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.

Standard American Diet Has 'Optimal' Fatty Acid Ratio to Induce Diabesity. Plus: Study Shows Doubling Saturated Fats Would Yield More Benefits Than Halving Them

Study confirms: The SAD diet yields 'optimal' results (img. forbes.com)

Since this post is already lengthy enough, I will spare you how saturated fatty acids have long falsely been accused as the sole driving force of the western obesity epidemic and how the tides appear to be slowly yet steadily appear to be turning, as scientists delve deeper and deeper into the interactions of the total fat content in the diet, its fatty acid composition and the interaction of both with the two other macronutrients and their specific forms and get right to the study at hand. A study that appears in the current issue of the Journal of Lipid Science and deals with the first of the aforementioned interactions. The one that focuses on the total fat content and the individual fatty acid make-up of the diet (Enos. 2013).

Fat shoot out: Saturated vs. mono vs. PUFA

As Enos et al. point out, the main purpose of their study was to examine the effects of three high fat diets differing only with respect to the percentage of total calories from saturated fats.

• SFA-6% - contained 6% saturated fats,
• SFA-12% - contained 12% saturated fats, and
• SFA-24% - contained 24% of saturated fats

While the the high fat diets were set to have an identical fat (40% of the energy), carbohydrate (45% of the energy) and protein content, the two control diets were low in total fat (12%/68%/20% of the energy from fat/carbs/protein). They did however likewise differ as far as their fatty acid composition is concerned, with the modified chow mirroring the ratios (!) not the amounts of mono- and polyunsaturated fatty acids of the high fat chow (see figure 1).

Figure 1: Fatty acid composition (left) and their sources (right) that were used in the different diets the rodents were fed for 16 weeks (based on Enos. 2013)

The diets were administered for 16 weeks. Body composition and metabolism (glucose, insulin, triglycerides, LDL-C, HDL-C, total cholesterol) were examined monthly.  Adipose tissue (AT) expression of marker genes for M1 and M2 macrophages and inflammatory mediators (TLR-2, TLR-4, MCP-1, TNF-α, IL-6, IL-10, SOCS1, IFN-γ) was measured and so on and so forth... and the results were... well, not exactly as you may have expected (the latter statement assumes that you expected the SFA to be either the savior or the doom of the human race, depending on which side of the LC/LF divide you are stading).

Figure 2: Body composition (left), adipocyte size (right) and fat pad weight (inset) of the rodents at the end of the study period (Enos. 2013) Values not sharing a common letter (abc) differ significantly over time within the given diet treatment (P≤.05)

If you take closer look at the data in figure 2, there are two things that will probably catch your eye right away. The first 'eye catcher' pertains to the influence of replacing a large amount of the omega-6 fatty acids by monounsaturared fatty acids, as you will find them in olive oil, for example.

• The rodents who received the modified standard chow, with a fatty acid composition identical to the high fat diets (SFA-6%, SFA-12%, SFA-24%) had the exact same body composition as their mates who received the standard chow with its 3.7x higher n6:n3 ratio. The removal of omega-6 fatty did thus not have any beneficial effects on adiposity in the low fat groups.

The second 'eye catcher' is the non-linear increase in adiposity with increasing amounts of saturated fatty acids in the diets. This does not mean that the expected increase in obesity and adipocyte size was totally absent (read the latest "Get Lean & Stay Lean" item for more information about the association of large fat cells and metabolic syndrome), though:

• The mice in the SF-6-24% did all gain significantly more body weight and body fat than their peers on the low fat diets, but there appears to be a turning point, when the saturated fat content exceeds 12%. After all the mice in the SFA-24% group had almost the same body composition as their peers on the SFA-6% diet.

So, what do we make of these 'eye catchers'? The first one, you could argue, shows that "omega 6 overload" is not a problem, as long as you are consuming a low fat diet, in the first place. Even with the major part of those 12.2% of energy your diet provides in form of various fatty acids belonging to the potentially inflammatory omega-6 fatty acids, that's still way too low to do any harm. It does, by the way, yet explain why low fat diets work so well in a society, where most high fat foods the public consumes are laden with omega-6 fatty acids - not an insignificant result, I would say.

The 12%-SF diet, most closely mimics the standard American diet

Apropos public, the second 'eye catcher' is even more telling in term of public health,... wait, I should write sickness. Why? Well, the 12%SFA high fat diet, which supplies ...

• 47% of energy in form of carbohydrates (380g sucrose, 100g maltodextrin, 50g cornstarch per 1kg of diet; identical for all SFA groups),
• 40% of energy in form of fats (of which 12% were saturated fats), and
• 13% of energy in form of protein (from casein),

... mimics, as the researchers point out, "most closely" (Enos. 2013) the standard American diet (SAD). And the result is obvious: Diabesity!

It's a fat balancing act of macro and micro ratios  - complex and far from being understood 

What's intriguing though, is that the adipogenic effects of the diet were ameliorated, when the SFA content was further increased and the diet contained 68.6g of lard per kg chow instead of just 35.4g and 96.7g of coconut oil instead of just 30g. Since this increase in SFA was at the expense of both mono- and omega-6 fatty acids, you could of course also argue that replacing at least the latter of the two with SFAs must be healthy. Unfortunately, even a brief glance back at figure 2 reveals that this is not necessarily correct. After all, the SFA-6% group was still better off than the SFA-24% group, although they had the highest amounts of oleic and omega-6 fatty acids in the diet.

By now you should actually have realized that this is once more a difficult balancing act. Where different baseline intakes of dietary fat and carbohydrates (total) are pair of setscrews and the individiual fatty acid composition of the diet is another one. And the way these setscrews are set will not just influence the body composition:

Figure 3: Serum IL-6, MCP-1, adiponectin and leptin levels, TNF-alpha mRNA expression in the adipose tissue (left), adipose tissue sample form the rodents receiving standard chow, the SFA-12% and the SFA-24% diet (Enos. 2013). The fat cells of the SFA-6% animals looked similar to those on the SFA-6% diets.

Based on the body composition data presented in figure 2 the marked increases in serum leptin and TNF-alpha mRNA expression in the adipose tissue of the rodents in figure 3 (left) should be about as unsurprising as the fact that the adipocytes of the SFA-12% group show the greatest macrophage infiltration and subsequent necrotic tissue.

If anything is surprising, it is the non-significance of the peak in IL-6 in the SFA-24% group (this was due to a very high standard deviation) and the fact that the serum level of MCP-1 a marker of increased macrophage activity was not elevated, while the adipose tissue mRNA expression was significantly higher (5-8x) in all SFA groups compared to both of the control diets. In the end this is yet only another clear sign that far more processes than we have previously thought happen locally and do not depend on circulating and thus endocrine signaling molecules.

Figure 4: Blood glucose and insulin levels of the mice over the course of the study period (Enos. 2013)

If you take the data from figure 4 into account as well, you will certainly agree with the statement Enos. et al. make pertaining to the negative effects of the SFA-12% diet, which is - just to remind you - the mirror image of the standard American diet:

"The 12%-SF diet, most closely mimicking the standard American diet, led to the greatest adiposity (absolute fat mass), macrophage infiltration, and IR [insulin resistance]." (Enos. 2013)

Figure 5: Total  cholesterol (TC, top) and LDL-C to HDL-C (bottom) ratios (Enos. 2013)

And I guess it would actually be about time to get to the bottom line, here, if it was not for the sentence that follows this assertion:

"Although the 24%-SF diet increased adiposity and produced IR, it did not significantly increase macrophage infiltration, it led to a lesser degree of AT inflammation, and it did not raise the TC/HDL-C ratio." (Enos. 2013)

Yep, you are reading right, as the data in figure 5 shows the total to HDL ratio of the SFA-24% group, which were those rodents who consumed the largest amount of "bad" saturated fat, was virtually identical to the one of the rodents on the standard and the modified standard chow and significantly lower than in those rodents who 'lived the American way of life' (SFA-12%). A similar trend was seen in the LDL:HDL radio and the triglyceride levels.

