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Chapter 22

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Conjugated Fatty Acids as a Prevention Tool for Obesity and Osteoporosis Yeonhwa Park* and Yooheon Park Department of Food Science, University of Massachusetts, Amherst, 102 Holdsworth Way, Amherst, MA 01003 *E-mail: [email protected]

Since the identification of conjugated linoleic acid (CLA) as an anticarcinogen from beef in the 1970s, it has been studied for a wide range of biological activities, including reducing development of atherosclerosis, enhancing animal growth, modulating immune responses, and interestingly reducing body fat while enhancing lean body mass. It is suggested that the variety of biological activities of CLA may be due to two main isomers, cis-9,trans-11 and trans-10,cis-12. In addition to CLA, other cognates of CLA have been tested for their bioactivities. Among them, a 19-carbon cognate of CLA, conjugated nonadecadienoic acid (CNA), showed greater efficacy on body fat reduction in an animal model, where CLA and CNA share biochemical mechanisms. CLA has also shown potential to improve bone mass. Thus conjugated fatty acids have great potential to be used to prevent obesity and osteoporosis in conjunction with currently available treatments.

Introduction Conjugated linoleic acid (CLA) is a group of geometric and positional isomers of linoleic acid. CLA was identified in the 1930s, however, its bioactivities were first discovered as an anticancer component from ground beef in the 1980s (1, 2). Since then, considerable research discovered a wide range of biologically beneficial effects of CLA, such as reducing a number of types of cancer, controlling atherosclerosis development, modulating immune responses, reducing body fat, and improving bone mass (3, 4). In particular, the effects of CLA on body fat © 2012 American Chemical Society In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

drew significant interest for use of CLA to prevent obesity (3, 4). Moreover there is significant interest in the effects of CLA with regard to osteoporosis prevention. As CLA has been approved as generally recognized as safe (GRAS) for use in certain types of food since 2008 in the US, there is great need to understand the mechanisms of CLA on health effects. This chapter will focus on the mechanisms as well as potential applications of CLA for controlling obesity and osteoporosis.


Origins and Isomers of CLA CLA is primarily found in beef, dairy products (milk, cheese, cream, butter, or yogurt), and meats from ruminant origin (5). This is because CLA originates as an intermediate product during the biohydrogenation process of linoleic acid to stearic acid by rumen bacteria (6). The main isomer found in food is the cis-9,trans-11 isomer, where 80-90% of CLA in food is this form (5). Alternatively, the cis9,trans-11 CLA isomer can originate by delta-9 desaturation of trans-11 vaccenic acid in mammalian tissue, which is also an intermediate for the biohydrogenation process and the most abundant trans fatty acids in natural sources (7–9). Among a number of other geometric and positional CLA isomers that have been reported, the other main CLA isomer of interest is the trans-10,cis-12 isomer (3, 10, 11). This isomer is found at very low levels in foods, however, when CLA is prepared synthetically from linoleic acid, this along with the cis-9,trans-11 isomer make up about 85-95% of total CLA, with approximately a 1:1 ratio of these two isomers, often called ‘50:50 mixture’ (5, 12). Most biological activities of CLA are suggested to be the result of interactions between these two isomers, cis-9,trans-11 and trans-10,cis-12 (3, 10, 11). Thus this chapter will focus on their bioactivities. Although the two major CLA isomers include a ‘trans’ configuration, it is important to note here that CLA is excluded from bing a ‘trans’ fat in the Nutrition Facts labeling. The ‘trans’ fat from the Nutrition Facts labeling includes nonconjugated trans fats from food, originated either from partially hydrogenated vegetable oils or from natural sources, such as ruminant origin (13, 14). This is based on the significant difference in biological functions between non-conjugated and conjugated trans fats, mainly CLA (3, 10, 13, 14).

