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1 Conjugated Linoleic Acids in Dairy Cow: Biological Biological Activities and Applications Applications Daniel G. Peterson, Ph.D. Ph.D. Animal Science Department Department California Polytechnic State University University San Luis Obispo, CA CA INTRODUCTION INTRODUCTION There has been an increasing recognition over past several years that dietary lipids can play important roles in metabolism and signaling in addition ir classical role as a source energy (e.g. Jump and Clarke, 1999; Chong and Marx, 2001). One example a family lipids that has been implicated in modulating such divergent processes as cancer development, lipid metabolism, bone mineralization and ors are conjugated linoleic acids, or. The interest in really began with an attempt by Pariza and coworkers identify carcinogenic compounds in cooked beef (reviewed by Pariza,.1999). Ironically, this project instead identified a compound with very potent anti-cancer properties that was finally identified as cis-9, trans-11. Parodi (1977) had identified this compound several years prior as a component cow's milk, and it is now clear that ruminant fat depots are most abundant natural source this fatty acid. Subsequent studies performed by Ip and coworkers (1991; 1999) elegantly demonstrated that is a potent anticarcinogen in mouse models mammary cancer and ors have demonstrated se anticarcinogenic properties in many or models (reviewed by Pariza, 1999). are actually a family related fatty acid forms, or isomers, each with apparently divergent biological activities. The structural differences lie in arrangement two carbon-carbon double bonds within molecule, each isomer having a unique combination position (9, 10, 11, 12, etc.) and geometry (cis- or trans-; Figure 1). There are two isomers that have received greatest attention in scientific investigations, cis-9, trans-11 ~nd trans-10, cis-12, each formed by isomerization cis 12 or cis-9 double-bonds linoleic acid, respectively (Figure 1). Figure 1. Structure linoleic acid and two coc"jllon isomers. Arrows indicate position carbon-carbon double bonds. linoleic acid (cis-g. cls-12) cis-g. trans-11 trans 10, cls-12 CiA

2 The cis-9, trans-11 isomer is implicated in anti-cancer properties. while trans-10, cis-12 isomer is generally associated...lith effects on lipid metabolism in models lactation as well as adipose and liver metabolism. Both se fatty acids naturally occur in ruminant lipids due ir production in microbial process biohydrogenation linoleic acid in rumen. While cis-9, trans-l1 is predominant isomer in milk and body fat ruminants, trans-10, cis-12 is but one more than a dozen or isomers that occur.i.n trace amounts in ruminant fat (Sehat et al., 1998; Fritsche et al., 2000). ENRICHMENT OF MILK FAT Rumen microbes are responsible for alteration many dietary components; indeed, without ir fermentation plant matter, ruminant would not survive: One alteration that is paramount interest in regard understanding is process biohydrogenation polyunsaturated fatty. acids (PUFA), or reduction PUFA saturated fatty acids (SFA). Intermediates in pathways biohydrogenation include isomers, as well as related fatty acids that contribute content ruminant fat. It is ironic that same pro~ess that is responsible for relatively high saturated fat content ruminant-derived foods, a characteristic fat generally considered be unhealthy, is also responsible for. formation, a fatty acid that may have health benefits. Early work characterizing process rumen biohydrogenation established that Cis-9, trans-1l was an intermediate in biohydrogenation linoleic acid stearic acid (Dawson and Kemp, 1970; Keeney, 1970; Harfoot 1978). The cis-9, trans-l1 isomer is most abundant in ruminant tissues and food products derived from ruminants due in large part its potential be synsized. endogenously from anor rumen biohydrogenation intermediate, trans-l1 18:1 (Bauman et al., 2003). This process is carried out by enzyme stearoyl CoA desaturase (SCD) that introduces a cis-9 double bond in trans-11 18:1 intermediate, forming cis-9, trans-11 (Figure 2)'. Rumen Tissues Linolenic acid Linoleic acid cis-9, cis 12, ds-15 18:3 cis-9, cis-1218:2 ~ ~ cis-9, trans-11, cis-15 18:3 cis-9, trans-11!...,.,. cis-9, trans-11 ~ 1 Stearoyl CoA Desaturase trans-11. cis-1518:2 18:2... trans-11 18:1 -,. trans-1118:1 ~ 18:0 Figure 2. Pathways for ruminal biohydrogenation and endogenous synsis cis-g. trans-ll. Pathways for biohydrogenation linolenic and linoleic acids yielding trans-ll 18: 1 are shown in rumen box and endogenous synsis by stearoyl CoA desaturase is shown in tissues bbx. Figure adapted from Bauman et al. (2003). 102

