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Department of Veterinary Science and Technology for Food Safety, University of Milan, Italy
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Abstract |
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 Top Abstract INTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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Key Words: nutrition • mammary gland • farm animal • lactation
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INTRODUCTION |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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). The event serves as a forum for presenting the results of basic and applied research on the mammary gland so as to increase understanding of lactation in farm animals and has been successful in encouraging the free exchange of scientific ideas on a broad range of topics centering on the biology of the mammary gland. Scientific progress has been rapid since 1992, and BOLFA meetings have reflected that progress. A key issue throughout all the meetings has been the relationship between nutrition and development, function, and health of the mammary gland.
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NUTRIENT SUPPLY AND THE METABOLIC SUPPORT OF LACTATION |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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). In fact, feeding greater amounts of concentrates increases milk protein concentration and milk yield. Infusion of casein or essential amino acids postruminally also increases milk protein concentration, but responses to feeding rumen-protected lysine and methionine have been variable and dependent on the stage of lactation, as presented by Rulquin (Rulquin et al., 1993) at the second BOLFA workshop in Minneapolis.
Metcalf and coworkers (1994) found that short-term udder infusion of amino acids in lactating dairy cows resulted in greater milk removal (i.e., 55 to 73%) from the infused mammary gland than from the noninfused gland. Those results indicated that mammary gland uptake of amino acids was influenced by blood levels of amino acids, although their subsequent fates were not entirely clear. Some information on the fate of amino acids in the mammary gland was provided by studies in goats that indicated that net uptake of amino acids available for protein synthesis (and therefore, not oxidized) by the mammary gland, were, in decreasing order, methionine, phenylalanine, threonine, histidine, and lysine (Bequette et al., 1994). This order of amino acid availability has been suggested as an indicator of amino acid priority for milk protein synthesis.
Although studies on the amino acids, which are limiting for milk production, have focused mainly on essential amino acids, the potentially limiting influence of nonessential amino acids also was investigated (Meijer and van der Koelen, 1994). Glutamine, in particular, has been studied both for its contribution to milk proteins, and for its multiple roles in the body. Glutamine and glutamate are the major amino acids of milk proteins, constituting approximately 20% of casein amino acids. Two other features of ruminant glutamine metabolism are important in this context: 1) the low capacity of ruminants to synthesize glutamine compared with monogastric animals and 2) the response of plasma and tissue glutamine pools to conditions of metabolic stress, including high milk production, which resemble those of most essential amino acids (Meijer et al., 1993). In the postpartum dairy cow, the rapid increase in milk yield, simultaneous increase in gut tissue growth, and the need to synthesize glucose may lead to glutamine deficiency, particularly in the early postcalving period, and thereby constitute a limitation on milk yield (Meijer et al., 1995).
At the 1998 BOLFA workshop in Denver, Colorado, Petitclerc et al. (2000) examined the genetic relationship among milk yield, feed intake, and feed efficiency; discussed how rumen function (i.e., carbohydrate digestion, vitamin B requirements, and fatty acid biohydrogenation) could be manipulated to influence milk yield and composition; and discussed the importance of glucose, which is essential for milk synthesis in both ruminants and nonruminants. In particular, postruminal glucose supply, which enhances glucose absorption, can balance glucose utilization by portally drained viscera, sparing endogenous glucose and glucose precursors and, therefore, increasing total glucose availability to the rest of the body, including the lactating mammary gland.
At the 2000 BOLFA meeting in The Hague, Hanigan et al. (2001) examined the various models proposed to predict milk protein yield. Important components of these models are mammary gland amino acid metabolism that is regulated by amino acid supply and other factors, such as energy metabolism, regulation of amino acids uptake, and mammary blood flow. The secretory side of the model also must be represented and requires terms for amino acid oxidation, as well as for protein synthesis. Hanigan et al. (2001) concluded that a multi-substrate Michaelis-Menten equation form is more consistent with experimental observations and appears to yield better predictions than single-limiting models.
