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4 Department of Animal Science, Cornell University, Ithaca, NY 14853 and 5 Department of Animal Sciences, The University of Arizona, Tucson, AZ 85721
* To whom correspondence should be addressed. E-mail: deb6{at}cornell.edu.
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ABSTRACT |
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 TOP ABSTRACT IntroductionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionLITERATURE CITED |
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Lactating ruminants have been of special value as a model to investigate milk fat synthesis. Knowledge of mammary uptake of nutrients, biosynthesis pathways, and the relation between diet and milk fat composition have been elaborated in studies with ruminants, and results have been extended and contrasted with those from other mammals (3,4). Although much is known about the biochemistry of milk lipid synthesis, the regulatory and cellular signaling systems of mammary fat synthesis are not well understood. The lactating bovine mammary gland synthesizes easily measurable quantities of lipid and thus is a unique model to study both the acute and chronic regulation of milk fat synthesis. When challenged, temporal changes in milk fat can be monitored in the same animal by sequential collection of milk samples and serial tissue biopsies. In contrast, quantifying milk yield, sequential collection of representative milk samples, and obtaining serial mammary biopsies are challenging in most other mammals. Similarly, investigations of lipid synthesis in nonlactating animal models generally require several weeks of treatment to quantify differences in adipose tissue accretion rates accurately, and multiple measurements are not typically obtained from the same animal over an experimental time course.
The discovery that certain conjugated linoleic acid (CLA)7 isomers are potent inhibitors of mammary lipid synthesis in dairy cows presents a unique opportunity to use this species as a model. CLA are produced during rumen fermentation, and their regulation of milk fat synthesis is a naturally occurring example of nutritional genomics in dairy cows that involves an interrelation between rumen digestive processes and mammary metabolism (4). In addition, CLA alter lipid metabolism and body fat accretion in nonlactating animals (5,6). Although the mode of regulation by CLA is not fully understood in either model, comparison of similarities and differences between its effects on mammary and adipose tissues provide additional mechanistic insight. In the following sections we address lactation responses to CLA, identify the specific CLA isomers that regulate milk fat synthesis, discuss recent investigations elaborating regulatory mechanisms, relate results to the low-fat milk syndrome in dairy cows, and, where appropriate, compare these findings to the reported antiobesity effects of CLA.
CLA inhibits milk fat synthesis in dairy cows
CLA is a generic term used to describe positional and geometric isomers of octadecadienoic fatty acids with a conjugated double bond. Although CLA were first identified in milk fat in the 1930s (7), interest in CLA increased dramatically when CLA were identified as anticarcinogens and shown to have a wide range of potential health benefits in biomedical studies with animal models (8,9). Ruminant-derived food products are the primary source of dietary CLA for humans (10), and initial studies in lactating cows were designed to examine the transfer of exogenous CLA to milk fat for the purpose of creating a "functional food." Unexpectedly, a dietary supplement containing a mixture of CLA isomers resulted in an immediate and dramatic reduction in milk fat secretion (11,12).
Most research investigating CLA effects during lactation has utilized dairy cows, and results have consistently demonstrated that the inhibitory effects are specific for milk fat; yields of milk and other milk components are generally unaffected (4). The reduction in milk fat secretion reaches a nadir by 4 to 5 d of supplementation and returns to previous levels in a similar temporal pattern when CLA treatment is terminated. Most studies have lasted a few days, but long-term studies (20 wk) indicate that the reduction in milk fat persists throughout the treatment period (13,14). Treatment has also encompassed all phases of the lactation cycle with no adverse effects on animal health and well-being (13–15). Interestingly, initial studies observed that CLA supplements were less effective at reducing milk fat during the first 3 wk postpartum (14,16). Subsequent studies have demonstrated that cows are responsive during this period, but a larger dose of CLA is required to achieve a similar reduction in milk fat yield (17,18).
Relation to low-fat milk syndrome
The low-fat milk syndrome, more commonly referred to as milk fat depression (MFD), is a naturally occurring situation in dairy production when cows are fed highly fermentable diets or dietary supplements of plant or fish oils (4). First described over a century ago, diet-induced MFD can result in a reduction in milk fat yield of up to 50%, and the decrease involves fatty acids of all chain lengths. Effects are also specific for milk fat, as yields of milk and other milk components are generally unaffected.