Bottom line: So, does that mean that we would just have to fry our potato chips in lard and all will be good? Not really, no. If we keep munching tons of plain sugar, even a saturated fat only diet is not going to save us from doom (I suspect there will be another inflection point at levels which exceed 50% SFA, anyway). What the study results do yet clearly implicate is that the macronutritent and fatty acid composition of the standard American diet is downright conspicuously obesogenic, pro-diabetic, inflammatory.

While the macronutrient ratio (high carb + high fat) appears to set the body into fat storage mode, the individual ratios of the fatty acids determine the efficacy of body fat storage, the negative effects on blood glucose management, and the degree of adipose tissue inflammation - and the standard American diet excels in all these disciplines.

As far as the saturated fats go (I wonder if it also plays a role that one of the main sources was coconut oil), the study suggests that you can achieve ameliorations of adiposity on both sides of the 'obesogenic optimum' of 12% saturated fats. If you take a last look at the data in figure 4, you will yet have to concede (or triumph?) that eating more not less saturated fat and thus frying your potatoes in lard, appears to be the more promising modification you could make, if the saturated fat content of the diet was your only set screw. Feels good to know it isn't right?

References:

• Enos RT, Davis JM, Velazquez KT, McClellan JL, Day SD, Carnevale KA, Murphy EA. Influence of Dietary Saturated Fat Content on Adiposity, Macrophage Behavior, Inflammation, and Metabolism: Composition Matters. J Lipid Res. 2013 Oct 28.

SuppVersity Science Round-Up Seconds: Supplement-Drug Interactions, Exercise and Psychology, Running vs. O-Lifting & Right Ventricular Hypertrophy, News on the N3-to-N6 Ratio, the CYP Enzymes, Endocannabinoids & Telomeres

The SuppVersity Science Round-Up every Thursday live on Carl Lanore's Super Human Radio -- tune in live at 1PM (EST=  6PM GMT)!

I hope that most of you have already had a chance to listen to yesterday's installment of the SuppVersity Science Round Up on Super Human Radio. In case you didn't, or have been waiting for me to post the link to the podcast (just a reminder: you can always download the latest show, from the navigation bar on the right, where it says: "Physical Culture for your Ears"), I'd suggest you go and download the podcast either now, or after going through today's SuppVersity Science Round Up Seconds.

The "Seconds" are as the name implies no "leftovers", but actually yet another selection from the selection of god knows how many interesting newsbits I usually pile up for the short 1h show, Carl and I are doing every Thursday. I would therefore encourage everyone to do both, listen to the podcast and read the "Seconds" one day later. After all, the things Carl and I discuss on the air won't reappear here, they are "SHR exclusives", so to say ;-)

Apropos, in yesterday's show, the topics we did cover were

• premature ejaculation, and how only two hormones seem to make a difference,  
• peptides as prostate cancer vaccine, and how Harvard scientists build them from scratch,
• supps vs. medications, and how fatal commonly overlooked interactions can be, and
• copper, and why it may well matter than raw milk has 2-3x more than pasteurized milk

and before we go on with the actual "seconds", I must acquit myself of a promise -- the promise to provide you with more information on #3 on the above list.

Supplemental data: Supplement vs. drug interactions

Figure 1: Important supplement drug interactions based on Tsai (2013)

Those of you who have already listened to the podcast will probably be waiting eagerly for the supplemental material with more information about the potential pitfalls with supplement-drug interactions, Carl and I have been talking about on yesterday's show. With some digging, typing, searching, excerpting and formatting on my part, I have actually come up with a quite comprehensive and for people who are not familiar with all the funky drug names, probably even more understandable version (see figure 1) of the tabular overview H.H. Tsai and colleagues from the China Medical University Hospital and the College of Pharmacy at the University of Illinois at Chicago have included in their latest review of the literature (Tsai. 2013).

What I left out are the two pages (!) part on St. John's wort. With 147 drug (!) interaction ranging from "A" as in "amiodarone" to "W" as in "warfarin" and covering almost every drug type from anti-depressants, protease inhibotors, calcium channel blockers, PDE-5 inhibitors (viagra & co), SERMs, proton pump inhibitors, etc.. In view of the fact that these are only the known interactions, it would be easier to list those drugs with which St John's does not conflict, anyway. So, unless you have a study at hand which conclusively shows that St. John's is no problem, I would rather err on the side of caution, than end up in the ER.

Top 5 of the most frequent interactions observed with medication that act on (ranked by frequency, figure in brackets indicates percentage of all drugs in the study; based on Lin. 2013):

1. nervous system (19.6%)
2. cardiovascular system (17.7%)
3. antiinfectives for systemic use (14.7%)
4. alimentary tract and and immunomodulating agents (12.2%)
5. musko-skeletal system (6.4%)

As far as the supplement list in figure 1 goes, the most frequent potential side effect due to supplement-drug interactions affected drugs / supplements that play a role in blood coagulation. Danshen, evening primrose, gingko, glucosamine, white willow bark, garlic, vitamin E, fish oil to name only the most common ones, they all can increase the risk of bleeding not only, but specifically in patients who are taking warfarin (aspirin, ibuprofen, heparin and others were on the list, as well).

"What’s wrong with telling a patient, 'If you don’t hear from us with your lab results a few days, give us a call'? The answer is plenty, if that patient is receiving warfarin therapy. Because warfarin has a narrow therapeutic range and complex pharmacology, insufficient monitoring or errors in dosing can lead to severe and possibly life-threatening bleeding and clotting in patients receiving it." (Bush. 2002)

In view of the "top 5" above, this certainly sounds counter-intuitive, but we are dealing with a practical research bias here. As I mentioned on the air, there is simply an overabundance of research on potential interaction with warfarin, because finding the right dosage and adapting it appropriately is already hard even when there are no confounding variables, so that a sudden supplement-drug interaction and subsequent increase in the risk of bleeding can potentially be fatal (see the quote in the red box to the right)!

Regardless of what medication you may be on, rules that apply for a healthy individual that does not take any medication chronically (not even 'harmless' NSAIDs), don't apply to you! So please for one, follow the recommendation you find on each and every supplement to "talk to your medical practitioner" before you add another 'harmless' supplement on top of the 'harmless' over-the-counter or prescription drugs you are taking.

The Seconds: Interesting news that have been missing from yesterday's show

After this pretty lengthy addendum, let's get to three other items I had actually planned to have on the show, two of them are exercise, while the third one is a health and supplementation... and, when I come to think about it, obviously also diet related news-item:

• Exercise makes you happy and puts an end to the greed for money! That's not exactly the result of a recently conducted study from the Charité in Berlin (Bothe. 2013), but it is more or less what follows from the differential response Bothe et al. observed in their untrained and highly trained subjects to monetary stimuli after they had completed a standardized running exercise (30 min at 60-70 % VO2max, T) or placebo (P).
  