From these studies, it was evident that although the amino acid supply influences milk protein concentration and yield (kg of protein/d), the transfer efficiency of dietary protein to milk is low. Probably this low efficiency of dietary protein to milk is a major factor accounting for the inability of diet to markedly alter milk protein content, as also reviewed recently by Jenkins and McGuire (2006). However, studies with cows under hyperinsulinemiceuglycemic clamp showed that mammary amino acid extraction can be adjusted to enhance milk protein secretion (McGuire et al., 1994). This finding indicates that substrate uptake from the blood can be responsive to changes in arterial amino acid concentrations, mammary blood flow, and metabolic activity.
Milk fat content is much more susceptible to dietary manipulation in relation to the origin of milk fatty acids in dairy ruminants. Approximately 50% of short- and medium-chain fatty acids (C4:0 to C16:0) in milk arise from de novo synthesis in the mammary gland from acetate and β-hydroxybutyrate of ruminal origin, whereas one-half the palmitic acid and most of the long-chain fatty acids of milk arise from uptake into the mammary gland of lipids from blood. In cows, diets rich in concentrates, vegetable oils, or fish oil, and those diets characterized by small particle size can induce major milk fat depression. By contrast, an increase in milk fat content occurs when encapsulated lipids are fed (Chilliard et al., 2001). However, these changes in milk fatty acid content are generally accompanied by a major modification in fatty acid profile. Chilliard and coworkers (2001), in the fifth BOLFA workshop, summarized the effects of dietary factors on milk fat secretion and composition, concentrating on the ability of different diet formulations to decrease milk fat content or enhance unsaturated fatty acid concentration to obtain healthier milk for human consumption (see subsequent discussion).
Other topics covered at BOLFA meetings were the roles of metabolic hormones in regulating milk synthesis, including the effect of insulin on milk protein and fat yields, and the modulation exerted by somatotropin and insulin-like growth factors (Flint et al., 2001; Knight, 2001). Insulin has acute effects on adipose lipogenesis (stimulatory) and lipolysis (inhibitory), but the ruminant mammary gland is unresponsive to changes in circulating insulin, which has no apparent effect on glucose uptake or utilization by the mammary gland. By inhibiting adipose lipolysis, insulin seems to limit the supply of milk fat precursors available to the udder, thus supporting the glucogenic-insulin theory as a cause of milk fat depression (Bauman and Griinari, 2001). With respect to increases in milk proteins, Petitclerc et al. (2000) suggested that insulin can act directly on either mammary epithelial cell proliferation or amino acids transport systems in the mammary cells or indirectly via increases in IGF-I that involve ST.
Somatotropin exerts a systemic effect on all types of nutrients repartitioning them toward the udder, and also on the local production of IGF in the mammary gland (Capuco et al., 2003). The effects of ST administration depend on nutritional status, and when nutritional status is excellent, it produces a substantial increase in milk yield. Specific changes induced by ST via IGF include greater milk synthesis by secretory cells and enhanced survival of secretory cells. Insulin-like growth factor-I was proposed to be a cell survival factor necessary to prevent apoptotic death, as well as being involved in remodeling events of mammary gland involution (Knight and Wilde, 1993). It may therefore be possible to use ST to extend lactation, as was discussed in Lillehammer (Knight, 1997; van Amburgh et al., 1997) and by Capuco et al. (2003) in Quebec City.
The influence of nutrient supply on lactation also has been investigated in other species, including sows (Hartmann et al., 1997; Farmer and Sørensen, 2001; Perèz Laspiur and Trottier, 2001), ewes (Baldi et al., 1997), goats (Knight, 1997; Wilde et al., 1997), and mares (Dell’Orto et al., 1994a,b; Deichsel and Aurich, 2005). Metabolic mechanisms relating nutrient intake and lactation performance in the sow were discussed in several BOLFA workshops. In particular, lipid metabolism in adipose tissue and dietary amino acids, particularly lysine, were shown to be key factors influencing milk production in sows (Pettigrew et al., 1993). In this field, further progress in amino acid nutrition to maximize genetic potential for litter weight gain and milk production of sows was provided by Trottier and Guan (2000). In discussing amino acid requirements of the sow, those authors indicated that it is essential not only to identify which amino acids pools are significant for the mammary system, but also to understand nutrient interactions in order to obtain an optimal response. Farmer and Sørensen (2001) highlighted the importance of optimal nutrition in prepubertal gilts as a factor influencing mammary development and subsequent milk production. Those authors also found that high energy intake by sows during gestation may have detrimental effects on mammary development and milk production, whereas dietary protein had limited effects on mammary development but could increase subsequent milk production.