Antiobesity Effects of CLA CLA has been shown to control body fat, which has drawn considerable interest (3). In mouse models, CLA effectively and consistently reduced total body fat, in some instances over 50% reduction of body fat compared to control (15, 16). At the same time, the lean mass as represented as total protein was significantly increased in these animals (15, 16). Earlier studies mainly focused on controlling fat accumulation by using relatively young fast growing animals to study CLA’s effects (3, 16), however, there are reports using older mice where CLA also effectively reduced body fat in these models, suggesting CLA reduces existing fat as well (3, 17). Among the two major isomers, the trans-10,cis-12 CLA isomer has been linked, while the cis-9,trans-11 isomer has no contribution, to CLA’s antiobesity effect (16, 18). 394 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Mechanisms of Antiobesity Effects by CLA Multiple mechanisms of action for CLA’s control of body fat have been suggested; increasing total energy expenditure, reducing fat accumulation and/or adipocytic differentiation, increasing fatty acid β-oxidation in skeletal muscle, and modulating adipokines and cytokines (3, 16). First, CLA has been shown to increase total energy expenditure, as shown in both animal and human studies (19–26). However, some human studies failed to show any significant effects of CLA on energy expenditure, even with reduced body weight or fat deposition (27–30). Secondly, CLA has significant influence on adipocytes; reducing fat uptake, reducing lipogenesis, increasing apoptosis, inhibiting preadipocytic differentiation, and increasing lipolysis, as supported by both in vitro and in vivo studies (4, 15, 16, 18, 31–35). Thirdly, CLA increased fatty acid β-oxidation in skeletal muscle, as shown by decreased respiratory quotient and increased carnitine palmitoyl transferase I expression and/or activity (26, 36–41). Lastly, CLA has been linked with modulation of adipokines and cytokines, such as leptin, tumor necrosis factor-α, or adiponectin, which may be involved in controlling food intake and satiety (42–44). Thus, all of these mechanisms may play roles in how CLA effectively reduces body fat.

Species Specificity for CLA’s Obesity Control Response to CLA with regard to body fat control was most pronounced in the mouse model, while other species, including humans, responded with less body fat reduction (3, 45–50). These differences may be related to dose administered, duration of study, differences in metabolic rates amongst species, and differences in experimental design (3, 3, 16, 47, 51). Previous CLA studies with mice used diets containing 0.5 w/w% CLA, which is equivalent to about 56g CLA/day/70 kg (52). In comparison, most human studies published used 0.7-6.8g CLA per day, which is substantially lower than doses used in mice. Secondly, a 4-week CLA feeding period is used for most mice studies. In comparison, human clinical trials with 4 weeks supplementation or shorter did not observe any effects of CLA on body fat reduction (3). However, in human studies of longer than 6 months duration, CLA has shown significant reduction in body fat (3, 45). Alternatively, differences in metabolism between species may provide the explanation of differing effects, as mice have a higher fat turnover rate and energy requirement per unit of body weight than other species (51). Another important possibility is the difference in dietary regimes; ad libitum in animal models (a positive energy balance) compared to dietary restriction in human trials (negative energy balance). It was previously reported in a mouse study that antiobesity effects of CLA were not observed during dietary restriction (negative energy balance) (17). Similarly, there was consistent observation that CLA had no effects on body fat in clinical studies, when a hypocaloric diet plan (particularly greater than 200 Cal restriction per day) was used regardless of dose or duration of CLA supplementation (3, 44, 53, 54). This suggests that CLA 395 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

may be most effective at reducing fat mass gain, particularly in humans, as shown previously (19, 21, 42, 44, 53, 55).


Application of CLA for Prevention of Osteoporosis Along with the observation that CLA reduces body fat, previous publications reported improved bone mass after CLA supplementation (3, 49, 56, 57). However, others reported inconsistent observations regarding CLA’s effect on bone health, in particular bone mineral content or bone mineral density in animal models (56–58). Currently, there are two human studies reporting beneficial effects of CLA on bone health (59, 60), while others do not report such an effect (61–63). CLA and Calcium Interaction Recently, we reported that the inconsistent effects of CLA on bone health may be due in part to the interaction between dietary CLA and calcium levels (57). CLA supplementation with additional calcium in the diet improved total ash weights as an indicator for total bone mass in mice (57). In fact, Brownbill et al. (59) reported a benefit of CLA intake among postmenopausal women consuming a calcium supplement. It is also important to point out that this study estimated CLA intake from dietary records, thus the major CLA isomer linked to this study was the cis-9,trans-11 isomer, not the trans-10,cis-12 isomer. The potential role of the trans-10,cis-12 CLA isomer along with calcium in humans is not clear at this moment. Mechanisms of CLA’s Effect on Bone Compared to extensive research on CLA’s mechanisms on body fat reduction, there is currently limited studies on mechanisms of CLA on bone health. As suggested in body fat reduction, multiple mechanisms of CLA on bone mass have been suggested; increasing calcium absorption, promoting bone formation, and suppressing bone resorption. First, it has been reported that CLA improved calcium absorption from the intestines (64–69). CLA increased calcium transport by involving transcellular and paracellular pathways in the Caco-2 human colon adenocarcinoma cell line (64–68). However, inconsistent results were observed with the two major CLA isomers’ effects on calcium transport (64–68). The exact mechanism of these two CLA isomers on calcium transport as well as CLA’s influence on hormones for calcium homeostasis needs further investigation. Secondly, CLA may influence bone remodeling by shifting to greater bone formation and less bone resorption. Bone remodeling is the process that occurs throughout life of bone formation by osteoblasts and/or bone resorption by osteoclasts (70). Osteoblasts originate from bone marrow mesenchymal stem cells, while osteoclasts originate from macrophage lineage hematopoietic stem cells (71, 72). Bone marrow mesenchymal stem cells can also differentiate 396 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