3 Estimates contribution endogenous synsis range from 60% and 90% in milk fat (Griinari et al., 2000; Corl et al., 2001; Kay et al., 2002). Even though SCD converts a portion cow's trans-11 18:1 in mammary gland, amount trans-11 18: 1 in milk fat is generally about 3-fold greater than amount. This is important because animals (including humans) consuming cow's milk also have SCD enzyme used endogenously synsize. In a particularly notable cancer study, Ip et al. (1999) demonstrated that -enriched butter produced by feeding cows promote - synsis is perhaps even more effective against cancer than purified cis-9, trans-11. This was postulated be due presence trans-11 18: 1 in lipid that can be converted cis-9, trans-11 in tissues (Ip et al., 1999). It has since been demonstrated that this conversion trans-11 18: 1 contributes significantly cancer-fighting properties natural -enriched milk fat (Corl et al., '2003). Dietary facrs that affect content milk fat' include addition biohydrogenation substrates such as linoleic and linolenic acids, and modification rumen environment promote incomplete biohydrogenation (see reviews by Griinari and Bauman, 1999; Bauman et al., 2001). Most attempts elevate milk fat content result in variable degrees success depending on individual; while one animal may respond very well, anor may have little no response. In an attempt furr characterize nature this variation, we conducted a study involving 3 groups animals (n=lo/group); one was fed a standard TMR, one fed a diet designed enhance milk fat, and one group was s""itched between se diets at 3 week intervals (Peterson et al., 2002b). Our diet designed, elevate mllk fat content employed full-fat extruded soybeans and led a significant increase in milk fat content cis-9, trans-11. Interestingly, when responses animals in alternating diet group were considered individually, it was noted that animals varied 2-3-fold in ir response, and that hierarchy among' animals remained largely constant across dietary shifts (see figure 3). The data from this study indicated that while diet has a major influence on milk fat content, individual animal differences also have a substantial effect. This animal-specific effect likely involves sed enzyme that is critical endogenous synsis from trans-11 18:1. Because importance this enzyme in synsis cis-9, trans-11, current research both in us and worldwide is focused on identifying variation in SCD gene that 'may be used for animal selection. 14, , 12 Figure 3. Temporal pattern in -en individual hierarchy in :5 ~ 10 milk fat CIA for cows u IV alternated between a >. standard diet (periods... ~ 8 1 and 31 and a diet ::.e designed elevate mel milk fat CIA (periods 2 u C, 6 and 41. The duration - E each period was 3 4 weeks. Figure from Peterson et al. (2002bl r------r----r-----i Period 103

4 AND MILK FAT DEPRESSION Milk fat content and composition can be impacted by many facrs, and one example is low-fat milk syndrome, also referred as milk fat depression (MFD). In this situation, cows fed diets high in readily fermentable carbohydrates and low in effective fiber, or diets containing supplements polyunsaturated oils eir plant or fish origin exhibit a dramatic and' specific reduction in secretion milk fat. These diets can reduce milk fat by up 50% without any effect on or aspects lactation, and this reduction is quickly rescued when dietary treatment is removed (reviewed by Bauman and, Griinari, 2001; Bauman et al., 2003). Boussingault was first document MFD in an 1845 report a reduction in milk fat secretion,in response feeding cows a diet containing beets (cited by Van Soest, 1994). Again in 1926, when Golding and coworkers (1926) were