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NUTRIENT UPTAKE, TRAFFICKING, AND FUNCTION AT THE CELLULAR LEVEL |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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; Purup et al., 2000).
Studies on secretory pathways within mammary cells led to important advances in our understanding of the biology of lactation. In the Hague meeting in 2000, Boisgard et al. (2001) noted that protein milk composition results from two main processes; the expression of milk protein encoding genes in the mammary epithelial cells and the transfer of plasma-borne proteins. An anterograde secretory pathway is responsible for the secretion of newly synthesized proteins in milk, such as caseins and whey proteins. Following this pathway, the proteins initially appear on the endoplasmic reticulum, transiently associate with elements of the Golgi complex, and then concentrate in post-Golgi secretory vesicles before being exported into milk. Beside this main anterograde transport, a transcytotic pathway is responsible for the transfer of bioactive components (e.g., hormones, growth factors, and immunoglobulins) from the blood or from stroma cells into milk (Boisgard et al., 2001). In vitro studies using mammary explants, immortalized cell lines, barrier systems, and alveoli-like structures were vital for elucidating these aspects of uptake and trafficking. In vitro experimental models of milk secretion also were appraised for investigating nutrient roles beyond that of supporting milk component synthesis. In particular, they were used to monitor the effects of interventions to alter the quality or composition of nutrient output during lactation (Clegg et al., 2001). An increasingly wide variety of biotechnological tools are now becoming available to elucidate the complex physiology of the mammary gland. Microarrays for transcriptional profiling and proteomic analyses for identifying protein expression patterns are useful technologies to investigate changes in the set of genes expressed in the mammary gland and in the proteome during different physiological stages. These approaches showed that a huge numbers of genes are differentially expressed in mammary epithelial cells during pregnancy, lactation, and involution. However, cellular biological approaches through in vivo and dynamic studies are necessary to elucidate the precise links between gene expression and protein synthesis in the mammary gland (Ollivier-Bousquet and Devinoy, 2005).
Extensive research on lipid uptake, trafficking, and secretion at the cellular level has been carried out over the last 20 yr. Much of our knowledge has been obtained by studying mechanisms of milk fat depression. In the Hague meeting in 2000, Bauman and Griinari (2001) presented their biohydrogenation theory of milk fat depression involving the concept that rumen biohyrogenation can produce trans-10, cis-12 CLA, which seems to be a potent inhibitor of milk fat synthesis. This concept is supported by data in the cow showing that postruminal infusion of trans-10, cis-12 CLA reduces the abundance in the mammary gland of mRNA for genes involved in fatty acid uptake [i.e., lipoprotein lipase (LPL), fatty acid transport (i.e., fatty acid binding protein; FABP), de novo fatty acid synthesis (i.e., acetyl-CoA carboxylase; ACC and fatty acid synthase; FAS), desaturation (i.e., stearoyl-CoA desaturase; SCD), and triglyceride synthesis (i.e., acylglycerol phosphate acyl transferase; AGPAT and glycerol phosphate acyl transferase; GPAT)]. Levels of trans-10, cis-12 CLA in milk fat were also found to correlate closely with the decrease in ACC transcript, and less closely, but still significantly, with the reduction in levels of the enzymes FAS, LPL, and GPAT, as recently reviewed by these same authors (Griinari and Bauman, 2006).
Another aspect of the regulation of fatty acid profile of milk by the mammary gland relates to unsaturated fatty acids. Desaturase activity in the mammary cells, that introduces a 
9 double bond in the cis conformation, not only converts stearic acid arising from ruminal biohydrogenation to oleic acid that is secreted in milk, but also is involved in the synthesis of CLA isomers in the mammary gland (Bauman and Griinari, 2001; Chilliard et al., 2001). However, the availability of substrates in the diet is the main factor influencing the content and profile of milk fatty acids, affecting the expression of various lipogenic genes at the level of the mammary gland, as also presented in the latest ruminant physiology symposium in Denmark (Bernard et al., 2006).
