative importance of the predominant placenta glucose transporters, GLUT-1 and GLUT-3, remain to be resolved. The quantity of macronutrients transferred to the fetus from the maternal bloodstream is greatly influenced by placental metabolism, which results in net consumption of large amounts of glucose and, to a lesser extent, amino acids. The pattern of fetal nutrient supply is also altered considerably by placental conversion of glucose to lactate and, in some species, fructose, and extensive transamination of amino acids. Placental capacity for transport of glucose and amino acids increases with fetal demand as gestation advances through expansion of the exchange surface area and increased expression of specific transport molecules. In late pregnancy, transport capacity is closely related to placental size and can be modified by maternal nutrition. Preliminary evidence suggests that placental expression and function of specific transport proteins are influenced by extracellular concentrations of nutrients and endocrine factors, but, in general, the humoral regulation of placental capacity for nutrient transport is poorly understood. Consequences of normal and abnormal development of placental transport functions for fetal growth, especially during late gestation, and, possibly, for fetal programming of postnatal disorders, are discussed.

Nutrition, Development and Efficacy of Growth Modifiers in Livestock Species

Somatotropin (ST) and synthetic beta-adrenergic agonists (beta-AA) are growth-modifying agents that increase the rate and sometimes, the efficiency of protein deposition in lean tissues of livestock species. The ST-induced increase in muscle protein deposition is effected by a relatively modest increase in protein synthetic rate. This is possibly mediated by the endocrine influence of marked increases in circulating IGF (insulin-like growth factor)-I, and other ST-dependent components of the IGF system; mediation by locally expressed IGF-I may also occur. Increased muscle protein accretion in animals treated with beta-AA seems to be directly mediated by binding of the synthetic agonist to muscle beta-1 or beta-2 receptors, leading to increased muscle protein synthesis, possibly accompanied or followed by decreased protein degradation. This response is transient, due to down-regulation of beta-adrenergic receptors. Maximal responses of muscle protein accretion to both ST and beta-AA are attenuated by feeding inadequate levels of total protein or specific, limiting amino acids. For ST, but not beta-AA, this effect in growing pigs is partially offset by increased efficiency of utilization of absorbed amino acids for protein deposition, with predictable consequences for dietary protein and amino acid requirements. Both ST and beta-AA are less efficacious in promoting muscle protein deposition in very young animals. For ST, this is related to postnatal development of the somatotropic axis; a mechanistic explanation for the similar lack of effect of beta-AA is lacking. In both cases, this phenomenon must be considered against the very high inherent capacity and efficiency of lean tissue protein accretion in the neonate.

Nutritional management of the transition cow in the 21st century – a paradigm shift in thinking

The transition period is defined as the 6–8 weeks encompassing late pregnancy and early lactation, involving coordinated changes across multiple tissues and an enormous increase in nutrient requirements. Failure to transition successfully can result in reduced DM intake, milk production, delayed oestrus, failure to conceive and increased incidence of metabolic and infectious diseases, many of which are inter-related. Modern technologies have enabled the measurement of transcriptional changes in genes involved in multiple biochemical pathways across the transition period, enabling a better understanding of the implications of management and nutritional changes on cow health and productivity. Most recent research efforts have focussed on the association between pre-calving energy intake and postpartum health and productivity, with a general recognition that the positive relationship between pre-calving energy intake (and relevant circulating metabolites) and postpartum health and productivity is, for the most part, not causative (i.e. responses are very likely to reflect the same metabolic perturbation, but one is not necessarily the cause of the other). This effect is consistent in both grazing systems and in systems where cows are fed total mixed ration in confinement. These results require a paradigm shift in the extension message to farmers. Because of the focus on energy nutrition, there has been only limited recent research on the requirements of cows for protein, with recommendations based largely on predicted requirements rather than measured responses. That said, metabolisable protein is unlikely to be a limiting nutrient for late-gestation dairy cows grazing up to 50% of their diet as high-protein forages, but could potentially be limiting prepartum mammary development in animals on lower-protein diets, such as total mixed rations formulated for dry cows. The physiological role of fatty acids, in addition to the role of fat as an energy source, is an emerging and important research area, with increasing evidence, at least in vitro, that specific fatty acids regulate metabolic processes. Knowledge gaps and future research areas that should be prioritised are identified and discussed.