Many theories have been proposed to explain the basis for diet-induced MFD, and most have proven inadequate (4,19). A key development was the demonstration that the reduction in milk fat was correlated with changes in the milk fatty acid profile, specifically an increased content of rumen-derived biohydrogenation intermediates. Referred to as the "biohydrogenation theory," the basis for diet-induced MFD relates to an inhibition of mammary lipid synthesis by specific fatty acids that are intermediates in the biohydrogenation of dietary polyunsaturated fatty acids and are produced only under certain conditions of rumen fermentation (20). The first of these unique intermediates to be identified as a potent inhibitor of milk fat synthesis was trans-10, cis-12 CLA, and for many situations of diet-induced MFD, the increase in milk fat content of trans-10, cis-12 CLA is correlated with the magnitude of the reduction in milk fat yield (20,21).
In certain situations of diet-induced MFD, the trans-10, cis-12 CLA content and magnitude of the reduction in milk fat yield do not align with the dose-response curve generated with abomasal infusion of relatively pure trans-10, cis-12 CLA. This suggests that in these situations this single isomer does not completely explain the extent of the decrease in milk fat. Thus, additional inhibitory biohydrogenation intermediates have been proposed (20,22), and 2 additional isomers (trans-9, cis-11 and cis-10, trans-12 CLA) have recently been identified, as discussed in a later section. However, careful accounting of the rumen production of CLA isomers under different situations of diet-induced MFD indicates that the isomers identified to date are still not adequate to fully explain the observed decrease in milk fat yield (23). Nevertheless, diet-induced MFD is a natural situation in which, under certain dietary conditions, the pathways of rumen biohydrogenation are altered to produce unique fatty acid intermediates that are potent inhibitors of milk fat synthesis.
Regulation of milk fat synthesis is related to specific CLA isomers
CLA are produced as intermediates in the biohydrogenation of linoleic acid by rumen bacteria. Cis-9, trans-11 is the major CLA isomer in ruminant fat (
75–90% of total CLA), and it arises mainly from endogenous synthesis via 
9-desaturase in the mammary gland; as the predominant CLA isomer in ruminant fat, cis-9, trans-11 is the CLA isomer with functional food implications (24). Milk fat, however, contains most of the other 24 possible CLA isomers, albeit each at a level generally 1% or less of total CLA. Studies in lactating and nonlactating animals have generally used a mixture of CLA isomers. We examined effects of relatively pure CLA isomers on milk fat synthesis and provided the isomers to dairy cows by abomasal infusion to avoid alterations by rumen bacteria (25). Results clearly demonstrated that trans-10, cis-12 CLA was responsible for the reduction in milk fat in dairy cows, and milk fat was rescued when treatment ceased (Fig. 1). In contrast, cis-9, trans-11 CLA had no effect on milk fat content or yield.
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De Veth et al. (31) combined results from 7 studies and indicated that abomasally infused trans-10, cis-12 CLA incorporation into milk fat was linear with a mean transfer efficiency of 22% (Fig. 2). Most importantly, a curvilinear relation was demonstrated between the increasing dose of trans-10, cis-12 CLA and the reduction in milk fat production. The median effective dose (ED50) corresponded to a 25% reduction in milk fat yield and occurred at a dose of 2.5 g/d of trans-10, cis-12 CLA (0.01% of dry matter intake), and the maximum inhibition of milk fat secretion was 50%.
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CLA regulates milk fat in other mammals
The ability of CLA to regulate milk fat synthesis has also been observed in other mammals including mice (35), rats (36,37), pigs (38,39), sheep (40,41), goats (42,43), and humans (44). Most of these investigations have used dietary supplements containing a mixture of CLA isomers. However, a study with rats demonstrated that milk fat content and nursing pup growth were reduced when trans-10, cis-12 CLA was provided as a dietary supplement, whereas cis-9, trans-11 CLA had no effect (35).
Variation in CLA dose, interval of administration, and response endpoint make it difficult to directly compare results from different lactating mammals to those from cows. Nevertheless, CLA supplementation has consistently resulted in a reduction in milk fat content, milk fat yield, and/or growth rate of the nursing neonate. Exceptions are studies with lactating women, where a reduction in milk fat content was observed in 1 study (44) and no effect was reported in another (45); interestingly, these 2 studies were conducted by the same group, and the basis for the difference in milk fat response to CLA supplementation is not obvious.
CLA-induced milk fat reduction alters nutrient partitioning
Investigations of CLA in dairy cows have predominantly involved established lactation (i.e., post peak during galactopoiesis) when nutrient intake is adequate and energy balance is zero or positive. During this period, studies have consistently demonstrated that basal plasma concentrations of glucose and insulin were unaltered with trans-10, cis-12 CLA administration, although the expected reduction in milk fat yield was observed (13,14,29,46,47). Furthermore, trans-10, cis-12 CLA did not alter plasma glucose response to an insulin challenge (29,47). In addition, administration of trans-10, cis-12 CLA had little or no effect on basal plasma nonesterified fatty acid concentrations (13,15,29,47) and negligible effects on plasma nonesterified fatty acid response to a β-adrenergic challenge (epinephrine) (29,47). Circulating leptin and insulin-like growth factor-I are related to energy homeostasis, and treatment with trans-10, cis-12 CLA had no effect on their plasma concentrations (25,29). Furthermore, CLA resulted in no unexpected changes in whole-body heat production (48) or indices of thermal load (49). Overall, results demonstrate that the CLA-induced reduction in milk fat yield occurs with no apparent alterations in glucose and energy homeostasis, thermal homeostasis, or whole-body bioenergetics.
