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Conjugated Linoleic Acids: All the Same Or to Everyone Its Own Function? Jean-Charles Martin, Karine Valeille

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Conjugated Linoleic Acids: All the Same Or to Everyone Its Own Function? Jean-Charles Martin, Karine Valeille Conjugated linoleic acids: all the same or to everyone its own function? Jean-Charles Martin, Karine Valeille To cite this version: Jean-Charles Martin, Karine Valeille. Conjugated linoleic acids: all the same or to everyone its own function?. Reproduction Nutrition Development, EDP Sciences, 2002, 42 (6), pp.525-536. 10.1051/rnd:2002042. hal-00900428 HAL Id: hal-00900428 https://hal.archives-ouvertes.fr/hal-00900428 Submitted on 1 Jan 2002 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Reprod. Nutr. Dev. 42 (2002) 525–536 525 © INRA, EDP Sciences, 2003 DOI: 10.1051/rnd:2002042 Review Conjugated linoleic acids: all the same or to everyone its own function? Jean-Charles MARTIN*, Karine VALEILLE Laboratoire de Physiologie de la Nutrition, Université de Paris-Sud, 91400 Orsay, France (Received 14 June 2002; accepted 6 November 2002) Abstract — Conjugated linoleic acid (CLA) is a generic term referring to a mixture of geometrical and positional isomers of linoleic acid in which up to 16 members have been identified. Many poten- tially beneficial health effects have been ascribed to these fatty acids when consumed as a mixture, and where generally 2 isomers dominate, e.g. the 9c,11t-isomer, the so-called rumenic acid, and the 10t,12c-isomer: anti-carcinogenic, immune modulator, anti-atherosclerotic, and anti-obesity among the most spectacular. The question arises as to whether the pleiotropic biological activity is sup- ported by one or several of the isomers. Recent studies using pure individual isomers have started to elucidate this issue, but many others are required to ascribe a respective role to each CLA isomer (the main ones as well as the minor ones), such as those occurring in some complex mixtures already commercially available, or even in foodstuff. The aim of the present study was to focus on the CLA-isomer specific effects depicted in the literature up to now. CLA isomers / rumenic acid / cancer / obesity / atherosclerosis 1. INTRODUCTION are 18 carbon chain-length fatty acids with 2 double bonds. These are therefore isomers A great deal of concern has arisen from of linoleic acid, but to the contrary to this the study of conjugated linoleic acids (CLA), essential fatty acid where the double bonds because of their considerable pleiotropic are methylene-interrupted, they are consec- effects: anti-carcinogenic, immune modu- utive (e.g. conjugated) in CLA (Fig. 1). The lator, anti-diabetic, anti-obesity, anti-throm- double bond system is localized on carbons botic and anti-atherogenic [4, 5, 47]. CLA 7,9; 8,10, etc. up to carbon 12,14 of the * Correspondence and reprints E-mail: [email protected] 526 J.-C. Martin, K. Valeille Figure 1. Natural origin of rumenic acid: rumenal synthesis from linoleic acid, and endogenous occurrence from delta-9 desaturation of trans-vaccenic acid (from [26], with permission). olefinic chain, including all possible geo- and ingested by ruminants (Fig. 1). Some of metrical combinations (cis/cis, cis/trans, the rumenic acid formed escapes total hydro- trans/cis et trans/trans). As many as genation and is taken up by the intestines 16 members have been identified thus far and reaches milk and muscle lipids. Trans- in marketed products [38]. The latter are vaccenic acid (18 carbons long, one trans- obtained by alkaline isomerization of veg- double bond located in the D-11 position, etable oil enriched with linoleic acid (saf- another by-product of the biohydrogenation flower oil, sunflower oil) and sold as food reaction), can also undergo delta-9 desatu- supplements. In this example, the CLA iso- ration in the intestines, liver, mammary meric distribution is generally dominated gland, and adipose tissue, and there it forms by 2 main isomers, e.g. the 9c,11t-isomer rumenic acid endogenously [25] (Fig.1). In and 10t,12c-isomer, including in some prepa- humans, trans-vaccenic acid occurring from rations the 8t,10c- and 11t,13c-isomers. Con- the intake of ruminant products can be versely, the 9c,11t-isomer is the main CLA similarly converted to the 9c,11t-isomer [1, occurring naturally in foodstuff (up to 80% 48], This comes in addition to the daily of total isomers) [23, 43], although the other 200–400 mg of pre-formed ingested rumenic isomers are also present in minor amounts acid [15]. and should therefore be considered as “nat- ural” compounds [43]. Importantly, the bal- When dealing with the bioactivity of ance between the various isomers is not the CLA, it is likely that their structural pecu- same in synthetic CLA