  

  Who would have thought that: Exercise reduces the anticipatory response to monitary incentive delay (MIT) test (Bothe. 2013)

  "Acute exercise was found to influence gain anticipation. In the P compared to the T group a more pronounced anticipation-related BOLD response was found in mesolimbic and mesocortical dopamine-innervated regions like the VS, hippocampus (Hipp) and subgenual anterior cingulate cortex (sgACC). [...] Additionally, several brain structures potentially associated with motor preparation (primary and supplementary motor areas) as well as structures belonging to the ventral (lingual gyrus) and dorsal (cuneus, precuneus) visual pathway showed stronger BOLD responses to gain anticipation in the P group compared with the T group." (Bothe. 2013)

  Moreover, according to the paper which is going to be published in one of the upcoming issues of Medicine and Science in Sports and Exercise, all 43 healthy men between the age of  20 - 32 years who participated in the study showed similar increases in mood (effect size F=11.70).
  
  With both, the beneficial outcome of the positive and negative affect schedule and the decrease in anticipatory signalling (= the greedy "I am about to win!") in the psychological testing session (the so-called monetary incentive delay) in an fMRI brain scanner, being identical it becomes evident that you don't have to be an athlete to monetize (all puns intended ;-) on the beneficial psychological effects of exercise.

• 

  Figure 1: Changes in total lean mass, aerobic fitness, strength (mind the scaling with x10!), right ventricular mass and end-diastolic volume in subjects in the endurance (runners) and strength training arm (O-lifting) of the 24-week study (based on Spence. 2013)

  Changes to the heart (right ventricular) due to exercise are mild, and if anything more pronounced in response to endurance than resistance training! " Left ventricular (LV) adaptation to exercise training has been the focus of 'athlete's heart' research to-date, information regarding right ventricular (RV) adaptation is sparse, due to its complex structure and imaging technique limitations." (Spence. 2013) So scarce, in fact, that this recent study that has been conducted by researchers form the The University of Western Australia, the University of Leeds, a and the Liverpool John Moore's University is the first to take a closer look at the impact endurance or resistance training have on the morphology of the RV.
  
  For their randomized trial, the researchers recruited twenty-three young untrained men.. The men were assigned to either
  
  • endurance training (E; n = 10)  - consisting of a progressively overloaded program of walking/jogging/running, divided into three training phases over the 24-week period, or
  • resistance training (R; n = 13) - with a focus on periodised R program was Olympic weightlifting with incorporated assistance exercises (e.g. deadlift, squat, bench press, overhead press) to develop overall strength and technique
  for a total timespan of 6 months, in the course of which body composition, aerobic fitness, muscular strength, RV morphology (MRI) and function (speckle tracking echocardiography) were continously monitored.
  
  The results Spence et al. are going to publish in one of the future issues of Medicine and Science in Sports and Exercise refute even two pieces of common "knowledge". Firstly, a still totally benign, right ventricular hypertrophy was exclusively observed in the endurance training group, yet not in the heavy lifters who were doing their squats, deadlifts and military presses (by 2.7g following E and by 1.4 g  following R training). Secondly, both strength and size gains were no prerogative of the lifting weight group. Contrary to the increase in total lean mass (+1.3 kg vs. +2.1 kg), the strength increase of +53.8 kg vs. +35.3 kg was yet much significantly more pronounced in the weight lifters.
  
  On the other hand only the endurance training group saw significant statistically improvements in their aerobic fitness level. This correspondence of endurance exercise, mild ventricular hypertrophy and increased fitness levels is unquestionably telling in terms of "how bad" a physiologically enlarged heart where the ratio of left-to-right ventricular  mass remains intact (which was the case in the study at hand), don't you think so?
• Omega-3s, omega-6s, telomere length, CYP enzymes, endogenous cannabinoid and the liver you need all of them to see the complete picture While the epidemiologists are still debating who will and who won't benefit from omega-3 supplementation, those who still care about how our bodies works and why their colleagues over at the epidemiology department are still debating, have made quite some progress as far as the underlying health benefits of rectifying the omega-3 to omega-6 balance are concerned.
  
  
  Why are endocannabinoids problematic? One of the answers is: "They will make you fat!" Basically we have known that forever, but a recent study which tracked the conversion of dietary linolic acid (n-6) to it's endocannabinoid metabolits, 2-AG and anandamide has recently confirmed not just that, but also that the provision of no more than 1% of the total energy of the diet in form of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) can already make a huge difference (Alvhem. 2013). With the addition of the long-chain omega-3s, the rodents in the study had a 8:1 ratio of linolic acid (LA) to long-chain omega-3 fatty acids in their diets. Still much higher than what you will hear is necessary, but sufficient to reverse the overabundance of arachidonic acid, in the phospholipids of liver and erythroctes, and the +200% increase in endocannabinoid levels that had been brought about, when the researchers had increased the linolic acid content of the diet from 1% to 8% of the total energy intake. In view of the fact that the same goes for the increased food intake, feed efficiency, and adiposity the mice had developed on the 60% fat (total) diet with a high linolic acid content, this study - despite being done on rodents - clearly shows that it does not necessarily have to be a 1:1 ratio to grasp major health benefits.
  
  If you get down from  30:1 to 8:1 you've come a tremendous way, already; and guess what: The easiest way to achieve that is to just cut out all seed and vegetable oils as well as processed foods that contain them.
  In a recent review on the differential effects of fatty acids on human metabolism in the Italian journal Medical and surgical pediatrics G. Caramia emphasizes the role of omega-6 derived endocannabinoids:
  

  "[E]ndocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol [that arise from the enzymatic conversion of linolic acid by enzymes from the cytochrome P450 family at the liver are] capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both [of the] cannabinoid receptor present on nervous and peripheral cell membranes." (Caramia. 2013; my emphases)

  Unfortunately, the same enzymes which are responsible for the generation of those endocannabinoids, are also responsible for the conversion of n-3 PUFAs into more potent metabolites of EPA and DHA, which will actually do most of the the vascular- and cardioprotective magic that is commonly ascribed to "fish oil".
  
  And how does all that relate to telomeres?
  
  These competitive effects in turn segue directly into the observations of a double-blind 4-month trial that involved 106 healthy sedentary overweight middle-aged and older adults. The participants supplemented their diets with capsules containing either (1) 2.5 g/day n-3 PUFAs, (2) 1.25 g/day n-3 PUFAs, or (3) a placebo that mirrored the proportions of fatty acids in the typical American diet.
  
  Now, it's not news that this led to decreases in inflammatory markers. I am not going to bore you with those, don't worry!
  
  What is news, and in my eyes very important, is that neither the provision nor the dosage of additional long-chain omega-3s had an effect on telomere length, the only variable that mattered was were the changes in the n-6:n-3 PUFA plasma ratios, which "helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios (p= 0.02)" (Kiecolt-Glaser. 2013).

That's it as far as today's seconds go... you want more? Man, I could certainly give you more, but you know that gluttony was once considered a sin, right? Tomorrow is another day, and if you can't wait, just head over to the SuppVersity Facebook wall, which is always bursting from the seems with the latest tidbits from the realms of health, exercise and nutrition sciences.  