into bone marrow adipocytes, where a negative correlation exists between bone marrow adipocytes and bone formation (71–74). Based on the observation that CLA reduces adipocytic differentiation, CLA has potential to improve bone mass by controlling bone marrow adipocytes (10, 16). It has been consistently observed that CLA significantly improves bone mass only when CLA reduces body fat in the same animals (15, 18, 31, 36, 75–84). This is supported further by the evidence that trans-10,cis-12 CLA, the active isomer for body fat reduction, is also responsible for improving bone mass (56). In fact, it has recently been reported that CLA indeed improves bone formation while decreasing bone adiposity in mesenchyme stem cells and animal models (83–85). Alternatively, CLA directly influences bone resorption by osteoclasts. CLA has been shown to reduce the markers of osteoclastogenesis ((83, 85, 86) and unpublished observation). Although there are still inconsistencies with regard to CLA’s effects on bone resorption, CLA is quite a promising dietary component for potentially improving bone mass and thus reducing osteoporosis.

Other Conjugated Fatty Acids To understand the key molecular structures for CLA’s bioactivities as well as to improve the efficacy of CLA’s body fat reduction in humans, a number of fatty acids, including novel conjugated fatty acids, were tested (26, 31, 80, 82). Structure-Activity Relationships Various mono-unsaturated octadecenoic acids were tested for their ability to inhibit lipoprotein lipase (LPL) activity in adipocytes, the results of which are summarized in Table 1. Inhibition of adipocytic lipoprotein lipase activity has been well correlated with the ability of these fatty acids to reduce body fat in the mouse model (31). Based on the results of various 18-carbon fatty acids, it was concluded that conjugated double bonds are required for CLA’s activity on body fat regulation. Other Conjugated Fatty Acids Conjugated fatty acids with different carbon-length were also tested, which include 19-, 20-, and 21-carbon conjugated fatty acids (Table 1). Among them, 19-carbon conjugated fatty acids, conjugated nonadecadienoic acids (CNA), inhibited LPL activity and further study indicated that CNA reduced body fat more effectively than CLA (26, 80). Meanwhile, 20-carbon conjugated fatty acids, conjugated eicosadienoic acids (CEA), inhibited LPL activity although they were less active than CLA (82). In the biological system CEA reduced body fat by converting to CLA as shown in animal studies using the mouse model (82). 21-carbon conjugated fatty acids, heneicosadienoic acids (CHDA), did not have any effects on lipoprotein lipase activity in adipocytes, which suggests no effects on body fat in an in vivo model (82). In addition, an elongated and desaturated form of CLA, cis-8,trans-12,cis-14 eicosatrienoic acid, did not have 397 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

any effect on lipoprotein lipase activity. This suggests that only CLA and CNA, but not other fatty acids including conjugated fatty acids tested, are linked to body fat reduction (31, 82). It has been recently reported that CNA exerts its effect on body fat regulation through mechanisms similar to those of CLA; increased energy expenditure and fatty acid β-oxidation (26). The improved efficacy of CNA on body fat reduction compared to CLA has been suggested to be linked to its ability to enhance lipolysis in adipocytes (26).

