Showing posts with label Research. Show all posts
Showing posts with label Research. Show all posts
Monday, October 17, 2016

The Leangains Study (Oct 25th Update)

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After last month's scientific debacle, there's finally a good study on intermittent fasting and lifting. This one comes from Italy and also involves Grant Tinsley, but the change in scenery and colleagues must have done wonders for the man, because this is truly a huge bump in quality compared to his last publication.

I'll remind you that the previous study that involved intermittent fasting and lifting was marred by intolerable food reporting. This study contains none of its predecessors glaring methodological flaws.

Thankfully, Greg Nuckols have already provided a good summary of the results. Since I also agree with most of his points and perspective, I'll just link it here:

The “Leangains” Intermittent Fasting Study Is Finally Here.

...And that saves me a lot of time in the sense that I can just skip over the boring parts and get right to the meat of things. 


Results


1. In this study, intermittent fasting beats out a normal diet, assuming we count points based on the overall impact on body composition. Over 8 weeks, subjects doing intermittent fasting a la Leangains, lost a lot more fat - and even gained more muscle - than subjects on a normal diet. 

2. True, the muscle gain is non-significant - scientifically speaking - but for someone in the real world, adding 1.4 lbs of muscle over 8 weeks is quite a bit, especially if you're simultaneously losing fat. 

3. These guys were not beginners either. Starting out with an average bench of 107-110 kg at 84 kg or so, they were well into the intermediate stage. It's worth noting that the intermittent fasters upped their bench by 3.3 kg, while the other group barely gained anything (0.7 kg). Increasing your bench press while losing weight is a bitch, that's why it's worth noting. On the leg press, gains were about equal in both groups (8-10 kg).




One glaring flaw in this study is the lack of seal rows.

Conclusion


All in all, I don't think I could have asked for better results if I so funded this study myself. It would lie in my best self-interest to make a bigger deal about it all, but I can't really muster up the same excitement when a good study comes along. I prefer to criticise and point out flaws and this study doesn't have many. 

Food reporting is a limitation, as always, but since you won't ever see a study where this potential confounder doesn't exist, you might as well spare people the redundancy of pointing it out every single time - unless the protocol is truly inadequate (which it was in the previous study, for example). 

Here, there is no major discrepancy between the food intake reported and the actual results. A contributing factor to the much more precise numbers obtained here compared to the previous study, I think, lies in the fact that the subjects had a good amount of weight training experience (5 years) and thus were a lot more likely to know the ins and outs of what they were eating. If you've accumulated 5 years of weight training experience, it's inconceivable that you aren't aware of what you're eating - this is in stark contrast to the previous study by Tinsley et al, which featured beginners with no weight training experience, and presumably matching diet experience, which is to say none.

Consequently, these results are as legit as they can be in my eyes. It would be cool to see them replicated, of course, but until that happens, it's the best study* on intermittent fasting and lifting to date.

* Unless you're counting my own "studies" of course. I will publish another one soon, but there are no great surprises here, because gaining muscle while losing fat is just business as usual in my book. Unless you're at the advanced stage, you should be gaining muscle on a diet. I'm not talking pounds or inches, but you can and should see measurable progress on most of your lifts on a monthly basis, as long as the deficit isn't too steep or the training regimen too dumb. Come to think about it, that's actually a lot to ask for, so feel free to browse around this site to get a clue if you feel that you need one. 





Beginners and intermediates have it good. At the advanced stage, some muscle loss is inevitable without drugs. I miss the days were I could increase my lifts while simultaneously dropping weight.



Update (Oct 25th)


Greg Nuckols rightfully mentions that several anabolic hormones decreased in the TRF-group but speculated that the decrease might not be explainable by the caloric deficit alone, which is something I don't entirely agree with.

Subsequently, he brought up an interesting point in a private conversation.

Greg Nuckols: "I was thinking about the drop in testosterone in the IF group in that study. Since testosterone levels can fluctuate 25-50%+ over the course of a day, it may just be that daily IF shifts the diurnal rhythm of testosterone secretion. That seems like a more likely explanation to me than the VERY slight calorie deficit, since it generally takes a much larger deficit to have that sort of effect on testosterone levels. I wish they took several blood draws throughout the day to compare 24-hr AUC, because it's well-known that eating patterns can shift the diurnal rhythm of other hormones."

