First, some background. Polyunsaturated fatty acids (PUFA) come mostly from omega-6 and omega-3 sources. Omega-6 and omega-3 are precursors to eicosanoids, a large and poorly understood class of signaling molecules that play a role in basically everything. Eicosanoids are either omega-6-derived or omega-3-derived. Omega-6 and omega-3 compete for the enzymes that convert PUFA into eicosanoids. Therefore, the ratio of omega-6 to omega-3 in tissues (related to the ratio in the diet) determines the ratio of omega-6-derived eicosanoids to omega-3-derived eicosanoids.
Omega-6 eicosanoids are very potent and play a central role in inflammation. They aren't "bad", in fact they're essential, but an excess of them is probably not good. Omega-3 eicosanoids are generally less potent, less inflammatory, and tend to participate in long-term repair processes. So in sum, the ratio of omega-6 to omega-3 in the diet will determine the potency and quality of eicosanoid signaling, which will determine an animal's susceptibility to inflammation-mediated disorders.
One of the key enzymes in the pathway from PUFA to eicosanoids (specifically, a subset of them called prostanoids) is cyclooxygenase (COX). COX-1 is expressed all the time and serves a "housekeeping" function, while COX-2 is induced by cellular stressors and contributes to the the formation of inflammatory eicosanoids. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen inhibit COX enzymes, which is why they are effective against inflammatory problems like pain and fever. They are also used as a preventive measure against cardiovascular disease. Basically, they reduce the excessive inflammatory signaling promoted by a diet with a poor omega-6:3 balance. You wouldn't need to inhibit COX if it were producing the proper balance of eicosanoids to begin with.
Dr. Kuang-Chung Shih's group at the Department of Internal Medicine in Taipei placed rats on five different diets:
- A control diet, eating normal low-fat rat chow.
- A "high-fat diet", in which 45% of calories came from a combination of industrial lard and soybean oil, and 17% of calories came from sucrose*.
- A "high-fat diet" (same as above), plus the COX-2 inhibitor celecoxib (Celebrex).
- A "high-fat diet" (same as above), plus the COX-2 inhibitor mesulid.
- An energy-restricted "high-fat diet".
Rats in group 2 not only gained weight, they also experienced increased fasting glucose, leptin, insulin, triglycerides, blood pressure and a massive decline in insulin sensitivity (seven-fold relative to group 1). Rats in groups 3 and 4 gained weight, but saw much less of a deterioration in insulin and leptin sensitivity, and blood pressure. Group 2 also developed fatty liver, which was attenuated in groups 3 and 4. If you're interested, group 5 (energy restricted high-fat) was similar to groups 3 and 4 on pretty much everything, including insulin sensitivity.
So there you have it folks: direct evidence that insulin resistance, leptin resistance, high blood pressure and fatty liver are mediated by excessive inflammatory eicosanoid signaling. I wrote about something similar before when I reviewed a paper showing that fish oil reverses many of the consequences of a high-vegetable oil, high-sugar diet in rats. I also reviewed two papers showing that in pigs and rats, a high omega-6:3 ratio promotes inflammation (mediated by COX-2) and lipid peroxidation in the heart. Are you going to quench the fire by taking drugs, or by reducing your intake of omega-6 and ensuring an adequate intake of omega-3?
*Of course, they didn't mention the sucrose in the methods section. I had to go digging around for the diet's composition. This is typical of papers on "high-fat diets". They load them up with sugar, and blame everything on the fat.
**Rats gain fat mass when fed a high-fat diet (even if it's not loaded with sugar). But humans don't necessarily gain weight on a high-fat diet (i.e. low-carb weight loss diet). What's the difference? Low-carbohydrate diet trials indicate that humans spontaneously reduce their caloric intake when eating low carbohydrate, high-fat food.
24 comments:
Stephan:
Interesting article, here's the diet for anyone who's interested:
http://www.researchdiets.com/pdf/Data%20Sheets/D12451.pdf
Once again, the terrible nature of the laboratory rat diet makes interpretation of the results difficult. That industrial lard is almost certainly hydrogenated. We already know that if you hydrogenate vitamin K1, bad things happen. What happens if you hydrogenate retinol (A) or cholecalciferol (D3) found in animal fats? There's no research on this topic, even though looking at their chemical structure it's clearly possible. Similarly how was the soy oil processed?
I will say that the calorie restricted rats did very well, although there's a distinct lack of quantitative information what 'calorie restricted' meant. Still, score another one for intermittent fasting... maybe.