References:

• Alvheim AR, Malde MK, Osei-Hyiaman D, Hong Lin Y, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity (Silver Spring). 2013 Oct;20(10):1984-94.
• Bothe N, Zschucke E, Dimeo F, Heinz A, Wüstenberg T, Ströhle A. Acute Exercise Influences Reward Processing in Highly Trained and Untrained Men. Med Sci Sports Exerc. 2013 Oct 10.
• Bush J. Preventing errors in your practice. Reducing risks for patients receiving warfarin. Fam Pract Manag. 2002 Jul-Aug;9(7):35-38.
• Caramia G. [Essential fatty acids and lipid mediators. Endocannabinoids]. Pediatr Med Chir. 2013 Mar-Apr;34(2):65-72.
• Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2013 Sep 23. pii: S0889-1591(12)00431-X.
• Spence AL, Carter HH, Murray CP, Oxborough D, Naylor LH, George KP, Green DJ. MRI-derived Right Ventricular Adaptations to Endurance versus Resistance Training. Med Sci Sports Exerc. 2013 Oct 15.
• Tsai HH, Lin HW, Simon Pickard A, Tsai HY, Mahady GB. Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review. Int J Clin Pract. 2013 Nov;66(11):1056-1078.

The Female(?) Athlete Triad - Part III/III: Road to Recovery! Step #2 = Accept There is No Magic Macronutrient Ratio

No need to raid another tomb, Lara, the quest for the one and only ideal macronutrient composition that will yield optimal results for the rest of your life ends here (img courtesy of Paramount)!

I am not planning to bore you with a longish summary of the previous installment(s) of this series, here. Still, I don't want to head on to the 2nd step of the "Road to Recovery", which is going to deal with the quest for the "optimal" macronutrient ratio, without a brief reminder of the central role of nutrient availability in both the etiology, as well as the recovery from the athlete triad - or, as Dr. Zanker from the Carnegie Research Institute at the Leeds Metropolitan University in the United Kingdom puts it, the simple fact that the "exercise associated reproductive dysfunction in women is attributable to deficits of readily available energy" (Zanker. 2006)

In a couple of more general remarks some of you have recently (not without good reason, by the way) criticized my excessive and in parts random use of mark-ups like bold print or underlining. In the introductory paragraph to today's post the word "readily" is however so important that the underlining is obligatory.

Your hypothalamus does not like to wait, therefore "readily" is the keyword, here!

It is after all the lack of appropriate readily available energy, primarily in the form of circulating glucose, liver glycogen, and adipose tissue triacylglycerol that precedes the low plasma insulin concentration and reductions in total body fat content and corresponding disturbance of leptin secretion, ghrelin, cortisol, thyroid and of course luteinizing hormone (see data in figure 1; the absolute levels from the healthy group may also serve as a reference to compare your own labwork to; mind the units!).

Figure 1: Hormonal and glucose metabolism (* indicates 24h values) of women with functional hypothalamic amenorrhea (not necessarily exercise induced) expressed relative to values in eumenorrheic control; values above the bars indicate the total values of the respective markers in healthy controls and may provide you with some orientation, when you are looking at your own bloodwork (data based on Loughlin. 1998)

In order to avoid / counter the reproductive and associated problems and break out of the vicious circle of the athlete's triad, Zanker proposes the following three steps (based on Zanker. 2006; yet with a couple of additions from my side): 

• Avoid abrupt and rapid weight loss and maintain an “adequate” body fat content, which may be individually specific, but coincides with regular reproductive function.
• Consume adequate amounts of energy to fuel your increased metabolic demands; never go below your resting energy expenditure, regardless of whether you  want to or even have to lose weight.
• Make sure you get an adequate amount of carbohydrates either on a continuous (low GI carbs with every meal) or in a cyclic manner as part of a low(er)* carbohydrate diet with a baseline intake of 90-120g/day and additional carbs after every workout.
  *compared to the RDA of ~60% carbs

"Carbohydrates? But aren't those just making you fat?" With this very question that's now probably on the mind of one or two (or three ;-) of you, we did eventually arrive at the topic of this episode of the Athlete's Triad Series:

Is there a ideal macronutrient ratio that will prevent the onset
and help you get rid of the athlete's triad?

To be honest, I don't know the answer to this question... and although I had almost typed the word "yet" win the place where you now see the "..." , I must admit that I am not even sure if there actually is a definitive answer to this question. What I do have to offer, though, is a couple of things to keep in mind, when it comes to the macronutrient make-up of your diet.

1. There is no such thing as a "bad" nutrient. There are about as many good arguments to vilify the overconsumption of protein, as there are arguments against the usual scapegoats, carbohydrates and fats.
2. Glucose and saturated fats can be essential, too. Just because your body can produce carbs and saturated fats on its own, this does not mean that you do not have to, let alone should not eat them.
3. The optimal macronutrient ratio will change over time - just like and in response to the way your physique, conditioning, lifestyle, training and general stress levels  will be changing. This implies that diet X, which may have worked magically for you, when you got rid of slabs of body fat is now that you are finally in the "normal range", let alone already so lean that your body's alarm bells are constantly ringing, hampering your progress.

And even if the previous comments on the importance of readily available energy and glycogen repletion would suggest that carbohydrates should make up the lion's share of the diet of any athlete trying to recover from the triad (or not to fall victim to it), an extreme high carbohydrate alone is neither guaranteed to solve the problem nor is it a sustainable way of eating you could stick to once you've "carbed" yourself out of the dark hole you have been digging over the past months.

Readily available energy? Does that mean I have to eat sugar all day?

Figure 2: Cortisol (left) and testosterone (right) levels in healthy men after 10 days on high protein vs. high carbohydrate diets (based on Anderson. 1987). Tegelman et al. report similar results from Swedish elite male Ice Hockey players after a reduction of fat and an increase in carbs (Tegelman. 2007)

On the one hand, we've known for over two decades that a high carbohydrate diet based on bread, vegetables, fruit, juices, pastry, and candy having a protein / carb / fat ratio of 10% / 70% / 20% will result in lower cortisol and higher testosterone levels (in men) than a high protein diet with a protein / carb / fat ratio of 44% / 35% / 21% that's based on lots of meat, fish, poultry, egg whites, and a liquid dietary supplement protein supplement (Anderson. 1987; see figure 2). On the other hand, a closer analysis of the data I compiled based on the tabular overview of pertinent studies on amenorrheic from the review by Manore (see figure 3 in the last installment) suggests that real.world advantage of carbohydrates depends on the deepness of the whole you already dug (the deeper the more advantageous) and your willingness / ability to cover or even surpass your daily energy requirements (the more you eat on a daily basis and in at least three square meals spread equally across the day, the less you will depend on the readily available energy from carbs).

Against that background, the high carbohydrate intake (62% of total energy from carbohydrates; nutrient ratio in grams 16% protein, 71% carbs, 14% fats) was probably necessary for the women in the eumenorrheic group with an energy intake of slightly less than 30g/kg body weight (figure 3, R5).

Figure 3: Macronutrient compositions (in kcal!) of amenorrheic and eumenorrheic women from 15 different studies (based on an overview in Manore. 2002)

For the eumenorrheic female athletes who were at, or way above the average mean energy intake of 35g/kg body weight, the "high" carbohydrate intake of 265g/day probably wasn't detrimental. On the other hand, it appears questionable, whether an increase in protein intake from 1.2g protein per kg of body weight to 1.5-2.0g/kg and a corresponding protein to carbohydrate ratio of 25% / 62% would not have been more facilitative to their goals (specifically if those include strength training). The same goes for both, the replacement of yet another part of the carbohydrate ration with an isocaloric amount of fats and the overall role of fats in the etiology of and the recovery from the athlete's triad.