Although most CLA supplementation trials have not detected an increase in either milk yield or component synthesis, experiments have typically been conducted while cows are in a positive energy and nutrient balance. There are, however, frequent situations when nutrient intake is insufficient to meet lactation demands (e.g., immediately postpartum and in pasture-based systems). Inducing a reduction in milk fat output with CLA supplements often results in an increase in the yields of milk and/or milk protein during early lactation (14,18,50) or with pasture systems and underfeeding models (46,47,50). A similar repartitioning effect was reported in sheep supplemented with trans-10, cis-12 CLA, resulting in an increase in milk and protein yields (40). Consequently, it appears that during times of inadequate nutrient intake, inducing a reduction in milk fat increases available energy that can be repartitioned toward the synthesis of milk or milk protein, and there are currently commercial CLA supplements available in some countries that are marketed for this specific purpose.
During periods when net energy intake is adequate, the CLA-induced reduction in milk fat yield coincides with marginal changes in feed intake (reduced) and body reserves (increased), although demonstrating statistical significance of these modest differences is difficult. The latter is best illustrated in bioenergetic studies where the 35% reduction in milk fat was accompanied by an increase in the energy retained in body tissues (48). Likewise, Harvatine et al. (51) demonstrated that the mRNA expression for lipogenic enzymes was increased in adipose tissue when CLA induced a reduction in milk fat of dairy cows. A repartitioning of energy to body fat reserves is also observed in diet-induced MFD (19).
Mechanism involves a coordinated regulation of mammary lipid synthesis
Phenotypic characterization of CLA-induced MFD provides key insight into the functional mechanism of CLA. Fat is the only milk component inhibited with trans-10, cis-12 CLA treatment, and the reduction involves fatty acids of all chain lengths, thereby demonstrating that mammary effects are highly specific for lipid synthesis and include biochemical pathways associated with both de novo synthesis and the use of preformed fatty acids. Expression of lipogenic enzymes is coordinately stimulated by a class of transcription factors known as master regulators of lipid synthesis, and 1 of these is the sterol response element-binding protein (SREBP) family (52). Specifically, SREBP1c is highly responsive to changes in mammary lipid synthesis and up-regulated at the initiation of lactation in the mouse (2). Disruption of the SREBP1c gene results in a 41% decrease in milk fat concentration in mice (53), and this is strikingly similar to the maximum milk fat reduction (50%) observed during trans-10, cis-12 CLA treatment (Fig. 2) or diet-induced MFD (4,31).
We first evaluated the SREBP-regulatory system in bovine mammary epithelial cells (MAC-T cell line) and observed decreased abundance of the nuclear SREBP1 protein (active fragment) during trans-10, cis-12 CLA inhibition of fatty acid synthesis (54). SREBP1 is highly expressed in bovine mammary tissue, and recent investigations demonstrated that mammary expression of SREBP1 and proteins involved in the activation and translocation of SREBP were reduced for both trans-10, cis-12 CLA treatment and diet-induced MFD (55). Many lipogenic enzymes have SREBP response elements in their promoter, and, consistent with this, transcription of mammary genes involved in the complementary pathways for milk fat synthesis was coordinately down-regulated during CLA- and diet-induced MFD (Table 2). Collectively, these observations are consistent with SREBP1 representing a major signaling mechanism in the regulation of fatty acid synthesis during CLA-induced MFD. Polyunsaturated fatty acids, especially long-chain (n-3) fatty acids, are well recognized to inhibit lipid synthesis, and SREBP1 is 1 of the predominant signaling mechanisms in the regulation of hepatic fatty acid synthesis (56,57).
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Some members of the nuclear hormone receptor family are known to bind and become activated by fatty acids, including CLA, and PPAR-centric mechanisms for the biological effects of CLA have been proposed for some tissues (64,65). To date, there is no evidence of a role of PPAR in regulation of milk fat synthesis in the mammary gland or as a mechanism of CLA-induced MFD. However, in extramammary tissues where the PPAR family of transcription factors are highly expressed and are key regulators of tissue-specific differentiation and inflammation, they may be important in functional responses to higher doses of CLA.