Also, I love the line in the discussion, "Obesity is a principle causative factor in the development of insulin resistance. " Isn't it the other way around?
everybody loves omega-3's except my body. O-3's *gives* me migraines that last for days. doesn't matter what form (pill,tuna, salmon, swordfish) it is nothing but pain
Ah interesting, oddly I'd never made the connection before, but presumably then consuming excessive amounts of o-3 relative to o-6 is undesirable insofar that it would inhibit the body's inflammatory response when it needed it? This ties into the 'lots of fish oil' discussion in the last thread of comments.
(Of course this is presumably less of a problem in our culture where we're more likely to suffer chronic inflammation that serious wounding or potentially deadly infection.)
Anyway is interesting for me especially since after cutting out my nuts/seeds I'm on around 4g o-6 per day, and getting a hugely skewed o-3/0-6 ration would be easy with my newly acquired fish oil. I'll stick with my 1:1-1:2 though following this...
Excellent find Stephan.
Whilst from drawing together the treads it would be expected that blocking COX2 would have this type of effect this is the first trial I have seen that confirms it categorically.
This is a trial in 2008 reporting curcumin had a similar effect. Curcumin is a COX blocker and antiinflammatory, which I found as the result of seeing a mention in a newspaper yesterday.
http://endo.endojournals.org/cgi/content/abstract/en.2008-0262v1
"We therefore conclude that orally ingested curcumin reverses many of the inflammatory and metabolic derangements associated with obesity and improves glycemic control in mouse models of type 2 diabetes. "
And here is another one taking a slight different tack but arriving in the same place.
http://jn.nutrition.org/cgi/content/abstract/139/5/919?etoc
nice to read about your profile..few people blog these days for commom interest ..max are doing for some kinda revenue generation ..or adsense..your..blog is clean and informative ..keep the good work on..
Cheers.
High Omega-6 Diet Lowers Omega-3 Status, but Low Omega-6 Diet Preserves
Nice to see others are making similar points. Research paper this is based on here
Dietary linoleic acid has no effect on arachidonic acid, but increases n-6 eicosadienoic acid, and lowers dihomo-γ-linolenic and eicosapentaenoic acid in plasma of adult men
interesting stuff as usual. good old nutrition diets...I'm glad you were actually able to find the dietary composition without having to dig ten papers deep!
i was wondering if you knew if there were any differences in leptin secretion form adipose tissue in response to diets with different fat composition(saturated, unsat, etc...) in either rats/mice or humans fed ad libitum who ARE leptin sensitive? so there is still normal leptin and insulin signalling going on
Nice article, thanks!
Country mouse: are you sure it's the omega-3s that are causing your migraines? It sounds like amines could also be the culprit: fish develops amines quicker than most other meats. You have to eat it very very fresh (like within 24 hours of catching it) in order to avoid the amine problem. If you also have trouble with bananas, aged beef, or expensive parmesan cheese, it's almost certainly the amines.
Ghost: I get a similar problem with fish oil causing moderate migraines, generally when the amount is more than a few grams a day. Both refined fish oil and flax seed oil produce a similar effect, so it is probably the omega-3 fatty acids, not the amines.
Curiously, sunflower seed oil is far worse for me; both roasted seeds and the refined oil do it. It is a trace component, since the same major fatty acids in other foods don't cause a problem.
Apologies to Stephan: If I've hijacked your comment thread, please delete.
Daniel: sunflower seeds are a reliable migraine trigger for me-- I had assumed it was because they are usually rancid when you purchase them in a store? But I don't know, and whether it is rancidity or trace elements, I would love to find out.
Oddly, amines, fish, and fish oil don't bother me at all.
Robert,
Yeah, and hydrogenating the lard will also preferentially remove any omega-3 in it. I also noticed that they didn't describe how they treated the caloric restriction group. That was really sloppy of them.
Dave,
I agree, going too far in the opposite direction probably isn't good either. Modern Inuit tend to bleed excessively, probably because they can't effectively form pro-clotting eicosanoids. On the other hand, they rarely have heart attacks.
Robert,
Curcumin is interesting. All these plant compounds that were thought to have beneficial effects from being antioxidants are turning out to basically be drugs. Resveratrol is another one. The antioxidant effect is somewhere between nonexistent and irrelevant in the body. It's no wonder the body gets rid of polyphenols ASAP; it doesn't want them hijacking control of its enzymes and signaling pathways.