I told him it was a great point and that he should add it to his article. He replied that I could add it to mine if I want to, as he generally avoids talking about hormonal stuff, since it usually doesn't play that big of a role in the grand scheme of things (in the physiological range). I can't help but agree.



Thursday, June 28, 2012

Why Does Breakfast Make Me Hungry? (Major Update July 16th)

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“Why does breakfast make me hungry?” When someone asked me that question for the umpteenth time since my methods became popular, I finally decided to indulge in a deeper exploration of what the plausible mechanism might be. I thought I’d share my thoughts on that with you today.

Note: Major Update July 16th and July 17th. See "Closing Point: Addendum" and "Short addendum" at the end of the article, a few P.S's, and a complete list of references.

It’s a fairly lengthy article, but hopefully interesting enough to keep your attention, informative enough to teach you a few things, and decent enough to mark my return back into the love-hate-relationship I maintain with the Internet (…and its potpourri of good and bad, smart and dumb, facts and bullshit).




My heart sank when it seemed they had provided overwhelming evidence for the benefits of breakfast a few months ago. But I proved them wrong.



Why Does Breakfast Make Some People Hungry?


As mentioned, it wasn’t without grounds that the question piqued my curiosity beyond that which could be attributed to food selection. In questionnaires, clients would often note that eating in the morning made them ravenous before noon, and sometimes no more than an hour after a steady breakfast.

On Facebook, in emails, and in casual conversation, anecdotes to a similar effect kept popping up too frequently to be explained by mere coincidence. Or to be shrugged off with a half-assed answer, with the underlying assumption that everyone’s eating crap for breakfast.

These folks weren’t eating Cheerios rounded off with a peanut butter sandwhich and a large glass of orange juice – you know, the usual Average Joe breakfast that would make anyone hungry an hour later.

No, these guys had your typical fitcentric breakfast with the kinds of foods that most of us ate at one point or another – oatmeal, dairy, eggs, etc. Often, but certainly not that often since the increasing popularity of Paleo, a meal characterized by moderate to high amounts of carb and protein, relatively low on fat, and more often than not a decent chunk of fiber.

You can spend all day arguing about the healthiness of whole grains and dairy (just not here, thanks), but fact remains that these foods could not singlehandedly explain the fact that breakfast triggered hunger in some people.

Hell, just google “why does breakfast make me hungry”, “hungry after breakfast”, or “breakfast makes me hungry”, and you’ll see that forums are swamped by people with the same experiences.

I’ll add myself to the aforementioned crowd. Omitting breakfast may have been the single greatest improvement to my diet when I embarked on my intermittent fasting regimen back in ’06, adherence wise.

For me, like countless other Leangains practitioners, breakfast was a huge pain in the ass and skipping it made all the difference in the world. Compared to before, dieting became almost effortless.

Not to mention long-term maintenance. No more counting the hours ‘till noon, and feeling like I was on a diet, regardless of whether I was actually dieting, maintaining, or “bulking.”





My favorite "breakfast" these days is the all-you can-eat-beef-buffet at 6 PM or later.


For me and many others out there, skipping breakfast keeps hunger away far better than eating in the morning – paradoxically enough. This is of course very interesting to me, because it’s a damn strange thing. Why is it that some people are better off not eating anything at all in the morning? How can you be better off with zero calories than hundreds of calories under these specific conditions? It just doesn’t make sense.

So I set out trying to answer that question, and finally arrived at a satisfying hypothesis a mechanism behind that mysterious post-breakfast hunger surge that so many of us experience.

The original article ended up being 12000+ words long with a ridiculously pretentious academic tone, branching out in all kinds of directions on semi-related issues. Far too long for most people’s attention spans, and way too technical for most peoples level of understanding.

Yesterday I sat down and rewrote the whole thing, trying to convey it all in the same manner I’d use when explaining it to my girlfriend, bro, or invisible friend, to which I’ve retold this whole thing to numerous times now. That’s Berkhanese for “some things are simplified from my perspective, but it’s still complex enough for the lay man, and hopefully decent enough to satisfy the expert.” Enjoy.