products and those liarities underly some of their radically dif- occurring from natural sources. Since most ferent actions when compared to linoleic of the CLA intake and therefore the 9c,11t- acid (reviewed in [4, 47]). Nevertheless, isomer arise from ruminant products, this only a few studies have addressed the dis- isomer is called rumenic acid. It is a by- crete potency of each isomer (Tab. I), or the product of microbial biohydrogenation that particular synergistic or competitive iso- takes place in the rumen from linoleic acid mers-effects of several isomers present (and a-linolenic acid) occurring from plants together in the same mixture. Table I. Summary of the biological effects involving selected isomers of CLA. Biological effects 9c,11t-CLA 10t,12c-CLA Other isomers Comments Anti-cancer + + ? Strong evidence for the 9c,11t- in animal models Decrease of fat body mass 0 + 0 (9t,11t-) Efficiency is species-dependent (requires confirmation in humans) Anti-atherosclerosis + (?) + (?) ? Needs further confirmation Insulin resistance 0 + or – ? In rats, not in humans, 10t,12c-CLA may improve glucose Biological effectofCLAisomers tolerance or induce strong insulin resistance depending on the initial physiological status Immune modulation ? ? ? No study reported with individual isomers Fatty acid desaturation – (delta 6) – (delta 9) + (delta 5) ? Eisosanoid synthesis – – – 9c,11t- is more potent for the constitutive PGH synthase, followed by 9c,11c, 9t,11t, and 10t,12c. All of these isomers are equally potent for COX-2 (inducible) Pro-inflammatory agents – – – 9c,11t-; 9c,11c-; 9t,11t-; and 10t,12c- isomers equally potent (cytokines and NO) PPARa ligand & activator + + + (9t,11t-) 9c,11t- is more potent PPARg activator + + + (9c,11c-; 9t,11t-) +: positive effect; –: negative effect; 0: neutral. For further details, refer to appropriate references and text section. 527 528 J.-C. Martin, K. Valeille 2. CANCER AND CLA: ble for the fat reduction observed upon CLA WHICH ISOMER IS POTENT? treatment [34]. This was demonstrated effec- tively by a mouse study in which different Fifteen years ago Pariza et al. [17] found purified isomers were used (10t,12c-, 9c,11t, that CLA of a fried ground beef extract was 9t,11t) and in which the 10t,12c-isomer was highly potent in reducing epidermal tumor the most efficacious in decreasing body fat incidence of mice topically treated with mass [35]. According to Pariza [34], CLA 12-O-tetradecanoylphorbol-13-acetate. This and specifically the 10t,12c-isomer blocks suggests that the anticarcinogenic effect body fat gain, but does not necessarily was due to one isomer, since the CLA in reduce the body fat level which had accu- ruminant products are mainly made up of mulated prior to the CLA administration 9c,11t-CLA. The potency of this isomer has (Fig. 2). been further confirmed by us [22] and Ip [19] in another carcinogenic model, e.g. We reached the same conclusion in our NMU-induced rat mammary carcinogene- experiments. We fed hamsters a lipid- sis. In these experiments, female rats were enriched diet (33% in energy) for 8 weeks, injected with a pro-carcinogen and fed for supplemented or not with CLA (1% by 6 months with diets containing either a CLA weight). Only the CLA diet containing the mixture (complex mixture), or a chemically- 10t,12c-isomer prevented the accretion of prepared 9c,11t-CLA [22], or a butter diet body triglyceride over time, while the diet naturally enriched in the 9c,11t-CLA, or containing the sole 9c,11t-isomer failed to artificially increased with a CLA mixture do so [8]. A recent human study examined (Ip study). In both experiments, CLA the effects of feeding obese men with the amounted to 1% by weight. The cancer risk metabolic syndrome for 12 weeks 3.4 g of was decreased in all CLA-diets, including either 10t,12c-CLA, or a CLA mixture con- those enriched with only the 9c,11t-isomer, taining equal amounts of both the 9c,11t- thereby indicating a high anticarcinogenic and 10t,12c-CLA [40]. The sagittal abdom- potency for this isomer, the so-called inal diameter and % body fat (determined rumenic acid. In addition, a recent case- by bioelectrical impedance analysis) control study carried out on Finish women decreased similarly in both CLA groups [3] demonstrated that breast cancer risk is compared to the baseline values, but not decreased by 2.5 fold (odds ratio of 0.4) compared to the placebo values at the com- in the women with the highest serum pletion of the study. It is noteworthy that 9c,11t-CLA concentrations as compared to those with the lowest concentrations. On the the treatment with 10t,12c-CLA, but not contrary, in vitro studies have also demon- with the CLA mixture, worsened the insulin strated that the 10t,12c-isomer is even more sensitivity in that population.
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