Ted,
Nice link. I see that first study was by Sheila Innis. She's done some really good work. One of the diet groups got 4% LA, which is the magic number I'll be talking about in later posts.
Theoddbod,
If I recall correctly, leptin sensitivity improves and fat mass decreases as the n-6:3 ratio decreases in rodents. At least in some studies. I don't know about the effects of saturated fat. I think it may lower insulin sensitivity in rodents, relative to monounsaturated. But PUFA composition is the dominant force.
Theoddbod,
I meant saturated fat may lower leptin sensitivity in rodents.
So, Stephan, would you say it's safe to assume that a low omega-6 intake would alleviate the need for omega-3 supplementation?
For example, if one were to eat butter or grass-fed lard as a primary fat source, do you suppose that something like fish oil would be unnecessary -- possibly even harmful as some folks have suggested?
Though the Inuit rarely have heart attacks, the whole excessive bleeding thing seems to be a sign of imbalance in the body to me. High intake of omega-3 PUFAs may be working against them. It's also damn cold where they live -- can that affect blood clotting times?
"But humans don't gain weight on a high-fat diet (i.e. low-carb diet); to the contrary. What's the difference?"
Maybe the fact that they are rats and we are humans. Two completely different species. Would you do nutrition studies on lions to gather information about an optimal diet for rabbits? So why are we analysing the results of studies on rats for the optimal dietary application on humans? Make any sense?
Rats tend to do very poorly on high-fat diets of any sort, and much better on low fat because rodents have evolved on all sorts of 'food' that contained very little fat. Humans on the other hand evolved on a high animal fat diet, like lions. This is evolution 101 yet we are still applying the results of a different species to ourselves. Perhaps I am missing something here.
Stephan, very nice post. Great explanation about eicosanoids, btw!
>>> All these plant compounds that were thought to have beneficial effects from being antioxidants are turning out to basically be drugs. Resveratrol is another one. The antioxidant effect is somewhere between nonexistent and irrelevant in the body.<<<
Stephan, by the broadest definition, a drug can be considered anything that changes the chemistry of a person's body, or expresses genes. Vitamins all do this. Resveratrol, too. This doesn't make it a bad thing.
I've noticed that just about everyone in the paleo blogger community has certain blind spots to areas that could improve their health. Clearly, supplementing is among your blind spots. Especially, non-mineral, non-vitamin supplements.
BTW, I totally agree that there's no evidence that polyphenols have a meaningful antioxidant effect in humans, but that's not the reason to take them. Curcumin, for example, has well studied anti-inflammatory benefits. Resveratrol is perhaps the most potent anti-cancer "drug" known to humans. Punicalagins from pomegranate are proven in humans to reverse arterial plaque. And many many more.
I've been on a hardcore self-taught practitioner in health for 10+ years, and have helped myself, numerous friends, and my 70+ yr-old parents all completely eliminate heart disease (plaque) and overcome cancer (father had prostate cancer 8 yrs ago, as well as a heart attack), using nutrition and supplements. It's almost child's play if people follow the right program.
I ate horribly up until about 37 yrs old, but at 48, my most recent heart scan and arterial imaging tests (Nov. 2008) showed zero sign of plaque, and all of my health markers (I measure over 100) are stunningly healthy, including hormone levels (which I also supplement--hgh, testosterone, etc.--all matching that of a 25-yr-old). Currently 9% bodyfat, and most people guess my age in the mid-30's.
Polyphenols and supplements overall (especially advanced ones, like glycation blockers, nootropics, etc.) play a big role in longevity, which is the prime focus of my ongoing interest and study. (I'm a Director of the Immortality Institute--imminst.org.)
Longevity should be the highest level goal of everyone interested in health, and the buck doesn't stop with paleo eating. Not by a long shot.
Ryan,
I don't think omega-3 supplementation is necessary by any means. It's just a way to bring your eicosanoids back into line if you're eating an excess of omega-6. I watch my omega-6 intake pretty closely, but even I have an imbalance due to whole grains, nuts and occasional restaurant food. So I cover it with small doses of cod liver oil (1/3 tsp per day). If you're super strict about your fat sources, I don't see any need for supplemental omega-3. There is a suggestion from animal studies that omega-3 intake isn't as relevant at low omega-6.
I agree that it's probably possible to overdo omega-3, especially from fish oil. It potently suppresses eicosanoid signaling, which may be good if you have an excess, but can probably be overdone.