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MILK AS MEANS OF DELIVERING NUTRIENTS AND BIOACTIVE COMPOUNDS |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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). Many milk proteins, lipids, lipid-soluble substances, and their digested products are bioactive, including peptides, triacylglycerols, diacylglycerols, saturated and polyunsaturated fatty acids, phospholipids, vitamins, and vitamin-like substances. Milk also contains protein hormones from the anterior pituitary (i.e., prolactin and ST), hypothalamus (i.e., ST releasing hormone and somatostatin) and gut (i.e., vasoactive intestinal peptide, gastrin, and substance P), numerous growth factors (including IGF-I and IGF-II, IGFBP, epidermal growth factor, transforming growth factors), prostaglandins E and F, lactoferrin, and transferrin (Baumrucker and Blum, 1993; Meisel, 1997; Schanbacher et al., 1997; Weaver, 1997; Zinn, 1997).
Schanbacher et al. (1997) reviewed the origins of bio-active peptides in milk, their biochemical properties, potential as nutraceuticals, and potential pharmacological applications. For example, lactoferrin is a multi-functional protein involved in immunoregulation, anti-inflammation, and especially iron metabolism. The biochemical and other properties of lactoferrin were discussed at the 1998 BOLFA meeting in Denver by Neville et al. (2000). Those authors noted that lactoferrin binding sites have been found in many cell types including intestinal cells, hepatocytes, mammary epithelial cells, and platelets. At the 2004 meeting in Bled, Baumrucker (2005) presented results showing that bovine lactoferrin is involved in the entry of IGFBP-3 into the nucleus of mammary cells.
At the 2000 BOLFA meeting in the Hague, the roles of IGF-I and IGFBP in milk were considered by Sejrsen et al. (2001) who noted that colostrum had greater mitogenic activity than did mature milk due to its high IGF-I levels; they proposed that the mitogenic activity of colostrum was important for mammary gland development, as well as for the developing neonate. Emphasis at this meeting was also placed on nutritional approaches to alter milk composition for the benefit of human health (Bauman and Griinari, 2001; Chilliard et al., 2001; Clegg et al., 2001). In particular, ways of increasing the polyunsaturated fatty acid content of milk were all considered (Bauman and Griinari, 2001; Chilliard et al., 2001) to thereby produce functional milks. At the most recent BOLFA meeting (2006, Pirassununga, Brazil), the issue of the CLA content of milk was taken up again (da Silva et al., 2006; Paschoal et al., 2006). As noted above, mammary lipogenic gene expression (and hence milk fat synthesis) in cows and goats seems to be regulated by trans fatty acids, with trans-10 C18:1 and trans-10, cis-12 CLA emerging as the main mediators of a milk fat-depressing effect. However, the molecular mechanisms involved in the nutritional regulation of gene expression have not been elucidated completely. Thus, although animal feeding regimens can increase the polyunsaturated lipid content of milk to make it "healthier", the milk thereby becomes more vulnerable to oxidation, and this stimulated much interest in milk antioxidants and their transfer from dietary components in dairy cows, as reviewed extensively at the seventh BOLFA workshop in Bled (Baldi, 2005; Debier et al., 2005; Meglia et al., 2005).
In addition to their antioxidant roles that will be discussed in the next section, vitamin E and other fat-soluble vitamins and provitamins (e.g., beta-carotene) are important nutrients per se, for which milk is an important delivery system. Debier et al. (2005) presented results on the roles of vitamins A and E in the early stages of life. Vitamin E is necessary to protect the newborn against oxidative stress, whereas vitamin A is required for growth and development. Both vitamins are essential for immune system development. These vitamins must therefore be provided to neonates in adequate amounts. Colostrum contains relatively high concentrations of vitamins A and E but mature milk contains much less. The transfer of these vitamins into milk does not seem to be simply a passive one associated with lipid transfer. Vitamin supplementation of gestating and lactating animals appears to increase levels of both vitamin E and A in milk and in neonatal serum. However, positive effects on young animals are difficult to document. Studies on seals have shed light on important aspects of the transfer of vitamins A and E from mother to offspring, although much remains to be learned about the metabolism of these vitamins during lactation (Debier et al., 2005). Administration of the natural vs. synthetic form of vitamin E can affect bioavailability and may also influence transfer to milk (Meglia et al., 2005). Like other fat-soluble micronutrients, fat-soluble vitamins are present in the milk fat fraction, and this has important implications for bioaccessibility and bioavailability from milk. In fact, the fat component of milk is a highly effective delivery system for fat-soluble vitamins.
