robertthoburn
04-25-2003, 08:15 PM
Does arachidonic acid interefere with CLA?
Here I provide some comments on CLA, such as:
-how it may work
-how n-6 fatty acids (e.g., linoleic and arachidonic) may get in its way
I provide the following comments concerning CLA in the hope that they may be of some use to you. (At the least, entertaining and thought-provoking.)
Personally, I haven't experimented with CLA for years, having noticed nothing when I did. Keep in mind, however, that I did not take the multi-gram quantities that may be necessary to produce body composition enhancement in humans.
The issue of how CLA manages to favorably affect body composition, in humans, if in fact it does, is quite complex. And the jury is still out, it would appear.
One thing seems clear: The fat reducing effects (likely anti-lipogenic) of CLA are isomer-specific. The trans10,cis12 isomer seems to produce fat loss, whereas the cis9,trans11 isomer does not. A mixture of isomers is found in currently available commercial blends. Associates of mine in Shanghai are working on isolating the trans10,cis12 isomer, for what it's worth.
Most authors I have seen the work of suggest that while CLA can reduce food intake, this is insufficient to explain all of its effects on fat loss.
One possibility is that CLA stimulates PPARalpha. This would be expected to switch your body's fuel-burning mixture in favor of fat, thereby promoting a negative fat balance --the sin qua non of losing body fat.
PPARalpha activation by CLA may simply reflect the body’s attempt to increase beta-oxidative degradation of CLA. CLA, you see, is likely to compete with enzymes involved in essential fatty acid metabolism, and may thereby be perceived as a 'threat' of sorts. In this case, PPARalpha activation is a metabolic defense mechanism. As a convenient side effect, you burn more fat.
Interestingly, a study currently going to press indicates that CLA produces substantially more fat loss in mice when they are fed essential fatty acid-deficient diets. This dietary scenario may 'free up' enzymes normally involved in essential fatty acid metabolism. The result is that they are more able to catalyze the conversion of CLA into more potent fat-reducing metabolites. Indeed, CLA per se may not be as important to fat loss as are some of its downstream metabolites.
Antagonism of PPARgamma may also be involved in the fat-reducing effect of CLA and/or other conjugated fatty acids. We know that CLA promotes apoptosis of adipocytes and inhibits lipogenic pathways. This is generally the opposite of what is expected with PPARgamma activation. (PPARgamma has been dubbed "the ultimate thrifty gene".)
PPARgamma agonists, like the fattening thiazolidinediones, promote differentiation of pre-adipocytes to form mature, fat-trapping adipocytes. PPARgamma activation also stimulates lipogenic enzyme expression and activities. This improves your glucose tolerance (more fat cells to scoop up glucose), but...you're fatter, too.
Hargrave et al. (2002) comments on the interaction of CLA with PPARgamma: "CLA has been shown to alter the type and amount of cellular fatty acids in 3T3-L1 cells; in particular, arachidonic acid content was reduced more than 50% (23). Arachidonic acid is a precursor to prostaglandins that act as ligands for peroxisome proliferator activated receptor-gamma, which activates genes important in adipogenesis. In fact, Brodie et al. (24) found reduced levels of peroxisome proliferator activated receptor-gamma in 3T3-L1 cells treated with CLA, and Evans et al. (12) showed that CLA supplementation reduced growth of preconfluent 3T3-L1 cells. Thus, CLA may interfere with normal cellular mechanisms involved in preadipocyte maturation. Susceptibility to apoptosis is higher in immature adipocytes (25); thus, CLA may act by increasing the proportion of cells that are susceptible to other factors that trigger apoptosis.”
If, in fact, CLA antagonizes PPARgamma, I would not be surprised if it is determined that CLA is most effective (even if only weakly so) in the clinically obese. PPARgamma is several-fold more abundant in adipocytes than skeletal muscle. Thus, in the obese, there may be more PPARgamma ‘targets’ for CLA action.
As the comment by Hargrave et al. suggests, there is accumulating evidence to show that CLA may facilitate greater fat loss in an essential fatty acid (in particular, n-6 fatty acid) deficient state. This should cause one to seriously question CLA supplements (or diets) containing an abundance of arachidonic acid and/or its precursor, linoleic acid.