The fat-phobia still loomed large, when the majority of studies was conducted

Part of the problem of reconciling theoretical considerations, such as the "availability advantage" of carbohydrates and the scarce and almost exclusively observational data based on which I compiled the overview in figure 3 of this, as well as the last installment of this series, is that eating patterns of both the eumenorrheic, as well as the amennorheic athletes was geared towards the dietary paradigm of the day. With "the day" being the late 1980s and 1990s, i.e. those years in which the fat-phobia literally climaxed, it should be obvious that the baseline diet was low in fat and high in carbs.

Against that background it should also be clear that anyone trying to "cut calories" would reduce the amount of fats, the "bad energy dense heart killers" and keep the intake of carbohydrates constant (=high). This is probably also, the reason that the ostensible disproportionate lack of fats in the diets of the amenorrheic women vanished, once I weighted the data with the number of participants.

Figure 4: Total dietary intake of protein, carbohydrates and fats (in g; left) and differences between women with and without regular menses (right); data expressed either as simple group averages or weighed for the number of study participants (same sources as figure 3)

The picture that emerges after this adjustment has been done (figure 4, right, light bars) is clear and stands in line with my initial remarks on the primary of readily available energy in the form of circulating glucose, liver glycogen, and adipose tissue triacylglycerol, of which at least the former are way more readily derived from carbohydrates than fats.

And even the triacylglycers do, as the name implies, require a certain amount of glucose for the glycerol backbone (could be produced in the liver from amino acids and/or fats, though) and a minimal amount insulin to be stored in the fat cells (can be secreted in response to high amounts of protein and fat, as well, though).

So no fats? Just carbs and some protein?

Yet though carbohydrates have the availability bonus and proteins are necessary to maintain, better even build muscle mass, you would be ill-advised to steer clear of all dietary fats and, even more so the many good foods that contain them. Not so much because of the "essential" polyunsaturated fatty acid, though. According to a study by Tomten and Høstmark the dietary intake of PUFAs in 20 female runners with regular (n=10) and irregular (n=10) menses (LH levels of 7.6 vs. 2.9 IU/l!) was not statistically different. The intake saturated fats (-28%) and even more the intake of MUFAs (-38%), on the other hand was (Tomten. 2009) and the corresponding total fat-intake of 1.1g/kg body weight was obviously not sufficient to maintain optimal hormonal levels in the presence of a training volume of 7.5h per week.

What about vegetarianism? I know a few of you won't like this, but unless you are at least ovo-lacto vegetarian, i.e. a person who eats dairy and eggs, you are going to have a hard time fueling your athletic endeavors appropriately. After all, vegetarianism is associated with hormonal and menstrual abnormalities even in the non-athletic population, when they are dieting (Pirke. 1986). If you combine a mild energy deficit, as it is often seen in vegetarian, let alone vegan athletes, simply because it's harder for them to cover their energy and specifically protein and fat requirements without guzzling omega-6 oils and soy shakes all day (both not advisable, by the way), it is actually not surprising that Benson et al. mention vegetarianism right along low calorie intakes, nutritional inadequacies and low body fat stores as one of the main contributers to the (female) athlete triad (Benson. 1996).

Now you can certainly argue that all this comes down to the energy density and the correspondingly lower overall energy intake and could have been compensated for, if the women with menstrual irregularities had simply eaten more carbohydrates. In view of the fact that they didn't do so, I can hardly refute this argument. On the other hand, we have seen in the previous installment that an overexpression of GH and ghrelin is in as much part of the problem as too little insulin and a pathologically high insulin sensitivity. And some more fat in the diet (alongside carbs / not as the sole energy source!) couId in fact come handy to get that back in check.

Moreover, having a carb to fat ratio of ~2:1 (in energy equivalents) and a baseline fat intake in the range  of 80-100g (total) as the female runners with regular menses in the Tomton sudy had, has the beauty of never having to throw away the egg yolks, being able to get your share of fatty fish, full fat dairy, Kerrygold butter, virgin coconut and olive oil and beef or better calf liver as well as nuts once in a while. This in turn will allow you not just to stay sane and flexible with your diet, but also to satisfy your need for all those vital micronutrients you won't find in any of E-number laden fat-reduced garbage from the "low fat" shelves at the supermarket.

You see, in the end it all comes back eating simply more of the usual suspects, many people would probably file under "a paleo diet with lots of (safe) starches & fruit to fuel the energetic demands of a hard working athlete", these days.

If we think of the hypothetical daily energy requirement of 2000kcal/day which is often used as a reference for the nutrition information on those products of which you are going to buy less in the future (most real foods don't have nutritional information printed on them, you know ;-), the corresponding "numbers" could be anywhere on a continuum

• from 110g protein / 190g carbs / 100g fats, for someone without an endurance component in his workouts*, 
• to 100g protein / 240g carbs / 80g fats for someone who has a major endurance component and / or follows a high volume lifting routine*
  *pre- and post workout nutrition are not included, here!

This approach would ensure that you get enough protein, appropriate amounts of readily available energy, mainly in the form of safe starches and fruit, quasi unlimited amounts of vegetables and so much fat that you don't have to resort to the devastating "chicken breast, rice and broccoli diet", which will only worsen your situation.


References:

• Anderson KE, Rosner W, Khan MS, New MI, Pang SY, Wissel PS, Kappas A. Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man. Life Sci. 1987 May 4;40(18):1761-8.
• Benson JE, Engelbert-Fenton KA, Eisenman PA. Nutritional aspects of amenorrhea in the female athlete triad. Int J Sport Nutr. 1996 Jun;6(2):134-45.
• Laughlin GA, Dominguez CE, Yen SS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1998 Jan;83(1):25-32.
• Manore MM. Dietary recommendations and athletic menstrual dysfunction. Sports Med. 2002;32(14):887-901.
• Pirke KM, Schweiger U, Laessle R, Dickhaut B, Schweiger M, Waechtler M. Dieting influences the menstrual cycle: vegetarian versus nonvegetarian diet. Fertil Steril. 1986 Dec;46(6):1083-8.
• Tegelman R, Aberg T, Pousette A, Carlström K. Effects of a diet regimen on pituitary and steroid hormones in male ice hockey players. Int J Sports Med. 1992 Jul;13(5):424-30.
• Tomten SE, Høstmark AT. Serum vitamin E concentration and osmotic fragility in female long-distance runners. J Sports Sci. 2009 Jan 1;27(1):69-76.
• Zanker CL. Regulation of reproductive function in athletic women: an investigation of the roles of energy availability and body composition. Br J Sports Med. 2006 Jun;40(6):489-90; discussion 490.

High Dose Omega-3 for Fat Loss? With 90% Lower Body Fat EPA Takes The Lead, DHA Second, ALA Distant Third... in Rats on Cornstarch or High Fat + High Sugar Diets

For Neo in the Matrix (courtesy of Warner Bros.) the choice was comparably easy. He had only two pills! You, however got to chose between ALA, EPA, DHA and, believe it or not, taking no pill at all!

I guess, those of you who are curious about the whereabouts of "your's truly" Adelfo Cerame Jr. will be disappointed to hear that he is currently so overwhelmed with clients and other duties that we have decided to turn the weekly contest prep series into a bi-weekly one.

