Docosahexaenoic Acid (DHA) Blunts Negative Side Effects of Conjugated Linoleic Acid (CLA) W/out Hampering Its Effects on Body Fat Loss & the Expression of Obesity Genes

She already knew what scientists have recently discovered and now confirmed: You better stack CLA and DHA if you want lean and health offspring ;-)

Conjugated linoleic acid (CLA) is not only an omega-6 fatty acid, it's also a trans-fat (though a natural one) and still even scientists believe that it could contribute to the solution of the diabesity epidemic, if it (a) finally yielded the same extreme fat loss (yep, just the blubber, nothing else) results in human beings as in rodents (cf. "CLA Annihilates Body Fat and Increases Endurance") and (b) anywhere near appropriate doses would not hold he risk of inducing fatty liver disease and insulin resistance (Clément. 2002). At least with respect to (b) a "bodybuilding approach" to CLA supplementation which is based on the "if hammering your head against the wall hurts, you better make sure you wear a helmet" principle of stacking CLA and PUFAs, esp. the long-chain omega-3 fatty acid DHA, has already yielded some promising results in a study that has been published earlier this year (Fedor. 2013a).

Since, the deposition of fat in the liver in response to CLA supplementation is in the end only the logical consequence of CLA's lipolytic (=fat releasing) and anti-lipogenic (=inhibition of fat storage) effects in the adipose tissue, the absence of adequate data on the amount of fat in adipose tissue and muscle or the fatty acid composition of liver, adipose tissue, and muscle, nor did we monitor the changes in the expression of genes involved in fatty acid metabolism in adipose tissue and muscle in the respective study did not allow for the conclusion that the co-supplementation of DHA would not blunt the beneficial fat loss effects of CLA, as well.

Is it possible that high dose DHA blunts the negative and the positive effects of CLA?

In a paper that's going to be published in the next issue of Metabolic Syndrome And Related Disorders Dawn M. Fedor et al. describe the results of a follow up study, which dealt with this very question and I guess I am not giving away more than what you will already inferred from the headline of this post, when I tell you that the answer to the question in the subheading is "No, DHA does not blunt the beneficial effects of conjugated linoleic acid on adipose tissue!"

Figure 1: Relative body weight, liver weight, periuterine fat mass, muscle weigh, liver total lipid weight, adipose total lipid weight, and muscle total lipid content of the mice after 4 weeks on a 0.5% CLA, 0.5% CLA + 1.5% DHA or 1.5% DHA diets expressed relative to respective data from mice on the standard chow (Fedor. 2013b)

If you take a closer look at the data in figure 1 you will realize that the provision of a diet that contained 0.5% CLA (only the "active", but potentially hazardous t10, c12 isomer was used in the study) and 1.5% DHA did not blunt the beneficial effects on total and periuterine body fat mass in eight-week-old, pathogen-free female C57BL/6N mice. On the other hand, it did mitigate the negative effects on liver weight and (and this is actually quite remarkable) had identical beneficial effects on liver fat as the DHA only diet.

DHA + CLA = perfect synergists

Although the "equation" above may sound as if I had taken it right from one of those shiny adds in a muscle mags, it does in fact look, as if the combination of CLA + DHA was the silver bullet for healthy body fat (and I repeat only body fat not lean mass!) reductions in the absence of any dietary and/or exercise interventions.

Figure 2: Expression of selected genes involved in the synthesis, storage and release of fatty acids from the adipose tissue; the respective values (in a.u.) of the control group were all 100, so you can thing of these as percentages, as well (Fedor. 2013)

Moreover, the analyses of the expression of pro- and anti-obesity genes in the adipose tissue does actually support this claim:

"CLA significantly decreased the expression of LXRb, PGC1a, PPARg, SREBP1C, ACOX1, and CD36 adipose mRNA when compared to the control group. We also observed a trend for CLA to decrease the expression of HSL (P=0.08). DHA was not able to prevent any of these decreases in gene expression. CLA significantly increased UCP2 mRNA expression when compared to control group; DHA again had no effect." (Fedor. 2013b)

If we translate all these acronyms the scientists use to describe the data I've plotted for you in figure 2 into plain cause and effect relations, we could simply state: CLA induced changes in the expression of genes in the adipose tissue of the rodents that would prevent the maturation of adipocytes and the synthesis and accumulation of fatty acids, while increasing their release into circulation,  and DHA did not effect these changes.

DHA takes care of the energy that's released / not stored in fat cells

What the co-administration of DHA did, however, was to prevent the deposition of the energy that was released, respectively not even stored in the adipocytes in the liver -- and it did that so effectively that the overall weight of the liver of the mice in the CLA + DHA group was not greater than the the liver weight of the rodents in the control group.