Jocelyn,
I agree that you have to be very cautious when interpreting studies on animals that are adapted to a different diet. Especially monkey studies, those are the worst because people assume that they will react the same since we're closely related. But the monkeys we use are typically herbivores or frugivores.
Scott,
Thanks for your comment. I remain skeptical about the role of polyphenols in human health. There is a big difference between vitamins- essential substances- and polyphenols, which are completely dispensable to normal growth and reproduction. I think it's notable that the body rids itself of polyphenols ASAP by degradation in the liver. And it prevents the majority of them from crossing into the bloodstream in the first place. The Women's Health Initiative and MRFIT weakened the idea that vegetables and fruit prevent chronic disease.
I agree that some specific polyphenols are anti-inflammatory (and other things like inducing nitric oxide synthase), and have shown a great deal of promise in rodent studies. But again, they are acting basically as drugs by blocking inflammatory signaling. If you don't have excessive inflammation to begin with, you don't need to block it. You might as well be taking baby aspirin.
Resveratrol has not been shown to prevent cancer in humans. I suspect part of the reason polyphenols may be effective in rodents is they are hormetic stimuli; they trigger mild cellular stress responses kind of like exercise. When you have an animal in an extreme low-stress environment like a mouse in a lab cage, any hormetic stimulus will extend survival. That may be why so many things are effective at preventing disease and extending life of lab rodents. Even CR doesn't work on mice that lived part of their lives in the wild, maybe their hormesis is already maxed out.
I think it's notable that many healthy cultures have diets low in polyphenols. You could say that their goals are different than yours, i.e. you are after maximum lifespan, but something tells me that avoiding chronic disease is closely related to extending lifespan. Have you read the study showing that blood antioxidant capacity increases dramatically on a low-polyphenol diet? It's not consistent with some other studies on the subject, but I point it out simply to say that it's complicated and the effects of polyphenols are poorly understood. I can dig that ref up if you want to see it.
I feel that supplementing large amounts of polyphenols is outside of the human ecological niche and its long-term effects on overall health are unproven. I will keep an open mind but I'm not going to be the first one to gamble.
I have no doubt that you are healthy and young-looking for your age. But what leads you to believe that's due to your supplement regimen? Something tells me you also eat well and stay in shape. I'll believe the results when I see people doing this kind of regimen pushing past the current maximum human lifespan.
Hi Stephan,
I've been looking up CR recently, and hadn't seen any mention of wild mice not responding to CR when moved to a lab. I'd assume there are few if any additional studies examining this? Do you have easy access to how the study was performed? Many studies have failed when initiating adult onset shock CR in mice(30-40% CR I believe), and have often resulted in a shortened maximum lifespan, but in '82 the first case of AACR success happened because of :
1. slow CR initiation, not shock
2. 20% protein+, as opposed to the bare minimum, and proper vitamin/mineral intake
It makes me wonder about the Okinawan centenarians, as supposedly their CR ended around the 1960s, one theory being that their results from only 40 years or so of CR, half their lifetime, can produce substantial results in humans.
But I'd love to see that rat study if you have the time!
Stephan,
Your last few posts have been very eye-openeing for me. While Scott has you on the subject of supplements, I was wondering your view of supplemental A (whether from natural cod liver oil or gel-cap). I've been very conflicted since I have a fair amount of carotenes in my diet from vegetables. I don't want to reproduce the famous A/beta carotene study in myself. Although the findings of that study relate mainly to smokers, apparently the A/carotene combo increases the risk of cancer in ferrets not exposed to smoke. I feel more bullish on A since reading Chris Masterjohn's articles (and since I take plenty of D), but am wondering if one should limit dietary beta carotene if taking decent amounts of retinol. For a reference point, I am getting about 20,000 IU of both A and D per week. Thoughts?
Ryan J,
here's the study abstract.
Dan,
In my opinion, there's no need to supplement vitamin A if you eat butter, eggs and sometimes liver. Weston Price did observe that the healthy cultures he studied had a very high intake of vitamin A relative to the diet of his time. But the diet of his time was exceptionally poor except for the well-off, so the amounts that these cultures were eating may not be much more than the modern American gets. I don't see how a Polynesian islander would get a ton of vitamin A.
Don't worry about your carotene intake, that's not going to give you excess vitamin A.
20,000 IU of A and D per week from all sources is pretty modest so I certainly wouldn't be concerned about toxicity. Unless you get a lot of sunlight, in which case you may want to take less D.
Ryan.