Since this was more or less a last-minute decision, I just picked the next best study from my "interesting finds" folder and ... it turns out to be one of your, yet certainly not my favorite topics: Omega-3 fatty acids! That I am still skeptic about the usefulness, let alone necessity of respective supplements, does yet not change mean that I am deliberately ignoring interesting research on the unquestionable beneficial effects they have on lazy couch-potatoes and respective rodent models.

ALA, EPA, DHA - different acronyms, different effects?

Speaking of rodents, the soon-to-be published study by Hemant Poudyal, Sunil K. Panchal, Leigh C. Ward and Lindsay Brown from the Universities of Queensland and Southern Queensland in Australia unquestionably belongs into this latter category of "interesting rodent research on the benefits omega-3 fatty acids" (Pudyal. 2013). In order to differentiate the effects of alpha linoleic acid (ALA), the short(er)-chain brother to the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) people often falsely refer to as "fish oil" (while fish oil contains them, the average fish oil cap has ~40% EPA/DHA or 400mg in a 1g gel cap), the scientists assigned 96 male Wistar rats (9–10 weeks old) randomly to one out of 8 different diets containing

Carbohydrate, fat and protein content (rel. to total energy)

• corn starch,
• corn starch +1.1g/d ALA-rich chia oil,
• corn starch +0.7g/d EPA,
• corn starch +0.8g/d DHA, or
• high-carbohydrate, high-fat, 
• high carbohydrate, high-fat +0.7g/d ALA-rich chia oil 
• high-carbohydrate, high-fat +0.7g/d EPA oil and 
• high-carbohydrate, high-fat+0.6g/d DHA oil

The n-3 PUFA supplemented diets were prepared by adding 3% of the oil replacing an equivalent amount of water in the diet. n-3 PUFA supplemented diets were administered for 8 weeks starting 8 weeks after the initiation of the corn starch or high-carbohydrate, high-fat diet. The drinking water in all high-carbohydrate, high-fat fed groups was augmented with 25% fructose for the duration of the study.

Profound anti-obesity effects of EPA and DHA

Over the course of the 8-week supplementation period the researchers took daily measurements of body weight, food and water intakes. They performed two oral glucose (OGTT) and insulin tolerance tests (ITT) before and after the 16 weeks trial and measured the body composition by Dual-energy X-ray absorptiometric (DXA).

Figure 1: Body composition, lipid profile, glucose management (left to right) in rodents after 8 weeks on chia seed oil (ALA), EPA and DHA supplemented diets (date expressed relative to cornstarch non-supplemented control; calculated based on Poudyal. 2013)

If you take a look at my plot of the data, you may be surprised about the significance of the results. While it has to be said that even the "normal" control diet was not exactly what I would deem healthy (even for a rodent), it is nevertheless astonishing how pronounced the anti-obesity effects actually were.

Downstream benefits on organ health, ...

Figure 2: Contrary to what we have seen in previous studies (see TTA+fish oil), the high doses of the different omega-3s (HED ~20-30g!) had no effect negative effects on either the transaminase (ALT, AST), lactate dehydrogenase (LDH), alkaline phosphatease (ALP) or bilirubin values or the histology (histologies of hepatcytes not shown) of the liver of the rodents (data based on Poudyal. 2013)

Compared to the effects of the high doses of long-chain omega-3s the ALA treatment had a comparatively low impact on the adiposity. This could partly be a result of the fact that the omega-3 fatty acid metabolism in skeletal muscle and adipose tissue appears to be specific. While EPA and DHA
accumulated readily in these organs, when they were directly supplemented, the provision of ALA did not increase the contents of long-chain omega-3 fatty acids in either body fat or skeletal muscle tissue.

On the other hand, all omega-3 fatty acids showed beneficial effects on heart and liver the function of which had already been compromised by the 8 weeks on the extreme high carbohydrate or high sugar + high fat diet (reduced cardiac fibrosis, hepatic steatosis and inflammation in both the heart and the liver). In that, both, both, the improvements in body composition, as well as organ health, were more pronounced in the low-fat diet compared to the high-carbohydrate, high-fat diet.

... but negative effects on glucose management

Against that background it is actually surprising that none of the omega-3 fatty acids actually did what they are often hailed for: Neither ALA, nor EPA or DHA did improve the profoundly reduced glucose tolerance of the carb-o-holic rodents. On the contrary,...

"[...] EPA and DHA supplementation increased basal blood glucose concentrations, decreased intestinal glucose absorption and maintained the blood glucose concentrations for two hours after glucose loading with normal insulin sensitivity." (Poudyal. 2013)

Interestingly, this effect was probably brought about by yet another unexpected effect the high dose (human equivalent ~20-30g) omega-3 treatment had on the sympathetic nervous system:

"These effects were accompanied by increases in sympathetic activation seen as increased heart rate and cardiac output, increased force of left ventricular contraction and increased vascular responses to noradrenaline and sodium nitroprusside as observed with the hypothalamus–pituitary– adrenal axis response to stress and low blood glucose concentrations " (Poudyal. 2013; my emphasis)

As Poudyal et al. point out, this could also explain the profound weight loss effect in the cornstarch groups, and the "relatively smaller but significant changes in [high fat + high sugar] rats that still have an abundance of fructose and fat to meet the energy requirements."

From rodents to humans, from humans to...  fishmen?

The latest on the usefulness of omega-3 supplementation for active individuals and athletes: One of the most recent reviews of the issue states: "[O]nly a few studies have evaluated the impact of omega-3 PUFA supplementation on exercise performance. It has been suggested that the ingestion of DHA of approximately 1-2 g per day, at a ratio of EPA to DHA of 2:1, may be beneficial in counteracting exercise-induced inflammation and for the overall health of an athlete. However, the human data is inconclusive as to whether omega-3 PUFA supplementation, at this dosage, is effective in attenuating the inflammatory and immunomodulatory response to exercise, and improve exercise performance." (Micleborough. 2013; my emphasis)

These (at least for me novel) effects of very high doses of EPA and DHA on the sympathetic nervous system as well as the modulatory effects of the baseline diet are certainly things to keep in mind. This is particularly true in view of the latest epidemiological data which suggests that the consumption of comparatively minuscule amounts of fish oil has a population (and thus probably diet-)dependent effect on diabetes risk  (Wallin. 2013), with

• 17% increased risk of type-2 diabetes per 0.30 g per day increment in long-chain n-3 fatty acids in US residents, and
• -2% reduced risk of type-2 diabetes per 0.30 g per day increment in long-chain n-3 fatty acids in Europeans

The same goes for the U-shaped dose-response curve, Crochemore observed in one of the most recent controlled trials in the course of which a low dose (1.5 g/d) fish oil supplement improved the body composition and fatty acid metabolism of 41 women (60.64 ± 7.82 years) with high blood pressure and diabetes mellitus, while only 1g more, i.e. 2.5g/day, did not simply yield less pronounced decreases in body mass and waist circumference, the "high" dose fish oil supplement also reduced the already highly compromised insulin sensitivity of subjects even further (Crochemore. 2013).

EPA & DHA can come to the rescue, but a healthy diet would render supplements obsolete

If I did not know that fish oil was an invention of the 1990s, I would speculate that the "fishman" in the 1954 horror blockbuster The Creature from the Black Lagoon (Universal Pictures) was a "fish oil fat loss supplementation experiment gone wrong" ;-) Or joke aside - you don't seriously consider popping 70 fish oil caps a day to get the human equivalent of the ~1g of EPA or DHA the rodents in the study consumed, do you?