* In regards to breakfast, I will be referring to breakfast in the traditional sense of the term throughout this article, i.e. eating upon arising. Not breakfast in the original sense of the meaning, i.e. as the first meal after an overnight fast.


Defining Post-Breakfast Hunger 


Trying to define post-breakfast hunger is an exercise in futility. It’s something you’ll instantly be able to relate to, because you have the same experience, or something that makes you wonder what the hell I’m talking about, because you simply don’t have that problem. I’m guessing most of my readers fall into the former category, so I won’t be spending much time on academic discourse in attempting to define the phenomenon beyond what I’ve already done. Simply put, some people get hungry, very hungry, and/or experience cravings of various magnitude shortly after eating breakfast in the morning.

In the scientific literature, researchers who specialize in research on appetite, hunger and addiction, make a distinction between the aforementioned terms (i.e. hunger, craving, etc), but since post-breakfast hunger has been described in subjective experiences from clients, forum posts, etc, and without any truly detailed inquiry from my side, I’m guessing most people refer to the same phenomena when they talk about post-breakfast hunger in terms of getting cravings, feeling hungry, feeling ravenous, and so forth. For me personally, the sensation can be described as hunger, in the sense most of you probably think of hunger.

Post-breakfast hunger sets in somewhere between morning and noon, usually 30 mins to 2 hours after breakfast, and doesn’t usually manifest in any symptoms beyond noticeable hunger. However, some people have mentioned that irritability and impaired ability to focus on tasks that require sustained amounts of concentration, co-occurs with post-breakfast hunger.

An important point is that the same meal will not trigger this early and/or pronounced sensation of hunger if consumed later in the day. Post-breakfast hunger cannot be explained by differences in food choice, but by certain individual factors, and their interaction with a time-of-day effect of feeding on hormonal profile and metabolism.




Cereal will make anyone hungry soon again, but an important point of this article is that post-breakfast hunger is independent of food choice (i.e. it cannot be attributed to the simple fact that people tend to eat different type of foods in the morning versus later in the day). By the way, the above is part of my post-workout meal, when I occasionally include a box of cereal. I might be having some beef, potatoes, and ice cream afterwards to celebrate the new deadlift PB I just scored. 600 lbs x 4 in case anyone's curious. Stay tuned for the video


A Primer on Cortisol


Cortisol is the main culprit behind for post-breakfast hunger, the up-until-now mysterious affliction that is the topic behind this article. Most of you probably associate cortisol with stress and muscle catabolism, and consequently with “bad” and “avoid.” This is partly correct, but mostly erroneous.

Since “partly correct” is to blame for many of the nonsensical diet myths out there, it’s useless. People claiming that eating six times a day will stoke your metabolism, and that fasting causes starvation mode, are “partly correct” – but mostly full of shit, as I explained in “Top Ten Fasting Myths Debunked.”

The context is often critical, and this is especially true in regards to cortisol - which is why I’m going to give you a very brief primer on this complex and multi-facetted hormone. There are almost as many definitions of stress as there are myths about cortisol, but in regards to the former, the one that appeals to me from a minimalist perspective is:

Stress can be defined as any challenge to homeostasis of an individuum that requires an adaptive response of that individuum.

- Newport & Nemeroff, 2002.

Cortisol is secreted in response to a stressor, in order to help you cope with the stressor efficiently, whether that stressor is a balls-to-walls-set of 20-rep squats, or a looming deadline for an article that needs to be finished. The role of cortisol during these challenges is to boost you, not cripple you, whether the stressor is physical (e.g. exercise, injury, cold) or psychological (e.g. a complex or cognitively demanding challenge) in nature (or both).

Thanks to increasing cortisol levels during training, we can push way past our non-stressed comfort level, and maintain an adequate rate of exertion for a longer period of time than what would have been possible otherwise, without being overtly distracted by pain, hunger and fatigue. Cortisol improves muscle and glucose metabolism, increases pain tolerance, diminishes fatigue and strengthens motivation.