“For example, if one were to eat butter or grass-fed lard as a primary fat source, do you suppose that something like fish oil would be unnecessary -- possibly even harmful as some folks have suggested?”
Omega three is an essential part of the structure of the brain, and is central to many functions within the body. Whilst our hunter gatherer ancestors may have been able to maintain their brains on a wide mixed diet, which probably included high-level sources of Omega three like brain, I do not think that that principle can be extended to our modern limited diets, even if the animals are grass fed. Wild animals would have had access to much wider grazing, and that is without the wider nutrient base of the hunter gatherer diet.
There are also many factors in the that diet that block the conversion of the plant-based fats to the longer fats. It is also very difficult to avoid Omega six if you eat any processed foods at all.
Alcohol removes DHA from the brain. I ancestors would have had very limited access to alcohol.
Generally our diets are nowhere near as nutrient dense as those of our ancestors.
All in all there are lots of reasons why it makes sense to ensure an adequate supply of long chain Omega Threes. When taken on balance the benefits far outweigh any risks.
“Though the Inuit rarely have heart attacks, the whole excessive bleeding thing seems to be a sign of imbalance in the body to me. High intake of omega-3 PUFAs may be working against them. It's also damn cold where they live -- can that affect blood clotting times?”
The results I have read on modern Inuit and bleeding times are a mixed, and while bleeding times are longer, they cannot be compared to those of the traditional Inuit. Every diet has risks and advantages particular to the diet.
Jocelyn
Is this trial not looking primarily at mechanisms which from all I have read are accepted as being largely common to rats and humans, rather than simply looking at outcomes such as obesity and fatty liver disease. The paper is arguing that certain pathways which can be blocked using Cox blockers are implicated in obesity, insulin control, and fatty liver disease. In turn Cox blockers are simply blocking the downstream effect of Omega six. The results in this paper are part of a huge jigsaw looking at a variety of mechanisms and had to be viewed in that light. Looked at in that perspective I think the paper is extremely important. There are a large number of reasons why Omega six should be implicated in obesity, and this trial provides more evidence that links to other papers on the subject that that is indeed the case.
Author Omega Six The Devils Fat
www.omegasixthedevilsfat
Omega-6 seems to be a big problem in the proinflammatory states when COX-2 is activated. But what activates COX-2; what causes inflammation in the first place? Fructose?
Robert wrote about curcumin which has anti-inflammatory activity. Curcumin is also an AMPK activator:
http://www.ncbi.nlm.nih.gov/pubmed/19020741
Just like green tea, omega-3 fatty acids, red wine polyphenols etc. Some statins act same way too. Quite interesting I think.
By the way fructose seems to increase intestinal translocation of proinflammatory endotoxins:
http://www.ncbi.nlm.nih.gov/pubmed/18395289
I was really oversupplementing with omega-3 and I cut myself when cooking and it bled really badly. Ick.
Now I don't monitor by grams, but by ratio. It's more important.
From the Queen of Fats by Susan Allport
"But by 1988 rates of heart disease in Eskimo and Danish populations were very similar; by 2003, there was no difference between the two groups. Yet the Eskimos in Igdlorssuit still consume large quantities of seal and fish, more seafood than any Western population. The explanation for the change in heart diseases that they now consume large amounts of other fats that compete with the fats in fish and seal.
A second population that is very revealing is that of Enugu Nigeria, an inland town where little fish is consumed. In the 1960s, Holman had a postdoctoral student from Nigeria in his lab; and in the 1980s, long after this student had returned to Africa, he sent Holman blood samples from 38 of his compatriots. Using his gas-liquid chromatograph to examine the fatty acids profiles of these healthy Nigerians from the town of Enugu, Holman found that their omega-3 content has higher than in any other population he had studied—about twice as a high as his Minnesota controls. These Nigerians didn’t eat very much fish, but they did eat a lot of greens and no high omega-6 vegetable oils. The major source of their dietary fat is fresh palm oil, which is high in saturated fats; and saturated fats, as Holman knew, are poor competitors of omega-3’s. "
Westie,
My feeling is that a lot of things activate inflammatory signaling: exercise, sunburns, high blood sugar, possibly wheat, excessive n-6, nutrient deficiencies, etc. Inflammatory stimuli are a part of life, but the question is, how does your body react to them? Will it go overboard with a strong and extended inflammatory response due to excess omega-6 HUFA, or will it respond appropriately to the problem due to balanced HUFA?
Thanks for the endotoxin paper, that's very interesting.
Melissa,
Thanks for the information.
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