Again, this apparent increase in CLA-mediated fat loss under n-6 fatty acid deficient conditions may reflect the importance of CLA metabolites (as opposed to just CLA per se). The authors of a soon-to-be-published study comment:
"The identification of 20-carbon metabolites of CLA isomers offers an additional explanation of the multiple effects of CLA. Not only could each CLA isomer have a specific effect, but also different metabolites of each CLA isomer may have a specific effect. If a metabolite of CLA causes the loss of body fat in mice, then a diet with reduced linoleic acid concentrations should allow for a greater loss of body fat because of greater metabolism of CLA when there is reduced competition for the desaturase and elongase enzymes. Reduced arachidonic acid concentrations could also allow for greater CLA-induced loss of body fat by allowing for greater utilization of the CLA-metabolites. To the authors’ knowledge, this is the first report of altered sensitivity to CLA-induced body fat loss due to diet-induced alterations in essential fatty acid concentrations. CLA-induced apoptosis in adipose tissue was not dependant upon dietary fat source, and therefore, does not appear to involve the same mechanism as CLA-induced body fat loss. Diets deficient in essential fatty acids can enhance response to dietary CLA. "
In their insightful article discussing the contribution of the trans10,cis12 isomer of CLA, Evans et al. (2002) add that “..dietary fatty acids, especially MUFAs [monounsaturated fatty acids] and n-6 fatty acids such as linoleic acid, may reverse CLA’s antiobesity effects. Therefore, CLA supplements may be most effective in combination with a fat-reduced diet, in physically active subjects, or in overweight subjects.”
Okay, that’s it for now. Hope this provides some thought-provoking fodder for your cognitive engines.
Let me know what your experiences are with CLA supplements. I'm very interested to know. And thanks very much for your attention.
Sincerely,
Rob
robertthoburn@hotmail.com
REFERENCES
Evans ME, Brown JM, McIntosh MK (2002). Isomer-specific effects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism. J Nutr Biochem, 13: 508.
Hargrave KM, Li CL, Meyer BJ et al. (2002). Adipose depletion and apoptosis induced by trans10, cis12 conjugated linoleic acid in mice. Obes Res, 10: 1284.
Here I provide some comments on CLA, such as:
-how it may work
-how n-6 fatty acids (e.g., linoleic and arachidonic) may get in its way
I provide the following comments concerning CLA in the hope that they may be of some use to you. (At the least, entertaining and thought-provoking.)
Personally, I haven't experimented with CLA for years, having noticed nothing when I did. Keep in mind, however, that I did not take the multi-gram quantities that may be necessary to produce body composition enhancement in humans.
The issue of how CLA manages to favorably affect body composition, in humans, if in fact it does, is quite complex. And the jury is still out, it would appear.
One thing seems clear: The fat reducing effects (likely anti-lipogenic) of CLA are isomer-specific. The trans10,cis12 isomer seems to produce fat loss, whereas the cis9,trans11 isomer does not. A mixture of isomers is found in currently available commercial blends. Associates of mine in Shanghai are working on isolating the trans10,cis12 isomer, for what it's worth.
Most authors I have seen the work of suggest that while CLA can reduce food intake, this is insufficient to explain all of its effects on fat loss.
One possibility is that CLA stimulates PPARalpha. This would be expected to switch your body's fuel-burning mixture in favor of fat, thereby promoting a negative fat balance --the sin qua non of losing body fat.
PPARalpha activation by CLA may simply reflect the body’s attempt to increase beta-oxidative degradation of CLA. CLA, you see, is likely to compete with enzymes involved in essential fatty acid metabolism, and may thereby be perceived as a 'threat' of sorts. In this case, PPARalpha activation is a metabolic defense mechanism. As a convenient side effect, you burn more fat.
Interestingly, a study currently going to press indicates that CLA produces substantially more fat loss in mice when they are fed essential fatty acid-deficient diets. This dietary scenario may 'free up' enzymes normally involved in essential fatty acid metabolism. The result is that they are more able to catalyze the conversion of CLA into more potent fat-reducing metabolites. Indeed, CLA per se may not be as important to fat loss as are some of its downstream metabolites.