attempting manipulate fat-soluble vitamin content milk, y observed a precipius decline in milk fat secretion when cows were fed a diet containing cod liver oil. Ever since se observations, investigars have sought determine mechanism behind this phenomenon with little success-until recently. Early attempts at enhancing content cis-9, trans-11 in milk fat included simply supplying chemically synsized isomers postruminally lactating dairy cows. It was quickly observed that se treatments led a precipius decline in milk fat yield (Loor and Herbein, 1998; Chouinard et al., 1999a; 1999b) which is also hallmark 150 year-old MFD phenomenon. This activity was subsequently attributed trans-10, cis-12 isomer, and we have established a dose-response relationship demonstrating extreme potency this compound in inhibiting milk fat synsis (Figure 4; Baumgard et al.; 2000; 2001; Peterson et al., 2002a). 0 ~ Figure 4. Relationship >. y =O.24x2-6.99x... between decrease in 10.ll! R 2 =0.99 milk fat yield and dose x. trans-lo, cis-li c~ E -20 abomasally infused in lactating dairy cows..~ All values represent III III 30 mean (n=4) decrease after III llj.. 5 days infusion at u -40 indicated dose. Figure -8 from Peterson et al.... c (2002a) II) 50 '0.. ụ. ell Q trans-10, ds-12 ela dose (g/d) Based in part on se observations, Bauman and Griinari (2001) proposed that MFD diets cause alterations in biohydrogenation pathways leading production alternative fatty acid intermediates such as trans-lo, cis-12. These fatty acids can n be absorbed in small quantities, and act inhibit lipid synsis in mammary gland. Subsequent studies revealed that diet-induced MFD led increases in abundance trans-lo, ~is-12 in milk fat 104

5 that were correlated with reductions in activity genes involved in lipid synsis in mammary gland (Peterson et al., 2003). Additionally, reductions in gene expression observed during diet induced MFD were very similar those observed during MFD induced by administration (Baumgard et al., 2002). These data support biohydrogenation ory as a unifying explanation for diet-induced milk fat depression. Our understanding anti-lipogenic properties trans-10, cis-12 has also provided a potentially valuable management ol. Fat is primary energy component in milk, and refore comprl ses greatest metabolic burden on a lactating animal. The strategic inhibition milk fat synsis can be used relieve metabolic strain during times nutrient insufficiency such as onset lactation when intake lags behind nutrient demand, or when adequate nutrients are not available as can occur at times, in a pasture-based system. Additionally, can be used alter milk composition better match market demands such as in areas where milk fat quotas are employed. CONCLUSIONS Conjugated linoleic acids are potent compounds that naturally occur in ruminant fats such as milk fat. The most abundant isomer in milk fat is cis-9, trans-11 and has been sho\~ possess potent anti-cancer activities. Also important is endogenous synsis this fatty acid from trans-11 18:1 via SCD enzyme both in terms enrichment milk fat as well as in terms cancer fighting effects in consumer. It is likely that ' animal--ani~al variation in milk fat content is due intrinsic facrs such as SCD. The trans-10, cis-12 isomer is produced in rumen under certain dietary conditions and is a potent inhibir milk fat synsis. In addition being implicated in condition known as milk fat depression, this isomer has potential for managing milk fat synsis improve animal health in response metabolic challenges, or match production markets. REFERENCES Bauman, D. E., B. A. Corl, L. H. Baumgard, and J. M. Griinari Conjugated linoleic acid () and dairy cow. In: Recent Advances in Animal Nutrition-2001 (P. C. Garnsworthy and J. Wiseman, eds.), pp Nottingham University Press, Nottingham, UK. Bauman, D. E., B. A. Corl, and D. G. Peterson The biology' conjugated linoleic acids in ruminants. In: Advances in Conjugated, Linoleic Acid Research (J.-L. Sebedio, W. W. Christie, and R. Adl, eds.) Vol. 2, pp AOCS Press, Champaign, IL. Bauman, D. E., and J. M. Griinari Regulation and nutritional nutritional manipulation milk fat: low-fat milk syndrome. Livest. Prod. Sci. Sci. 70: : Baumgard, L. H., B. A. Corl, D. A. Dwyer, A. saeb0, and D. E. Bauman. Bauman Identification conjugated linoleic acid isomer that that inhibits milk fat synsis. Am. J. Physiol. 278:R179-R184. Baumgard, L. H., E. Matitashvili, B. A. Corl, D. A. Dwyer, and D. E. E. Bauman trans-10, cis:12 decreases lipogenic rates and and 1b5