By the way, does this answer those of you who have asked me about my thoughts on pre-workout cortisol blockers? No? OK, then all I can say is good luck with those squats, buddy..

Due to cortisol in response to a cognitive challenge, we can recall important facts faster and in greater detail than otherwise, maintain focus, stay alert and pull all-nighters in front of the computer if needed. Cortisol increases sensory perception, memory recall, and wakefulness.






Most of the above is covered in Robert Sapolsky’s excellent book Why Zebras Don't Get Ulcers, in which he also explains when and why cortisol becomes bad for us. Briefly, prolonged exposure to a stressor results in chronically elevated cortisol, which then does all sorts of bad things to us. There’s a time and place for cortisol. In this day and age, the line between work (stress) and leisure time (rest) is often blurred.

With constant self-imposed demands, never ending obligations, and endless opportunities to work (in the office, at home, etc), the stressors of modern society are of the psychological variety and they are always present if you allow them in.

In stark contrast, the stressors of the past were more often of the intermittent and physical variety. While they were probably more severe and often life threatening, there was a clear-cut line between the start and the end. And this explains the title of Sapolsky’s book, which I cannot recommend highly enough, and which I urge you to read if you want a more detailed explanation of stress and the workings of cortisol.

What Sapolsky doesn’t cover in great detail however, is the cortisol awakening response and the acute effects of cortisol on insulin secretion.



The Cortisol Awakening Response


Most people get the concept of exercise and work as stressors, “challenges to homeostasis”, which require an adaptive response (cortisol). But few people think of waking up from sleep and rising out of bed as a particularly stressful event. However, waking up from sleep is indeed a profound challenge to homeostasis, if you think of stress in those terms.

The transitioning between the passive sleeping state to the active wake state is – in a way – like a leisurely walk interrupted by an all-out-sprint. In endocrinology, there’s a special name for the events that transpire to wake you up in the morning: the cortisol awakening response (CAR), on which there exists a substantial amount of research.

Awakening stimulates ACTH secretion in the pituitary, which then stimulates cortisol secretion in the adrenal glands. The rapid increase and peak in cortisol level after awakening is termed the cortisol awakening response (CAR). Although it is thought that CAR is a distinct part of diurnal cortisol rhythm, CAR and diurnal cortisol rhythm actually represent two separate adrenocortical activities.

- Shin et al., 2011.


As the body prepares to start up for the day, cortisol gradually starts to rise in the second half of the night, almost resulting in a climax as you open your eyes. But as you waddle out of bed on the way to the shower, cortisol will continue to climb. It will reach a peak 30-45 minutes later – which is right around breakfast time.

We’ve now reached a key point in this hypothesis behind post-breakfast hunger, because the precise timing of the circadian cortisol peak (CAR) and breakfast consumption has some very interesting effects on insulin secretion.


The Cortisol Awakening Response and Insulin Secretion


So you’ve taken your shower, dressed for the day, and done whatever else you like to do in the morning that’s none of my business, and now you sit down to eat breakfast before work, school, or whatever else. I’m guessing it’s now some 30-45 minutes after you stepped out of bed if you’re like most people.

As you sit down to eat, or at some point right around that time, cortisol reaches the highest point of the day, which would be 20-30 nmol/l. That’s compared to 2-5 nmol/l between evening and midnight, which is the lowest point during the circadian cycle if you want some numbers. It might go higher later during the day depending on the magnitude of stress you’re exposed to, but that’s besides the point.

The early insulin response to a meal is higher in the morning than in the afternoon, and this fact can only partially be explained by a moderately increased secretion of incretins. Rapid non-genomic effects of higher cortisol levels in the morning might be, at least in part, responsible for this finding.
- Vila et al., 2011.


The point is that the circadian cortisol peak coincides with breakfast, and that this is the only point during the day that cortisol reaches high enough levels to exert an acute and pronounced effect on feeding-induced insulin secretion.