Figure 3: Liver fatty acid composition (µmol/g) and omega-3 : omega-6 ratio after 4 weeks on regular (control), 0.5% CLA, 0.5% CLA + 1.5% DHA and 1.5% DHA diets (Fedor. 2013b)

In fact, the co-administration of conjugated linoleic acid and DHA did even reduce the total fatty acid content of the liver (not to a statistically significant degree, though) and brought about profound changes in its fatty acid content - most prominently, a whopping +975% increase in the omega-3 : omega-6 ratio (see small graph in figure 3) that were even slightly more pronounced in the CLA + DHA group than in the DHA only group (you do remember that CLA is an omega-6 trans-fat, right?).

Finally a stack that works -- but will it work in humans, as well? 

I don't know if it dawned on you, already, but dairy and butter from grass cows already has both CLA and DHA in it - what a lucky coincidence, isn't it? Still, there is one downside: You simply cannot eat enough of it to get anywhere close to the human equivalents of the amounts that are used in rodent studies.

Now, although both the changes in body fat levels in the CLA + DHA group were consistent with those observed in the CLA only group and the effects of the combination treatment on the changes in hepatic fatty acid composition were consistent with those observed in the DHA only group, there is still one question we have to answer: Are we going to see similar esults in humans?

To be honest, I still cannot answer this question, but if you take into consideration that no previous human trial used dosages in the 20-30g range simply because that would be unethical given the associated side effects, we may soon get an answer to this question - as soon as scientists dare to slowly escalate the dosage, trusting on the ability of supplemental DHA to blunt the negative, while conserving the beneficial effects of CLA.


References:

• Clément 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 Sep;43(9):1400-9.
• Fedor DM, Adkins Y, Mackey BE, et al. Docosahexaenoic Acid prevents trans-10, cis-12-conjugated linoleic Acid-induced nonalcoholic Fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation.Metab Syndr Relat Disord. 2013a;10:175–180
• Fedor DM, Adkins Y, Newman JW, Mackey BE, Kelley DS. The Effect of Docosahexaenoic Acid on t10, c12-Conjugated Linoleic Acid-Induced Changes in Fatty Acid Composition of Mouse Liver, Adipose, and Muscle. Metab Syndr Relat Disord. 2013b Nov 21.

CLA Destroys Body Fat & Increases Endurance! But at Which Costs? It Almost Triples Liver & Doubles Spleen Weight and Increases Blood Glucose & Cholesterol Levels!

Image 1 (Zhu. 2013): The allegedly leaner mouse on the left has a certain gene defect due to which it developed both lipodystrophy (fat loss) and diabetes early in life. Now guess what the mice on the 5% CLA diet developed after 6 weeks?

It is quite funny how the same people who are terrified by the thought that creatine (suggested read "The Pharmacokinetics of Creatine") could damag their kidneys cast caution to the wind, when it comes to magical fat loss pills. "CLA does help fat loss? How can I get more of it?" While the non-existence of conclusive evidence that conjugated linoleic acid does even work in human and the presence of at least 28 isomers of linoleic acid, which are mainly found in the meat and dairy products from ruminants (Banni. 2002) and of which only one seems to "work" is one thing, the ignorance people display for the potential negative side effects high doses (so high that they would maybe help you burn body fat) can have on liver function, glucose metabolism, oxidative stresses and more (cf. Dilzer. 2013) is potentially hazardous.

"CLA is from grass-fed cows so it must be good, right!?"

Sometimes I get the feeling the above statement conveys an accurate representation of the counter-productive black-and-white thinking that is so prevalent among some of the health nuts on the Internet, these days. And in fact, if you take a cursory look at the heavily quoted studies on the effects of CLA on all sort of things ranging from its general antioxidative effects (Reynolds. 2010), over the profane reduction of unaesthetic body fat (in rodents, cf. Wang. 2004) to its purported anti-cancer effects (Tanaka. 2011) it does conjugated linoleic acid is probably second only to vitamin D and fish oil in terms of its contemporary idolatry and, if we regard the fat loss effects in isolation and focus solely on a recent study by scientists from the Department of Food Science at the University of Massachusetts rightly, so!

After all, the results Kim et al. present in the latest issue of Lipids are unquestionably impressive: 70% reduced body fat levels in normal-weight rodents with nothing but 0.5% CLA (as trans-10,cis-12 CLA) in regular rodent chow within 6 weeks!? You can hardly argue that this isn't an impressive result.

Figure 1: Tissue weights (left, large), muscle and liver glycogen content (left small, inset) after and body weight (right, top) as well as food intake (right, bottom) in the course of the 6-week study period (adapted from Kim. 2013)

Aside from the only at first sight remarkable -77% reduction in body fat in the presence of an almost 30% increased food intake (!), the data in figure 1 does yet also confirm other, outcomes we already know from previous studies:

1. only the trans-10,cis-12, but not the cis-9,trans-11 CLA isomer will yield the desired anti-obesity effects
2. instead of healthy weight loss in obese or at least overweight animals, CLA induces what in every other context would be called full-blown lipodystrophy (=pathologic loss of body fat, cf. image 1 and Jaudszus. 2010) in the lean perfectly healthy 129Sv/J mice in the study at hand - and that in the presence of ~30% increased food intake (see figure 1, bottom right)
3. worrisome increases in liver and spleen weight, the latter of which exceed the +76% increase in hepatic glycogen storage capacity by more than a factor 2x (!)