Only a limited number of mechanisms have been investigated in CLA-induced MFD and these predominantly at the level of gene expression. The coordinated down-regulation of lipogenic enzymes during MFD is expected to involve multiple regulatory systems and the interaction of multiple signals. Mechanisms regulating lipid synthesis and SREBP1c continue to be identified and will provide strong hypotheses to test the regulation of milk fat synthesis. Specifically, AMP-activated protein kinase (66), protein kinase B (67), and extracellular signal-related kinase (68) signaling have not been investigated during MFD and represent logical mechanisms known to regulate lipid synthesis.
Relation to antiobesity effects of CLA
Coinciding with initial studies examining CLA effects on milk fat synthesis was the discovery that dietary supplements of CLA, specifically trans-10, cis-12 CLA, caused a reduction in body fat accretion in mice (69,70). Subsequent studies extended these results to other animal models as well as humans (5,6,71,72). In general, there exists substantial inter- and intraspecies variation in the ability of CLA to induce body weight changes and reduce adipose tissue accretion among studies. This is in contrast to the relatively consistent results observed across lactation studies with trans-10, cis-12 CLA as discussed earlier. Reasons for these discrepancies are not entirely clear, but there are many examples of similarities and differences in lipid metabolism between lactation and growth.
Comparison among studies is difficult because the effect of CLA can be influenced by the CLA isomer mixture and dose as well as duration of treatment. The majority of studies have used a mixture of 2 or more isomers of CLA, although a few investigations have used relatively pure preparations of cis-9, trans-11 CLA and trans-10, cis-12 CLA. CLA isomers are known to differ in biological effects, but there is a consensus that the reduction in body fat is caused by the trans-10, cis-12 isomer (5,6). The amount of CLA necessary to reduce milk fat synthesis (<0.01–0.05% of diet) is very low (Fig. 2) compared with the amount of CLA reported to reduce body fat accretion (0.5–2.0% of diet). In contrast to the situation for milk fat synthesis, there are few well-defined dose-response curves for effects on body fat. Dose relations have been established only in the growing pig where the reduction in fat accretion was found to be linearly related to dose (dose range = 0.1–1.0% dietary intake) (72,73) and humans where meta-analysis indicated a linear relation between the reduction in body fat mass and the increase in CLA dose (dose range = 1–7 g/d) (71). However, establishing a dose-dependent relation involving adipose tissue accretion is more difficult because the endpoint is based on cumulative effects, whereas daily milk fat secretion can be quantified routinely.
Numerous theories have been advanced to explain the effects of trans-10, cis-12 CLA on lipid metabolism in adipose tissue, and some of the major ones include 1) increased basal metabolic rate and energy expenditure, 2) increased mobilization and oxidation of fatty acids from adipose tissue, 3) reduced preadipocyte proliferation and/or differentiation, and 4) increased adipocyte apoptosis (5,6,8). None of these corresponds to the effects of CLA on milk fat synthesis. The absence of effects on bioenergetics and heat expenditure and glucose and energy homeostasis during the CLA-induced reduction in milk fat was discussed previously. Likewise, effects related to decreases in proliferation/differentiation or increases in apoptosis are not part of the response in the CLA-induced reduction in milk fat; of the milk components synthesized by the mammary gland, fat is the only one that is affected by CLA treatment of cows, and this is reversed when CLA treatment is terminated.
The CLA-induced reduction in adipose tissue has also been correlated with adverse side effects in some situations, including insulin resistance and fatty liver (6,74–76). Insulin resistance is unlikely to play a role in the reduction of milk fat synthesis because ruminant mammary tissue, in contrast to adipose tissue, is largely refractory to changes in circulating insulin (4). As discussed earlier, plasma insulin levels are unchanged, and glucose response to an insulin challenge is unaltered, in lactating cows treated with trans-10, cis-12 CLA. Furthermore, liver lipid content is not altered in cows receiving CLA treatment (14,15). Consequently, supplementing CLA to lactating dairy cows, either to enhance the CLA content in milk or to improve whole-animal energetics during specific stages of lactation, has no apparent negative effects on animal health and well-being. Furthermore, the level of trans-10, cis-12 CLA observed in milk fat when CLA supplements are used (31) is several orders of magnitude less than that needed to supply the CLA levels used in antiobesity studies (71).
Final comments
Ruminant synthesis of milk fat has proven a unique model that has provided novel mechanistic insight in the regulation of fatty acid synthesis by CLA. This article highlights new discoveries but also raises additional challenging questions relating to fatty acid biosynthesis. For example: Are there other rumen biohydrogenation intermediates that regulate milk fat synthesis, and what is structurally/biologically different about the CLA isomers that do? Compared with adipocytes, what is the basis for the greater sensitivity of mammary epithelial cells to the CLA-induced inhibition of lipid synthesis? Following CLA uptake by mammary cells, what events are upstream of the SREBP response? To what extent are other fatty acid sensor proteins, cellular signaling factors, and molecular mechanisms involved in the lipogenic response to CLA? These questions serve to illustrate that regulation of fatty acid synthesis by CLA will remain an exciting research area, and the lactating ruminant will continue to be a valuable model to address scientific questions in this area.