Regardless of the "optimal dosage", we should not lose sight of the influence and importance of the basal diet, when we evaluate the effects of DHA and EPA on body composition, lipid metabolism and not the least glucose management. It is, for example, very unlikely that we would see anywhere similarly pronounced effects in humans who are following a whole-foods based, "paleo-esque" diet without tons of cornstarch in it (control group), or plain sugar (and 17% additional fructose) that are on top of that hilariously protein-deficient (5%-6% is - if anything - enough not to die).

If you chose grass-fed over regular butter / dairy (makes sense only for high fat dairy), eat fish once or twice a week and replace the grain-based oils in your diet with coconut and olive oil, anything that goes beyond the occasional one or two fish oil caps will probably do more harm than good. And let's be honest, you don't really believe that you would get rid of the blubber that may still be covering your abs by copying the supplementation protocol of the study at hand and taking 70 fish oil caps every day to get your 20-30g of EPA and DHA, do you?

References:

• Crochemore IC, Souza AF, de Souza AC, Rosado EL. ω-3 polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity. Nutr Clin Pract. 2013 Aug;27(4):553-60.
• Mickleborough TD. Omega-3 Polyunsaturated Fatty Acids in Physical Performance Optimization. Int J Sport Nutr Exerc Metab. 2013 Sep 4.
• Poudyal H, Panchal SK, Ward LC, Brown L. Effects of ALA, EPA and DHA in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. J Nutr Biochem. 2013 Sep 28. pii: S0955-2863(12)00207-0. .
• Wallin A, Di Giuseppe D, Orsini N, Patel PS, Forouhi NG, Wolk A. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care. 2013 Apr;35(4):918-29.

Caffeine Protects Brain Function Against Stress & SAD Diet; Coffee Withdrawal, Anxiety & More; Giardia, Messy Subtenant W/ Gusto For Arginine; Vit B6 & n6:n3 PUFA Ratio

19 Billion Euro that's the estimated 2011 financial burden due to lung cancer, alone, here in Europe and the On Short Notice figure of the week (information based on ESMO2013 press release)

Those of you who are also following the SuppVersity facebook news, will probably recognize the figure on the right: 16,000,000,000€ or $24,419,000,000, that's the estimated economical burden due to lung cancer, alone, here in Europe (cf. "Who cares if people are dying as long as the economy is thriving?"). An enormous financial loss, and still not the reason that this is my figure of the week. Rather than the financial damage, itself, it is the tragic fact that only the latter, yet not the fate of the patients and their families, would make a valid argument, when policy makers were debating a long overdue, total and all-encompassing public smoking ban... but now for a couple of more sciency, yet not less intriguing news from the past week.

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Problems thinking straight? Guess what: 3-4 cups of coffee could help :-) According to a soon-to-be-published paper by scientists from the Jordan University of Science and Technology in Irbid, Jordan, the ingestion of the human equivalent of approximately 3.8mg caffeine per kg body weight or 3-4 cups of coffee per day, can inhibit both, the stress, related as well as diet induced (we are talking of the "typical" Western diet (WD), that's both high in carbohydrates and fat) cognitive impairments (Alzoubi. 2013)... well, at least in the researchers 3-months rodent study it worked like a charm

• learning trial: animals in the caffeine/stress, caffeine/WD, and caffeine/stress/WD groups made fewer errors, than non-supplemented stressed or WD animals; overall their performance was comparable to those of the control
• memory tests: treatment reduced the number of error and restored short-term memory and long-term memory during chronic stress and/or WD (P < 0.05) to normal levels

With respect to the underlying mechanisms the scientists speculate that caffeine may "act mainly by inhibiting adenosine receptors" (Alroubi. 2013), which has in turn been shown to to inhibit long term potentiation (LTP) in rat hippocampal slices and disrupt the process of learning and memory at the synaptic level by blocking release of glutamate (de Mendonca. 1994).

Additionally, caffeine has also been shown to increases the expression of hippocampal brain-derived neurotrophic factor (BDNF) and its receptor, which is impaired in response to chronic stress and a hypercaloric Western diet (Aleisa. 2006; Molteni. 2004) and leads to deteriorations in cognitive performance. In the long run those effects could also contribute to the anti-dementia and anti-Parkinson's effects, I mentioned in the recent SuppVersity post on the insulin sensitizing effects of coffee.

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Figure 1: While the Hedonic tone and alertness reduced to baseline on day 5 of caffeine withdrawal, the habitual caffeine consumers had >15% higher anxiety scores on day 7 after giving up on their daily dose of methylxanthine (data calculated based on Smith. 2013).

Don't worry, caffeine will also work for humans. And what's best, upon short-term withdrawl (8 days) your cognitive performance is not going to suck - at least not as much as when you are stressed or living on pizza and French fries, only. All that and a couple of interesting other results have been published ahead of print in the online version of the Journal of Pharmacology (Smith. 2013).

To probe the effects of acute caffeine ingestion on cognitive performance and the influence of previous caffeine consumption and withdrawal, Andrew P Smith, Gary Christopher and David Sutherland recruited 70 volunteers (25 male, 45 female; mean age 22.8 years). The 35 consumers (>100mg caffeine /day, mean 300mg; range 110–600 mg) were put on withdrawal and tested on day 2, alone and without caffeine, and day 8 together with the non-consumers in a double-blind placebo-controlled fashion. During the caffeine challenge, the cognitive performance was tested twice, once before and once 30min after the provision of the caffeinated beverages.

Anxious, but smart: Caffeine gives you the edge

The results of the trial clearly indicate that the ingestion of 2 mg/kg of caffeine, which were served in decaffeinated coffee or tea 30min before the testing procedures, were associated with faster simple reaction times, fewer long responses, greater detection of targets in the cognitive vigilance task, and faster encoding of new information.

"The results confirmed previous findings, with ingestion of caffeine being associated with a faster simple reaction time, fewer long responses, more targets detected and faster encoding of new information. There were no main effects of consumer status, nor were there any significant interactions between caffeine and consumer status." (Smith. 2013)

Notwithstanding, I believe that many of you will probably be more interested in the effects of caffeine withdrawal on overall withdrawal symptoms (figure 1, top), as well as the alertness, hedonic tone and anxiety (figure 1, bottom) and the cognitive performance on day 2 of the withdrawal period (figure 2, left), than in any of the well-established performance cognitive performance boost, right?

Figure 2: Performance on day 2 of withdrawal phase (w/out caffeine) and on day 8 before (w/out caffeine) and after (w/ caffeine)the ingestion of decaffeinated tea or coffee with 2mg/kg caffeine in it (data based on Smith. 2013)

As you can see on the left-hand side of figure 2 there was a minimal performance decline on day 2 of the withdrawal phase, but the latter was statistically not significant and all measured markers of cognitive function had returned to normal on day 8 (remember longer response times = worse performance!), when the resumption or first time provision of caffeine spiked the reaction times and lowered the mistakes in all tests, irrespective of whether the subjects were former habitual consumers on withdrawal, or not.

Outside of controlled experiments "real" coffee and tea do at least as well

Since a large cup of coffee contains about the same amount of caffeine the scientists simply added to decaffeinated beverages, to ensure that the drinks could not be distinguished (by their smell for example), you can simply stick to your regular coffee and if you want to enjoy similar benefits. And to be honest, in view of the plethora of benefits of chronic low dose coffee consumption, I would not even think for a second about whether or not you may be missing out on the occasional boost, when you are not "going on withdrawal" from time to time...