Figure 2: Serum levels of triglycerides, glucose, total cholesterol, non-esterified fatty acids, lactate and blood urea nitrogen in CLA supplemented expressed relative to non-supplemented control (large) and additional figure showing expressions of selected genes from skeletal muscle (based on Kim. 2013)

Let's be honest, if you observed similar increases in food consumption that are accompanied not by gains, but by profound reductions in body fat in your dog, cat, bird, pig or whatever pet you may have, you would interpret that as a clearcut sign that something is awfully wrong with your loved one and seek medical advice right away - correct?

A brief note on the figures in this paragraph: While the examples are hypothetical, the figures I came up with reflect the reductions in body fat and increases in liver weight, glucose and total cholesterol you see in figure 2.

So, why on earth would you even remotely consider going to your local GNC then to get yourself a family pack of CLA cabs in order to get rid of the flab that's still covering your abs? Are you keen on taking yourself to the Dr. after 6-weeks, when you are down from 15% body fat to 4.5% (=70% reduction) and you formerly flabby belly is now bulging because your liver, which does now weigh 4kg instead of the regular 1.5kg, is oozing out from under your ribcage? If that's what you are looking for, you probably won't be worried if your blood glucose shot up from 90 to 112pts and your Dr. is about to prescribe an (in your case particularly unnecessary) statin to sooth your ~50% increased cholesterol levels, either!? You are lean, now! And as Kim et al. euphorically point out your endurance may even increase by 70%(!) while there is still some muscle or liver glycogen or body fat left to fuel the PPAR-gamma driven fat burning wreck you have become...

Image 2: One of the best CLA supplements there is - ok, it's a proprietary blend with small amount of omega-3, omega-6 and important and increasingly scarce vitamins as vitamin A and vitamin K, but you can trust in the divine wisdom of its inventor - mother nature ;-)

Implications: If all the irony has not yet allured you from the idea that you'd better be lean and sick, than somewhat chubby and healthy, you may be disappointed to hear that the human equivalent dose of the trans-10,cis-12 CLA (remember no other form will do this black magic!) is roughly 30g/day and thus probably more expensive than liposuction ;-)

This dosage issue does yet bring us back to where we came from: Grass-fed cows!  After all, it is not only unrealistic, but simply impossible to get this amount of CLA (let alone only t-10,c-12) from your diet- regardless of how much meat and dairy from grass-fed cattle you consume! And based on the the results of the study at hand, you could even argue that nature has rendered that impossible for a good reason, your protection.

So don't pretend you are smarter than nature and stick to your Kerrygold golden grass-fed Irish butter - not so much for the CLA content, though, but for the whole package of synergistically acting power-nutrients nature has put into her original "fat supplement" ;-)

References:

• Banni S. Conjugated linoleic acid metabolism. Curr Opin Lipidol. 2002 Jun;13(3):261-6.
• Dilzer A, Park Y. Implication of conjugated linoleic acid (CLA) in human health. Crit Rev Food Sci Nutr. 2013;52(6):488-513.
• Jaudszus A, Moeckel P, Hamelmann E, Jahreis G. Trans-10,cis-12-CLA-caused lipodystrophy is associated with profound changes of fatty acid profiles of liver, white adipose tissue and erythrocytes in mice: possible link to tissue-specific alterations of fatty acid desaturation. Ann Nutr Metab. 2010;57(2):103-11.
• Kim JH, Kim J, Park Y. trans-10,cis-12 Conjugated Linoleic Acid Enhances Endurance Capacity by Increasing Fatty Acid Oxidation and Reducing Glycogen Utilization in Mice. Lipids. 2013 Jul 11.
• Reynolds CM, Roche HM. Conjugated linoleic acid and inflammatory cell signalling. Prostaglandins Leukot Essent Fatty Acids. 2010 Apr-Jun;82(4-6):199-204. Epub 2010 Mar 7.
• Tanaka T, Hosokawa M, Yasui Y, Ishigamori R, Miyashita K. Cancer chemopreventive ability of conjugated linolenic acids. Int J Mol Sci. 2011;12(11):7495-509. Epub 2011 Nov 2. 
• Wang YW, Jones PJ. Conjugated linoleic acid and obesity control: efficacy and mechanisms. Int J Obes Relat Metab Disord. 2004 Aug;28(8):941-55. Review.
• Zhu. Ncb5or in Fatty Acid Desaturation and Metabolic Diseases. Zhu Diabetes Research Group. University of Kansas School of Health Professionals. < http://www.alliedhealth.kumc.edu/school/research/zhu/more_info.html > retrieved July 22, 2013