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FOOTNOTES |
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2 Supported in part by National Research Initiative Competitive Grants Program, Cooperative State Research, Education, and Extension Service, United States Department of Agriculture (grant 2006-35206-16643) and by Agricultural Experiment Stations at Cornell University and the University of Arizona.
3 Author disclosures: D. E. Bauman is coinventor on a CLA use patent that is assigned to Cornell Research Foundation, Inc.; J. W. Perfield II, K. J. Harvatine, and L. H. Baumgard, no conflicts of interest.
6 Present address: Obesity and Metabolism Laboratory, JM-United States Department of Agriculture HNRCA at Tufts University, Boston, MA 02111.
7 Abbreviations used: CLA, conjugated linoleic acid; MFD, milk fat depression; S14, Spot 14; SREBP, sterol response element-binding protein.
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LITERATURE CITED |
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TOPABSTRACTIntroductionLITERATURE CITED |
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1. Bauman DE, Currie WB. Partitioning of nutrients during pregnancy and lactation: a review of mechanisms involving homeostasis and homeorhesis. J Dairy Sci. 1980;63:1514–29.
2. Rudolph MC, McManaman JL, Phang T, Russell T, Kominsky DJ, Serkova NJ, Stein T, Anderson SM, Neville MC. Metabolic regulation in the lactating mammary gland: a lipid synthesizing machine. Physiol Genomics. 2007;28:323–36.
3. Neville MC, Picciano MF. Regulation of milk lipid secretion and composition. Annu Rev Nutr. 1997;17:159–83.[CrossRef][Medline]
4. Bauman DE, Griinari JM. Nutritional regulation of milk fat synthesis. Annu Rev Nutr. 2003;23:203–27.[CrossRef][Medline]
5. Brown JM, McIntosh MK. Conjugated linoleic acid in humans: regulation of adiposity and insulin sensitivity. J Nutr. 2003;133:3041–6.
6. Wang YW, Jones PJ. Conjugated linoleic acid and obesity control: efficacy and mechanisms. Int J Obes Relat Metab Disord. 2004;28:941–55.[CrossRef][Medline]
7. Booth RG, Dann WJ, Kon SK, Moore T. A new variable in butter fat. Chem Ind. 1933;52:270.
8. Pariza MW. Perspective on the safety and effectiveness of conjugated linoleic acid. Am J Clin Nutr. 2004;79:1132S–6S.
9. Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem. 2006;17:789–810.[CrossRef][Medline]
10. Parodi PW. Conjugated linoleic acid in food. In: Sebedio JL, Christie WW, Adlof RO, editors. Advances in conjugated linoleic acid research, Volume 2. Champaign, IL: AOCS Press; 2003. p. 101–22.
11. Loor JJ, Herbein JH. Exogenous conjugated linoleic acid isomers reduce bovine milk fat concentration and yield by inhibiting de novo fatty acid synthesis. J Nutr. 1998;128:2411–9.
12. Chouinard PY, Corneau L, Barbano DM, Metzger LE, Bauman DE. Conjugated linoleic acids alter milk fatty acid composition and inhibit milk fat secretion in dairy cows. J Nutr. 1999;129:1579–84.
13. Perfield JW II, Bernal-Santos G, Overton TR, Bauman DE. Effects of dietary supplementation of rumen-protected conjugated linoleic acid in dairy cows during established lactation. J Dairy Sci. 2002;85:2609–17.
14. Bernal-Santos G, Perfield JW II, Barbano DM, Bauman DE, Overton TR. Production responses of dairy cows to dietary supplementation with conjugated linoleic acid (CLA) during the transition period and early lactation. J Dairy Sci. 2003;86:3218–28.
15. Castaneda-Gutierrez E, Overton TR, Butler WR, Bauman DE. Dietary supplements of two doses of calcium salts of conjugated linoleic acid during the transition period and early lactation. J Dairy Sci. 2005;88:1078–89.
16. Gervais R, Spratt R, Leonard M, Chouinard PY. Lactation response of cows to different levels of ruminally inert conjugated linoleic acids under commercial conditions. Can J Anim Sci. 2005;85:231–42.
17. Moore CE, Hafliger HC, Mendivil OB, Sanders SR, Bauman DE, Baumgard LH. Increasing amounts of conjugated linoleic acid progressively reduces milk fat synthesis immediately postpartum. J Dairy Sci. 2004;87:1886–95.