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NUTRITION AND MAMMARY GLAND HEALTH |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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). A growing body of evidence indicates that metabolic disorders associated with negative energy balance may impair fertility, immune status, and antioxidant status. During the transition period in dairy cattle, the total antioxidant capacity is most susceptible to be compromised. Higher oxygen demand for milk synthesis and secretion increases the production of reactive oxygen metabolites within the mammary gland. Sordillo (2005) reported that mammary gland cells from periparturient dairy cows produce more cytokines than those from midlactation animals, resulting in transient increases in intracellular reactive oxygen species and indicating that during lactation onset, mammary gland epithelial cells are exposed to significant levels of free radicals. The resulting oxidative damage is a possible cause of increased susceptibility to intramammary infection at this time. In such situations, the availability of antioxidants to the mammary cells becomes crucial. The antioxidant system is an integrated system, and deficiencies of one component can affect the antioxidant efficiency of the others. Nutrition has a major influence on balance of prooxidants and antioxidants because several antioxidant system components are micronutrients or are dependent on dietary micronutrients. Vitamin E, beta-carotene, and selenium are known to be effective dietary antioxidants in ruminants, whereas several others are under investigation and cannot yet be recommended as routine dietary supplements. In this regard, Baldi (2005) presented results indicating that adequate vitamin E status is important for maintaining health and production in dairy cows. Vitamin E also seems to be crucially involved in immune system function, such that supplementation with supranutritional levels of the vitamin E, in some instances, results in improved immune responses. Vitamin C and other substances (e.g., glutathione and selenium) that are associated with antioxidative defenses, may also be important in maintaining vitamin E status and function and, hence, vitamin E availability at the cellular level. The extent of oxidative stress probably also affects tissue consumption of vitamin E.
Although vitamin A does not have all the activities of classical antioxidants, it seems to play a role in mammary gland immunobiology, remodeling, and polymorphonuclear leukocyte function during the peripartum period. In vitro studies of the effect of retinoids on function of polymorphonuclear leukocytes indicate that they directly affect oxidative burst activity and apoptosis, but not chemotaxis (Meyer et al., 2005). Vitamin A also has been suggested to play a role in the morphogenesis, differentiation, and proliferation of the mammary gland. Retinol and retinoic acid have been reported to be potent inhibitors of bovine mammary epithelial cell proliferation in vitro (Cheli et al. 2003). Although the exact mode of action at the cellular level remains unknown, the main protective effects of retinol and retinoic acids may be due to regulatory effects on the growth of normal cells by controlling gene expression of several growth factors.
The metabolic health status effects of folate, vitamin B12, and vitamin-like choline also was investigated and it was found that supplies of these micronutrients are not always sufficient to maximize health and productivity of dairy cows. Supplementation, especially during early lactation, can improve lactational performance, metabolic health, and the nutritional quality of milk (Girard and Matte, 2005; Pinotti et al., 2005). However, it also has emerged from these studies that our knowledge of interactions between these 3 micronutrients is incomplete in the dairy cow, and that a nutritional approach based on the supply and utilization of individual nutrients is inadequate, further indicating the need to reappraise the requirements for B-complex vitamins in dairy cows.
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SUMMARY |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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Footnotes |
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2 Corresponding author: antonella.baldi{at}unimi.it
Received for publication May 21, 2007. Accepted for publication July 17, 2007.
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LITERATURE CITED |
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TopAbstractINTRODUCTIONNUTRIENT SUPPLY AND THE...NUTRIENT UPTAKE, TRAFFICKING,...MILK AS MEANS OF...NUTRITION AND MAMMARY GLAND...SUMMARYLITERATURE CITED |
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This article has been cited by other articles:
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  G. E. Dahl The Eighth International Workshop on the Biology of Lactation in Farm Animals: Introduction J Anim Sci, March 1, 2008; 86(13_suppl): 1 - 2. [Full Text] [PDF]
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