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Figure 3: W/out arginine (Arg-) intestinal epithelial cells can't proliferate (graph based on Stadelmann. 2013)

Giardia eats away your guts arginine supply and makes itself at home within an increasingly morbid digestive tract! As a group of scientists from Sweden and Argentina reports in their latest paper, the protozoan parasite, Giardia intestinalis, feasts on the arginine your gut cells need to proliferate (Stadelmann. 2013). This will lead to reduced polyamine levels and upregulated cell cycle inhibitory genes, which will eventually disrupt the the cell cycle of the intestinal epithelial cells. The reduced intestinal epithelial cell proliferation, on the other hand, allows the gut pathogen to thrive and will, in the long run, disrupt the intestinal tissue homeostasis and thus initiate the decay of the intestinal epithelium  - a central feature of so many of the wide-spread gut pathologies.

Provision of additional arginine + citrulline can help ... in the short run

Now, the good news about all that is that the in-vitro data in figure 3 clearly suggests and anecdotal, as well as the effective therapy of diarrhea patients with arginine/citrulline actually confirm that the provision of supplemental arginine (or citrulline) constitutes a cheap and readily available way to ameliorate the decay, until the bugs have been eradicated by antimicrobial drugs.

A pros pos, antimocrobial drugs, with regard to latter, Noa Tejman-Yarden and Lars Eckmann write in a recent review of the latest drug innovations, that despite the fact that metronidazole and other antimicrobials are usually effective, "treatment failures are common and antimicrobia resistance occurs" (Tejman-Yarden. 2011), so that it would appear as if complex derivatives of 5-nitroimidazole and benzimidazole, which form the core structure of the most widely used antigiardial drugs, will replace them in the short-run. At least for so long, until several new classes of antigiardial drug candidates that have already been identity by high-throughput screening of large compound libraries, will eventually hit the market (Tejman.Yarden. 2011)

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More about vitamin B6: Helps with neurotransmitters synthesis; is involved in nerve function and necessary for normal brain development & function; influences mood, and melatonin production; effects circadian clock; is needed for B12 absorption and thus red blood cell production

When low: "Pins and needles" in extremities, mental disorders, seborrheic dermatitis, estrogenic PMS, dizziness, irritability, kidney stones, abnormal EEG, anemia, convulsions, edema (water retention), hypothyroidism, migraine-headaches, glossitis, lymphopenia

When high: Depression, suicidal tendencies, severe fatigue, mood swings, low blood sugar, migraine-headaches, heart palpitations, thyroid abnormalities (hyper- in the short, hypo in the long term), numbness in hands and/or feet, spinal / nerve degeneration, muscle spasms / cramps, osteoporosis, arthritis, higher blood pressure (short-term suppl.), lower blood pressure (long-term suppl.), mineral imbalances (high phosphor & magnesium vs. low sodium & calcium), restlessness, insomnia, vivid dreams, decreased estrogen & prolactin, depressive PMS.

RDA (adults): 1.3 mg*
*higher for pregnant women & >50y

Upper tolerable limit: 30-100mg*
*depending on the source of information

Food sources: chicken, turkey, tuna, salmon, shrimp, beef liver, milk, cheese, lentils, beans, spinach, carrots, brown rice, bran, sunflower seeds, wheat germ, and whole-grain flour

n6:n3 ratio does not depend on dietary intake alone: A marginal deficiency in vitamin B6 will skew your serum PUFA levels towards the N6-side That's the long and short of the results of a study that's going to be published in the October issue of the Journal of Nutrition.

Mei Zhao and her colleagues analyzed the fatty acid profiles in plasma, erythrocytes, and peripheral blood mononuclear cells (PBMC) of healthy men and women who had been fed a low-vitamin B-6 (pyridoxine) diet for 28 days and observed that contrary to the plasma HDL and LDL cholesterol concentrations, the amount of free fatty acids (FFA) in the blood and the erythrocyte and PBMC membrane fatty acid compositions, neither of which showed any statistically significant changes, the amount of all long-chain polyunsaturated fatty acids, i.e. arachidonic acid (n6) and EPA and DHA (n3) decreased from 548 ± 96 to 490 ± 94 μmol/L, 37 ± 13 to 32 ± 13 μmol/L, and 121 ± 28 to 109 ± 28 μmol/L, respectively.

The subsequent 8% increase in the total n6:n3 PUFA ratio from 15.4 to 16.6 is not alarming, but if this trend would continue linearly, it would certainly become problematic, in the long run. Moreover, the decrease in both n6 and n3 long-chain PUFAs (of which people tend to forget that the "inflammatory" arachidonic acid is as vitally important as its "anti-inflammatory" omega-3 counterparts) could provide an alternative / complementary mechanistic explanation for the increased cardiovascular disease risk that has been associated with vitamin B-6 deficiency.

In view of the fact that the RDA is not exactly high and can easily be achieved from dietary sources, along (as long as you follow a diversified whole foods diet), and considering the fact that high levels of B6 have been associated with more negative side-effects than B6 deficiency (see infobox on the right; please note that I collected the information on a couple of trustworthy websites on RDAs & co and did not verify the research on each of them!), I would however caution against the typical Western "more helps more" supplementation mentality.

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Figure 4: Easy come, easy go - the mass you gain and the fat you lose by doing nothing than simply injecting testosterone is lost / regained within 6 months after discontinuation of the "testosterone therapy" (Forbes. 1992); read more about the role of testosterone in skeletal muscle hypertrophy in the Intermittent Thoughts on Building Muscle

In view of the fact that (a) today's short news items are pretty long(ish) and you still got a couple of interesting facebook news to check out, such as...

• health related: "Vitamin D: We probably won't know before 2017, whether supplementation is advisable", "Aromatase inhibitors to treat endometriosis", or 
• muscle related: "The muscle sparing effects of CLA + Omega-3" and a true classic "Muscle mass gained on injectable testosterone is lost, when injections are seized", 

... and a plethora of additional gems from the realms of health, exercise, nutrition & supplementation, I will call it a day for today and save the exercise and a couple of other exciting On Short Notice items for later next week.


References:

• Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA. Chronic psychosocial stress-induced impairment of hippocampal LTP: possible role of BDNF. Neurobiology of Disease 2006;22:453–62. 
• Alzoubi KH, Abdul-Razzak KK, Khabour OF, Al-Tuweiq GM, Alzubi MA, Alkadhi KA. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet. Behav Brain Res. 2013 Sep 20.
• ESMO. Press releases related to the ESMO 2013 Congress of the European Society for Medical Oncology in Vienna.
• Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992 Jan 15;267(3):397-9.
• de Mendonca A, Ribeiro JA. Endogenous adenosine modulates long-term potentiation in the hippocampus. Neuroscience 1994;62:385–90.
• Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gomez-Pinilla F. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience 2004;123:429–40.
• Smith AP, Christopher G, Sutherland D. Acute effects of caffeine on attention: a comparison of non-consumers and withdrawn consumers. J Psychopharmacol. 2013 Sep 19.
• Stadelmann B, Merino MC, Persson L, Svaerd SG. Arginine Consumption by the Intestinal Parasite Giardia intestinalis Reduces Proliferation of Intestinal Epithelial Cells. PLoS ONE. 2013; 7(9): e45325. 
• Tejman-Yarden N, Eckmann L. New approaches to the treatment of giardiasis. Curr Opin Infect Dis. 2011 Oct;24(5):451-6.