Antagonism of PPARgamma may also be involved in the fat-reducing effect of CLA and/or other conjugated fatty acids. We know that CLA promotes apoptosis of adipocytes and inhibits lipogenic pathways. This is generally the opposite of what is expected with PPARgamma activation. (PPARgamma has been dubbed "the ultimate thrifty gene".)
PPARgamma agonists, like the fattening thiazolidinediones, promote differentiation of pre-adipocytes to form mature, fat-trapping adipocytes. PPARgamma activation also stimulates lipogenic enzyme expression and activities. This improves your glucose tolerance (more fat cells to scoop up glucose), but...you're fatter, too.
Hargrave et al. (2002) comments on the interaction of CLA with PPARgamma: "CLA has been shown to alter the type and amount of cellular fatty acids in 3T3-L1 cells; in particular, arachidonic acid content was reduced more than 50% (23). Arachidonic acid is a precursor to prostaglandins that act as ligands for peroxisome proliferator activated receptor-gamma, which activates genes important in adipogenesis. In fact, Brodie et al. (24) found reduced levels of peroxisome proliferator activated receptor-gamma in 3T3-L1 cells treated with CLA, and Evans et al. (12) showed that CLA supplementation reduced growth of preconfluent 3T3-L1 cells. Thus, CLA may interfere with normal cellular mechanisms involved in preadipocyte maturation. Susceptibility to apoptosis is higher in immature adipocytes (25); thus, CLA may act by increasing the proportion of cells that are susceptible to other factors that trigger apoptosis.”
If, in fact, CLA antagonizes PPARgamma, I would not be surprised if it is determined that CLA is most effective (even if only weakly so) in the clinically obese. PPARgamma is several-fold more abundant in adipocytes than skeletal muscle. Thus, in the obese, there may be more PPARgamma ‘targets’ for CLA action.
As the comment by Hargrave et al. suggests, there is accumulating evidence to show that CLA may facilitate greater fat loss in an essential fatty acid (in particular, n-6 fatty acid) deficient state. This should cause one to seriously question CLA supplements (or diets) containing an abundance of arachidonic acid and/or its precursor, linoleic acid.
Again, this apparent increase in CLA-mediated fat loss under n-6 fatty acid deficient conditions may reflect the importance of CLA metabolites (as opposed to just CLA per se). The authors of a soon-to-be-published study comment:
"The identification of 20-carbon metabolites of CLA isomers offers an additional explanation of the multiple effects of CLA. Not only could each CLA isomer have a specific effect, but also different metabolites of each CLA isomer may have a specific effect. If a metabolite of CLA causes the loss of body fat in mice, then a diet with reduced linoleic acid concentrations should allow for a greater loss of body fat because of greater metabolism of CLA when there is reduced competition for the desaturase and elongase enzymes. Reduced arachidonic acid concentrations could also allow for greater CLA-induced loss of body fat by allowing for greater utilization of the CLA-metabolites. To the authors’ knowledge, this is the first report of altered sensitivity to CLA-induced body fat loss due to diet-induced alterations in essential fatty acid concentrations. CLA-induced apoptosis in adipose tissue was not dependant upon dietary fat source, and therefore, does not appear to involve the same mechanism as CLA-induced body fat loss. Diets deficient in essential fatty acids can enhance response to dietary CLA. "
In their insightful article discussing the contribution of the trans10,cis12 isomer of CLA, Evans et al. (2002) add that “..dietary fatty acids, especially MUFAs [monounsaturated fatty acids] and n-6 fatty acids such as linoleic acid, may reverse CLA’s antiobesity effects. Therefore, CLA supplements may be most effective in combination with a fat-reduced diet, in physically active subjects, or in overweight subjects.”
Okay, that’s it for now. Hope this provides some thought-provoking fodder for your cognitive engines.
Let me know what your experiences are with CLA supplements. I'm very interested to know. And thanks very much for your attention.
Sincerely,
Rob
robertthoburn@hotmail.com
REFERENCES
Evans ME, Brown JM, McIntosh MK (2002). Isomer-specific effects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism. J Nutr Biochem, 13: 508.
Hargrave KM, Li CL, Meyer BJ et al. (2002). Adipose depletion and apoptosis induced by trans10, cis12 conjugated linoleic acid in mice. Obes Res, 10: 1284.