18. Odens LJ, Burgos R, Innocenti M, VanBaale MJ, Baumgard LH. Effects of varying doses of supplemental conjugated linoleic acid on production and energetic variables during the transition period. J Dairy Sci. 2007;90:293–305.
19. Griinari JM, Bauman DE. Milk fat depression: concepts, mechanisms and management applications. In: Sejrsen K, Hvelplund T, Nielsen MO, editors. Ruminant physiology: digestion, metabolism and impact of nutrition on gene expression, immunology and stress. Wageningen, The Netherlands: Wageningen Academic; 2006. p. 389–417.
20. Bauman DE, Griinari JM. Regulation and nutritional manipulation of milk fat: low-fat milk syndrome. Livest Prod Sci. 2001;70:15–29.
21. Loor JJ, Ferlay A, Ollier A, Ueda K, Doreau M, Chilliard Y. High-concentrate diets and polyunsaturated oils alter trans and conjugated isomers in bovine rumen, blood, and milk. J Dairy Sci. 2005;88:3986–99.
22. Peterson DG, Matitashvili EA, Bauman DE. Diet-induced milk fat depression in dairy cows results in increased trans-10, cis-12 CLA in milk fat and coordinated suppression of mRNA abundance for mammary enzymes involved in milk fat synthesis. J Nutr. 2003;133:3098–102.
23. Shingfield KJ, Griinari JM. Role of biohydrogenation intermediates in milk fat depression. Eur J Lipid Sci Technol. 2007;109:799–816.[CrossRef]
24. Lock AL, Bauman DE. Modifying milk fat composition of dairy cows to enhance fatty acids beneficial to human health. Lipids. 2004;39:1197–206.[CrossRef][Medline]
25. Baumgard LH, Corl BA, Dwyer DA, Saebo A, Bauman DE. Identification of the conjugated linoleic acid isomer that inhibits milk fat synthesis. Am J Physiol Regul Integr Comp Physiol. 2000;278:R179–84.
26. Saebo A, Saebo PC, Griinari JM, Shingfield KJ. Effect of abomasal infusions of geometric isomers of 10,12 conjugated linoleic acid on milk fat synthesis in dairy cows. Lipids. 2005;40:823–32.[CrossRef][Medline]
27. Perfield JW II, Lock AL, Griinari JM, Saebo A, Delmonte P, Dwyer DA, Bauman DE. Trans-9, cis-11 conjugated linoleic acid reduces milk fat synthesis in lactating dairy cows. J Dairy Sci. 2007;90:2211–8.
28. Perfield JW II, Saebo A, Bauman DE. Use of conjugated linoleic acid (CLA) enrichments to examine the effects of trans-8, cis-10 CLA, and cis-11, trans-13 CLA on milk-fat synthesis. J Dairy Sci. 2004;87:1196–202.
29. Baumgard LH, Corl BA, Dwyer DA, Bauman DE. Effects of conjugated linoleic acids (CLA) on tissue response to homeostatic signals and plasma variables associated with lipid metabolism in lactating dairy cows. J Anim Sci. 2002;80:1285–93.
30. Loor JJ, Herbein JH. Reduced fatty acid synthesis and desaturation due to exogenous trans10,cis12-CLA in cows fed oleic or linoleic oil. J Dairy Sci. 2003;86:1354–69.
31. de Veth MJ, Griinari JM, Pfeiffer AM, Bauman DE. Effect of CLA on milk fat synthesis in dairy cows: comparison of inhibition by methyl esters and free fatty acids, and relationships among studies. Lipids. 2004;39:365–72.[CrossRef][Medline]
32. Baumgard LH, Sangster JK, Bauman DE. Milk fat synthesis in dairy cows is progressively reduced by increasing supplemental amounts of trans-10, cis-12 conjugated linoleic acid (CLA). J Nutr. 2001;131:1764–9.
33. Peterson DG, Baumgard LH, Bauman DE. Short communication: milk fat response to low doses of trans-10, cis-12 conjugated linoleic acid (CLA). J Dairy Sci. 2002;85:1764–6.
34. Bell JA, Kennelly JJ. Short communication: Postruminal infusion of conjugated linoleic acids negatively impacts milk synthesis in Holstein cows. J Dairy Sci. 2003;86:1321–4.