6 expression genes involved in milk lipid synsis in dairy cows. J. Dairy Sci: 85: Baumgard, L. H., J. K. Sangster, and D. E. Bauman Milk fat synsis in dairy cows is progressively reduced by increasing supplemental amounts trans-10, cis-12 conjugated linoleic acid (). J. Nutr. 131: Chong, L., and Marx, J Lipids in Limelight. Science 294:1861. Chouinard, P. Y., L. Corneau, D. M. Barbano, L. E. Metzger, and D. E. Bauman. 1999a. Conjugated linoleic acids alter milk fatty acid composition and inhibit milk fat secretion in dairy cows. J. Nutr. 129: Chouinard, P. Y., L. Corneau, A. Saebo, and D. E. Bauman. 1999b. Milk yield and composition during abomasal infusion conjugated linoleic acid in dairy cows. J. Dairy Sci. 82: Corl, B. A., D. M. Barbano, D. E. Bauman, and C. Ip cis-9, trans-11 derived endogenously from trans-11 18:1 reduces cancer risk in rats. J. Nutr. 133: Dawson, R. M. C., and P. Kemp Biohydrogenation dietary fats in ruminants. In: Physiology Digestion and Metabolism in Ruminant (A. T. Phillipson, ed.), pp , Oriel Press, Newcastle upon-tyne, UK. Fritsche, J., Fritsche, S., Solomon, M.B., Mossoba, M.M., Yurawecz, M.P., Morehouse, K., and Ku, Y Quantitative Determination Conjugated Linoleic Acid Isomers in Beef Fat.. Eur. J. Lipid Sci. Technol. 102: Griinari, J. M., and D. E. Bauman Biosynsis conjugated linoleic acid and its incorporation in meat and milk in rum~nants. In: Advances in Conjugated Linoleic Acid Research (M. P. Yurawecz, M. M. Mossoba, J. K. G. Kramer, M. W. Pariza, and G. J. Nelson, eds.) eds.) Vol. 1, pp AOCS Press, Champaign, IL. IL. Golding, J., K. M. Soams, S. S. Zilva The influence cow's diet on fat-soluble vitamins winter milk. Biochem. J. 20: Harfoot, C. G Lipid metabolism in rumen. 17: : Prog. Lipid Res. Res. Jump, D.B., and S. D. Clarke Regulation gene expression. by. dietary fat, Ann. Rev. Nutr. 19: Ip, C., S. F. Chin, J. A. Scimeca, and M. W. Pariza, Mammary Mammary cancer prevention by conjugated dienoic derivatives linoleic acid. acid. Cancer Res. 51: : Ip, C., S. Banni, E. Angioni, G. Carta, J. McGinley, H. J. Thompson, D. D. Barbano, and D. E. Bauman Conjugated linoleic acid-enriched acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk risk in rats. J. Nutr. 129: : Keeney, M Lipid metabolism in rumen. In: Physiology Digestion and Metabolism in Ruminant (A. T. Phillipson, ed.), pp ~ Oriel Press, Newcastle-upon-Tyne, UK. 106

7 Loor, J. J., and J. H. Herbein Exogenous conjugated linoleic acid isomers reduce bovine milk fat concentration and yield by inhibiting de novo fatty acid Synsis. J. Nutr. 126: Pariza, M.W The biological activities conjugated linoleic acid. In: advances in conjugated linoleic acid research (M. P. Yurawecz, M. M. Mossoba, J. K. G. Kramer, M. W. Pariza, and G. J. Nelson, eds.), Vol. 1, pp AOCS Press, Champaign, IL. Parodi, P.W Conjugated octadecadienoic acids milk fat, J. Dairy Sci. -60: Peterson, D. G., L. H. Baumgard, and D. E. Bauman. 2002a. Short communication: milk fat response low doses trans-10, cis-12 conjugated linoleic acid (). J. Dairy Sci. ~5: Peterson, D. G., J. A. Kelsey, D. E. Bauman. 2002b. Analysis variation in cis-9, trans-ii conjugated linoleic acid () in milk fat dairy cows. J. Dairy Sci. 85: Peterson, D. G., E. A. Matitashvili, and D. E. Bauman Diet induced milk fat depression in dairy cows results in increased trans 10, cis-12 in milk fat and coordinate suppression mrna abundance for mammary enzymes involved in milk fat synsis. J. Nutr. 133: Sehat, N., J. K. G. Kramer, M. M. Mossoba, M. P. Yurawecz, -J. A. G. Roach, K. Eulitz, K. M. Morehouse, and Y. Ku Identification conjugated linoleic acid isomers in cheese by gas chromagraphy, silver ion high performance liquid chromagraphy and mass spectral reconstructed ion priles. Lipids 33: Van Soest, P. J." Nutritional Ecology Ruminant. Cornell University Press, Ithaca, NY. 107