If that sounds vague for the endocrinology enthusiasts out there and those of you who are familiar with cortisol, allow me to provide you with a brief explanation in language you can appreciate it. What I mean here is that, at the CAR peak, cortisol climbs high enough to agonize glucocorticoid receptors. This changes the non-genomic interaction between cortisol and insulin action from being permissively restraining by the former, as seen at other times during the day due to mineralocorticoid binding dominance, to a non-genomic stimulating, or synergistic if you will, effect (Vila et al., 2010; Dallman et al., 1995)

If the last paragraph doesn’t make much sense to you, then you know why I had to rewrite the whole article and simplify it.

Short-term* exposure to cortisol powerfully augments insulin secretion and this is the key point here.

* In stark contrast, long-term exposure has the opposite effect.


Average Joe Eats Breakfast


So, what happens then, as you start eating? Bad things? No, not necessarily, depending on the other variables in this equation – more on that very soon.

Enter Average Joe, who is average as it gets, with all its implications. Meaning fat, poor insulin sensitivity, and out of shape, according to our standard, but average according to the standard for modern man used in the scientific literature.

Average Joe sits down to eat his breakfast, and due to the influence of cortisol, his pancreas responds with a rapid and – relative to other points during the day, all else equal – high burst of insulin. This forces blood glucose down faster to baseline than later in the day, which in this context is a desirable effect.

Although the feeding-induced insulin peak comes much faster and is much higher, due to the meal coinciding with the circadian cortisol peak, the net effect should be that average insulin secretion and blood glucose in the post-prandial period post-breakfast is lower than later in the day, under a low-cortisol fed condition. In a way, Average Joe’s sluggish pancreas might actually benefit from the augmented insulin response in the morning,

That’s Average Joe. But what about Fit Joe? This is when it gets interesting.


Insulin Sensitivity and Insulin Resistance: Brief Primer


Something has always struck me as very peculiar and far too common of an observation to be coincidental.

When I first started dieting way back in the day, I did just fine with on your run-of-the-mill high meal frequency diet, with your run-of-the-mill fitcentric oatmeal based breakfast. I started out pretty fat at around 225 lbs, and lost about 40 lbs give or take, on a fairly generic approach mostly.

Sure enough, I did tons of beginner mistakes, especially in the cardio department (overdoing it), and subsequently suffered for it. I had my setbacks, like everyone else, but I powered through them all. I wrote about this journey a few years ago, in case you care to read more about it. There’s a few photos from back in the day too, which does a decent job of showing my overall development throughout the years.

Anyway, it wasn’t until at a later stage, leanness wise, that breakfast really started becoming a problem. First of all, I always felt that it was an unnecessary caloric burden that interfered with dieting. I wasn’t that hungry in the morning, but more so in the evening.




I would never have been able to maintain this conditioning with breakfast.

Had I known better back then, I would have started skipping breakfast earlier, of course, but back then everyone was preaching the virtues of breakfast and you didn’t really dare to break all these golden rules of the fitness game.

(And you’d still be eating breakfast if I didn’t put my ass on the line to set you straight 5-6 years ago, or whenever you first read my stuff. Am I right or am I right?)

Second of all, it seemed like the post-breakfast hunger surge increased in amplitude and frequency for every damn ounce of body fat I lost beyond a certain point. At some point, it became overwhelming, and that’s when the wheel-spinning started, progress wise. Until I finally decided to do my own research, no longer swallowing down the bullshit fed to me by so-called fitness gurus and the Journal of Broscience. The rest is history.

Anyway, let me put my labcoat back on again, and explain to you how this fits in with everything else I’ve talked about so far. We’ve now reached the second key point in this hypothesis behind post-breakfast hunger. The first key point, as you might recall, was the CAR and its peak coinciding with breakfast.

The second key point is insulin sensitivity. What happens when an insulin sensitive person eats something? Briefly, rising blood glucose levels feeds back to the pancreas (i.e. tells it that insulin is needed), and the pancreas responds with insulin. In turn, insulin then shuttles glucose from the blood to places where its needed (e.g. liver and muscle), which lowers blood glucose and prevents it from accumulating in the blood.

High blood glucose levels for longer periods of time (as seen in untreated type 2 diabetes, insulin resistance or poor insulin sensitivity, etc) does all sorts of bad things to us, which is why we want to bring it back to a healthy baseline as soon as possible. This is why high insulin sensitivity is a good thing.