35. Loor JJ, Lin X, Herbein JH. Effects of dietary cis 9, trans 11–18:2, trans 10, cis 12–18:2, or vaccenic acid (trans 11–18:1) during lactation on body composition, tissue fatty acid profiles, and litter growth in mice. Br J Nutr. 2003;90:1039–48.[CrossRef][Medline]
36. Ringseis R, Saal D, Muller A, Steinhart H, Eder K. Dietary conjugated linoleic acids lower the triacylglycerol concentration in the milk of lactating rats and impair the growth and increase the mortality of their suckling pups. J Nutr. 2004;134:3327–34.
37. Hayashi AA, de Medeiros SR, Carvalho MH, Lanna DP. Conjugated linoleic acid (CLA) effects on pups growth, milk composition and lipogenic enzymes in lactating rats. J Dairy Res. 2007;74:160–6.[CrossRef][Medline]
38. Bontempo V, Sciannimanico D, Pastorelli G, Rossi R, Rosi F, Corino C. Dietary conjugated linoleic acid positively affects immunologic variables in lactating sows and piglets. J Nutr. 2004;134:817–24.
39. Poulos SP, Azain MJ, Hausman GJ. Conjugated linoleic acid during gestation and lactation does not alter sow performance or body weight gain and adiposity in progeny. Anim Res. 2004;53:275–88.
40. Lock AL, Teles BM, Perfield JW II, Bauman DE, Sinclair LA. A conjugated linoleic acid supplement containing trans-10, cis-12 reduces milk fat synthesis in lactating sheep. J Dairy Sci. 2006;89:1525–32.
41. Sinclair LA, Lock AL, Early R, Bauman DE. Effects of trans-10, cis-12 conjugated linoleic acid on ovine milk fat synthesis and cheese properties. J Dairy Sci. 2007;90:3326–35.
42. de Andrade PV, Schmidely P. Effect of duodenal infusion of trans10,cis12-CLA on milk performance and milk fatty acid profile in dairy goats fed high or low concentrate diet in combination with rolled canola seed. Reprod Nutr Dev. 2006;46:31–48.[CrossRef][Medline]
43. Rovai M, Lock AL, Gipson TA, Goetsch AL, Bauman DE. Trans-10, cis-12 conjugated linoleic acid reduces milk fat synthesis in lactating goats. J Dairy Sci. 2006;90: Suppl.1:294.
44. Masters N, McGuire MA, Beerman KA, Dasgupta N, McGuire MK. Maternal supplementation with CLA decreases milk fat in humans. Lipids. 2002;37:133–8.[CrossRef][Medline]
45. Mosley SA, Shahin AM, Williams J, McGuire MA, McGuire MK. Supplemental conjugated linoleic acid consumption does not influence milk macronutrient contents in all healthy lactating women. Lipids. 2007;42:723–9.[Medline]
46. Mackle TR, Kay JK, Auldist MJ, McGibbon AK, Philpott BA, Baumgard LH, Bauman DE. Effects of abomasal infusion of conjugated linoleic acid on milk fat concentration and yield from pasture-fed dairy cows. J Dairy Sci. 2003;86:644–52.
47. de Veth MJ, Castaneda-Gutierrez E, Dwyer DA, Pfeiffer AM, Putnam DE, Bauman DE. Response to conjugated linoleic acid in dairy cows differing in energy and protein status. J Dairy Sci. 2006;89:4620–31.
48. Shingfield KJ, Beever DE, Reynolds CK, Gulati SK, Humphries DJ, Lupoli B, Hervas G, Griinari JM. Effect of rumen-protected conjugated linoleic acid on energy metabolism of dairy cows during early to mid-lactation. J Dairy Sci. 2004;87: Suppl 1:307.
49. Rhoads M, Rhoads RD, Odens LJ, Burgos R, Baker S, Pollard B, Moore CE, Kay JK, VanBaale MJ, et al. Effects of dietary CLA on thermogenesis and body temperature indices in lactating dairy cows. J Dairy Sci. 2005;88: Suppl 1:211.
50. Kay JK, Roche JR, Moore CE, Baumgard LH. Effects of dietary conjugated linoleic acid on production and metabolic parameters in transition dairy cows grazing fresh pasture. J Dairy Res. 2006;73:367–77.[Medline]
51. Harvatine KJ, Dwyer DA, Bauman DE. Expression of lipogenic genes in adipose tissue increases during milk fat depression induced by treatment with trans-10, cis-12 conjugated linoleic acid (CLA). J Dairy Sci. 2007;90: Suppl 1:206.
52. Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004;86:839–48.[Medline]
53. Rudolph M, Marians R, Burns V, Russell T, Neville MC. SREBP1-c plays a regulatory, but not essential role in mammary lipogenesis during lactation. The Endocrine Society's 87th Annual Meeting Abstracts 2005;604.
54. Peterson DG, Matitashvili EA, Bauman DE. The inhibitory effect of trans-10, cis-12 CLA on lipid synthesis in bovine mammary epithelial cells involves reduced proteolytic activation of the transcription factor SREBP-1. J Nutr. 2004;134:2523–7.