Influences on fetal and placental weights during mid to late gestation in prolific ewes well nourished throughout pregnancy.

This study investigated associations between fetal and placental weights from 85 to 130 days gestation in 49 fetuses from 21 ewes of a prolific genotype used as an experimental model of intrauterine growth retardation. The proportion of variation in fetal weight explained by placental weight increased from zero at 85 days to 91% (residual standard deviation (RSD) = 260 g) at 130 days. Overall, stage of pregnancy plus placental weight accounted for 96% of fetal weight variation (RSD = 212 g). Litter size and number of fetuses per uterine horn also influenced individual fetal weights. Gestational age, litter size, placental weight per ewe, and liveweight and condition score of ewes during early to mid gestation (initial LW and CS) explained 99.5% of the variation in fetal weight per ewe (RSD = 236 g). Most variation (86%) in placental weight was explained by stage of pregnancy, litter size, number of placentomes, and initial LW and CS (RSD = 53 g). Placental weight per ewe was influenced by stage of pregnancy, litter size and initial ewe LW and CS (R2 = 0.97; RSD = 89 g). The association of fetal and placental weights with initial ewe LW was positive, and with initial CS was negative. The results show that in the absence of overt nutritional restriction of pregnant ewes, fetal and placental weights are tightly coupled during late gestation and ewe fatness during early pregnancy is inversely related to placental and fetal weights. They demonstrate that placental weight explains most of the variation in fetal weight in the present intrauterine growth retardation model.

Relations between plasma non-esterified fatty acid metabolism and body tissue mobilization during chronic undernutrition in goats.

1. Eleven mature goats were offered 140 kJ metabolizable energy/kg per d (M) of lucerne (Medicago sativa) hay-oaten grain (1:1, w/w) for at least 1 month before plasma non-esterified fatty acid (NEFA) kinetics and tritiated water space (TS) were determined. 2. Goats were then fed at M, 0.5 M or 0.25 M for 34 (SE 6) d, at which time the experimental procedures were repeated. 3. Chronic undernutrition resulted in elevated NEFA concentrations and NEFA entry rate, with a tendency for the ratio plasma NEFA:glycerol to increase, suggesting that body-fat mobilization during prolonged underfeeding is due more to decreased lipogenesis and intracellular NEFA re-esterification rather than to increased lipolysis. 4. Plasma NEFA concentrations and NEFA entry rate, as well as being highly correlated with each other, were significantly related to calculated energy balance and body fat losses estimated from changes in live weight and TS. 5. Increases in NEFA entry rate were highly correlated with, and of the same magnitude as, body fat losses, confirming that NEFA kinetics do quantitatively reflect lipid mobilization.

EFFECT OF CHRONIC INFUSION OF PLACENTAL LACTOGEN ON OVINE FETAL GROWTH IN LATE GESTATION

To test the hypothesis that placental lactogen (PL) is a humoral regulator of fetal growth, six singleton sheep fetuses received a continuous intravenous fusion of 1.2 mg/d of purified ovine PL (oPL) for 14 d, beginning on Day 122 of gestation. The plasma concentration of oPL was approximately four-fold higher in infused fetuses than in six control fetuses that received a continuous infusion of saline. The circulating insulin-like growth factor 1 (IGF-I) concentration was also significantly elevated in PL-infused fetuses (43.1 +/- 1.7 vs. 31.9 +/- 4.1 ng/ml; P < 0.05). Animals were slaughtered on Day 136, and the placenta and all major fetal tissues were dissected, weighed, and subsampled for chemical analysis. Fetal weight and crown-rump length were not significantly affected by treatment; however, the aggregate weight of the brain, liver, lungs, and heart tended to be larger (85.3 +/- 2.1 vs. 79.9 +/- 1.5 g/kg fetus; mean +/- SE, P = 0.07) and the thyroid gland was smaller (0.18 +/- 0.1 vs. 0.26 +/- 0.02 g/kg fetus; P < 0.05) in the PL-infused fetuses. The livers of the PL-infused fetuses had also accumulated additional glycogen (13.1 +/- 1.7 vs. 8.4 +/- 0.7 g; P < 0.05). In late gestation, PL within the fetal compartment increases fetal plasma IGF-I concentration and hepatic glycogen deposition and may affect the growth of several vital organs.