Table 1. Effects of fatty acids on adipocytic lipoprotein lipase activity1 Downloaded by UNIV OF GUELPH LIBRARY on May 21, 2012 | http://pubs.acs.org Publication Date (Web): March 6, 2012 | doi: 10.1021/bk-2012-1093.ch022

Fatty acids

Inhibition of LPL2 Activity

18-carbon fatty acids Mono-unsaturated cis-9 (oleic)

-2

cis-11

-

cis-12

-

cis-13

-

trans-9

-

trans-10

-

trans-11

-

trans-12

-

trans-13

-

Poly-unsaturated cis-9,cis-12 (linoleic acid)

-

trans-9,cis-12

-

trans-10,cis-12 CLA2

++2

cis-9,trans-11 CLA

-/+

trans-9,trans-11 CLA

-

19-carbon fatty acids cis-10 nonadecenoic acid

-

trans-10 nonadecenoic acid

-

cis-10,cis-13 nonadecadienoic acid

-

cis-10,trans-12/ trans 11-,cis-13 CNA2

++

20-carbon fatty acids -

cis-11,cis-14 eicosadienoic acid

Continued on next page.

398 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Table 1. (Continued). Effects of fatty acids on adipocytic lipoprotein lipase activity1 Fatty acids

Inhibition of LPL2 Activity

cis-11,trans-13 and trans-12,cis-14 CEA2

+

cis-11,trans-13 CEA

-

cis-8,cis-11,cis-14 eicosatrienoic acid

-

cis-8,trans-12,cis-14 eicosatrienoic acid

-


21-carbon fatty acids cis-12,cis-15 heneicosadienoic acid

-

cis-12,trans-14/ trans-13,cis-15 CHDA2

-

1 Data are summarized from (26, 31, 80, 82).

2 -, no change; +, inhibition; LPL, lipoprotein lipase activity; CLA, conjugated linoleic acid; CNA, conjugated nonadecadienoic acid; CEA, conjugated eicosadienoic acid; CHDA, conjugated heneicosadienoic acid.

Other CLA Metabolites In addition to being metabolized by elongation and/or desaturation, CLA is reported to be subjected to fatty acid β-oxidation (4, 82). Reported metabolites of CLA generated by fatty acid β-oxidation are conjugated hexadecadienoic (conj. Δ16:2), tetradecadienoic (conj. Δ14:2), and dodecadienoic (conj. Δ12:2c3,t5/t4,c6) acids (82, 87–90). Currently none of these CLA metabolites has been tested for activities.

Potential Concerns Safety concerns associated with CLA uptake are fatty liver, milk fat depression, glucose tolerance, and increased oxidative markers (3, 4, 10). There were pronounced effects of fatty liver in mouse studies with CLA. This coincided with tremendous lipid mobilization from adipose tissue and increased hepatic fatty acid synthesis (91, 92). Animal studies suggest that effects of CLA on the liver may be transient and reversible responses (93, 94). Human clinical trials reported minimal changes in serum markers for liver functions (21, 44, 60, 95, 96). However, there was a report of a single case of CLA induced acute hepatitis, thus there is need for careful determination regarding CLA supplementation and possible liver toxicity (97). CLA also decreased milk fat content in cow’s milk (98, 99). Thus concerns over lactating humans were raised. However, studies showed no effect of CLA on milk fat content in humans, but human studies used a relatively short supplementation period, less than 5 days, to draw any conclusion for CLA’s effect on human milk fat reduction (100, 101). Inconsistent effects of CLA on glucose metabolism have been reported in both animals and humans (3, 4, 29, 94, 102–107). It is suggested that 399 In Emerging Trends in Dietary Components for Preventing and Combating Disease; Patil, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


CLA modulates glucose metabolism through changes in fatty acid β-oxidation, cytokines, adipokines, and/or glucose uptake (108–115). However, it is important to note that human studies with longer than 6 months of CLA supplementation reported no changes in glucose or insulin levels and insulin sensitivity (21, 44, 53, 60, 62, 95, 96, 106, 116, 117). Thus influence of CLA on glucose metabolism may be a transient effect (3). There are consistent observations of increased oxidative markers after CLA supplementation from human studies (20, 118–125). This is associated with both cis-9,trans-11 and trans-10,cis-12 CLA isomers (118–122). The significance of this observation is not clear at the moment and needs careful evaluation in the near future.

Conclusion Although there are safety concerns associated with CLA supplementation, CLA has great potential to be used along with other available supplements or treatments for obesity. In addition, CLA has been shown to be beneficial for bone health. With current GRAS status of CLA in the US, there are great opportunities to use CLA to improve health as well as challenges for evaluating CLA’s safety issues.

Acknowledgments We thank Ms. Jayne M. Storkson for assistance with manuscript preparation. This work was supported in part by the American Heart Association, NIH 1R21AT004456, and USDA CSREES MAS00919. Dr. Yeonhwa Park is one of the inventors of CLA and CNA use patents that are assigned to the Wisconsin Alumni Research Foundation.

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