55. Harvatine KJ, Bauman DE. SREBP1 and thyroid hormone responsive spot 14 (S14) are involved in the regulation of bovine mammary lipid synthesis during diet-induced milk fat depression and treatment with CLA. J Nutr. 2006;136:2468–74.
56. Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty acid regulation of hepatic gene transcription. J Nutr. 2005;135:2503–6.
57. Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr. 2005;25:317–40.[CrossRef][Medline]
58. Baumgard LH, Matitashvili E, Corl BA, Dwyer DA, Bauman DE. Trans-10, cis-12 conjugated linoleic acid decreases lipogenic rates and expression of genes involved in milk lipid synthesis in dairy cows. J Dairy Sci. 2002;85:2155–63.
59. Piperova LS, Teter BB, Bruckental I, Sampugna J, Mills SE, Yurawecz MP, Fritsche J, Ku K, Erdman RA. Mammary lipogenic enzyme activity, trans fatty acids and conjugated linoleic acids are altered in lactating dairy cows fed a milk fat-depressing diet. J Nutr. 2000;130:2568–74.
60. Ahnadi CE, Beswick N, Delbecchi L, Kennelly JJ, Lacasse P. Addition of fish oil to diets for dairy cows. II. Effects on milk fat and gene expression of mammary lipogenic enzymes. J Dairy Res. 2002;69:521–31.[Medline]
61. Kay JK, Moore CE, Bauman DE, Rhoads RP, Sanders SR, Keating AF, Baumgard LH. Temporal effect of trans-10, cis-12 conjugated linoleic acid on mammary lipogenic gene expression. J Dairy Sci. 2007;90: Suppl 1:58.
62. Cunningham BA, Moncur JT, Huntington JT, Kinlaw WB. "Spot 14" protein: a metabolic integrator in normal and neoplastic cells. Thyroid. 1998;8:815–25.[Medline]
63. Zhu Q, Anderson GW, Mucha GT, Parks EJ, Metkowski JK, Mariash CN. The Spot 14 protein is required for de novo lipid synthesis in the lactating mammary gland. Endocrinology. 2005;146:3343–50.
64. Belury MA. Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action. Annu Rev Nutr. 2002;22:505–31.[CrossRef][Medline]
65. Khan SA, Vanden Heuvel JP. Role of nuclear receptors in the regulation of gene expression by dietary fatty acids. (review) J Nutr Biochem. 2003;14:554–67.
66. Suchankova G, Tekle M, Saha AK, Ruderman NB, Clarke SD, Gettys TW. Dietary polyunsaturated fatty acids enhance hepatic AMP-activated protein kinase activity in rats. Biochem Biophys Res Commun. 2005;326:851–8.[CrossRef][Medline]
67. Porstmann T, Griffiths B, Chung YL, Delpuech O, Griffiths JR, Downward J, Schulze A. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 2005;24:6465–81.[Medline]
68. Botolin D, Wang Y, Christian B, Jump DB. Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J Lipid Res. 2006;47:181–92.
69. Park Y, Albright KJ, Liu W, Storkson JM, Cook ME, Pariza MW. Effect of conjugated linoleic acid on body composition in mice. Lipids. 1997;32:853–8.[Medline]
70. Park Y, Storkson JM, Albright KJ, Liu W, Cook ME, Pariza MW. Evidence that the trans-10, cis-12 isomer of conjugated linoleic acid induces body composition changes in mice. Lipids. 1999;34:235–41.[Medline]
71. Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans. Am J Clin Nutr. 2007;85:1203–11.
72. Ostrowska E, Muralitharan M, Cross RF, Bauman DE, Dunshea FR. Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs. J Nutr. 1999;129:2037–42.
73. Ostrowska E, Suster D, Muralitharan M, Cross RF, Leury BJ, Bauman DE, Dunshea FR. Conjugated linoleic acid decreases fat accretion in pigs: evaluation by dual-energy x-ray absorptiometry. Br J Nutr. 2003;89:219–29.[CrossRef][Medline]
74. Clement L, Poirier H, Niot I, Bocher V, Guerre-Millo M, Krief S, Staels B, Besnard P. Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. J Lipid Res. 2002;43:1400–9.
75. Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10,cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Diabetes Care. 2002;25:1516–21.
76. Degrace P, Demizieux L, Gresti J, Chardigny JM, Sebedio JL, Clouet P. Association of liver steatosis with lipid oversecretion and hypotriglyceridaemia in C57BL/6j mice fed trans-10,cis-12-linoleic acid. FEBS Lett. 2003;546:335–9.[CrossRef][Medline]
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