If you’re insulin sensitive, the pancreas responds fast, with a big burst of insulin, in response to glucose, and then tapers off when it’s no longer needed. A sharp peak of insulin, with a prompt decline. The net result is lower readings of post-prandial blood glucose and insulin levels.

In contrast, insulin resistance results in a sluggish response, with a small burst of insulin, and a slow decline. The net result is higher readings of post-prandial blood glucose and insulin.

Imagine a graph tracking insulin secretion in the post-prandial period, with time on the X-axis and insulin on the Y-axis. Now picture a peak-like pattern for an insulin sensitive person, and a hill-like pattern for an insulin resistant person – that’s how it would look.

An important point in the above scenario is that insulin reaches a higher max in the insulin sensitive example.


Insulin and Blood Glucose Regulation

Recall that cortisol augments insulin secretion. When you have high levels of cortisol (i.e. at the peak of the CAR) and eat something, insulin secretion is boosted. The pancreas responds faster and stronger.

But Fit Joe already boasts a really robust insulin response, because he is insulin sensitive. Now add the insulin boosting effect of CAR on top of that, and what do you get? In theory, a very strong and sharp insulin surge. And what is the consequence of that?

Put differently – just as an example – what is the consequence of injecting too much insulin relative to needs (i.e. glucose)? If you overdo it by a wide margin, you risk all the horrors of life threatening hypoglycemia, with the result being extreme hunger, confusion, coma, brain damage and death, in that order.

While the above presents a real danger for diabetics, it doesn’t for healthy individuals. We have evolved an extremely efficient regulatory system for preventing blood glucose from dropping too low, to levels where it can compromise bodily functions and cognition, and impair our chances for survival.

Indeed, blood glucose regulation is a very secure system, with redundant mechanisms able to increase glucose output to meet needs in case one part of the system fails. Glucagon, epinephrine (adrenaline), cortisol and growth hormone are different hormones that cooperate to fulfill the role of another in case it fails to do its job properly.

But this system has not evolved to deal with blood glucose that is just low enough to trigger hunger, without any serious side effects beyond that. In fact, low blood glucose as a hunger signal was the focus of one of the earliest theories on appetite regulation.


Why Does Breakfast Make Fit Joe Hungry?


In the “glucostatic theory”, Jean Mayer in the 1950’s proposed that low blood sugar served as the primary hunger-triggering signal that prompted us to feed (Mayer, 1953). Later studies has taught us that appetite regulation is way more complicated than that, but there is clearly a role for blood glucose in this equation.

Building on Mayer’s theory, Campfield has proposed a more complex and refined theory, in which he – briefly summarized – suggests that falling blood glucose levels might serve as a hunger signal (Campfield & Smith, 2003). This has been echoed elsewhere, in the sense that the speed of which blood glucose falls can serve as an alarm signal in a sense – while a prompt lowering of post-prandial blood glucose levels is desirable, too steep of a decline can be interpreted as danger, and trigger a hunger signal.

So when insulin sensitive Fit Joe eats breakfast right at the peak of his CAR, he gets a lot of insulin to go with that meal, with the result being a very speedy drop in blood glucose.

Now consider the meal itself. What does a typical fitcentric breakfast look like? Odds are that it’s higher on the protein and carb side of things, low on fat, and quite often includes a source of dairy or milk protein. Any one of these components further contributes to insulin secretion, independent of each other.

As a consequence of the above, hunger rears its ugly face shortly after the meal. Either as a result of blood glucose dipping slightly to low, or as a result of it dropping too fast within a narrow time-frame.


Putting It All Together


And that, my friends, was my abbreviated explanation for post-breakfast hunger. If you give it some thoughts, it fits right in with my personal experience, my observations, and the many anecdotes I’ve come across throughout the years.

Post-breakfast hunger is something that occurs more frequently, and more noticeably so, in fairly lean individuals. I’d estimate that it’s fairly common in the 12-14% range. As you close in on single digit body fat percentage, it becomes very common indeed - and a serious obstacle for many.

Gradually, as we get leaner, we become more insulin sensitive. Little by little, as insulin sensitivity goes up, we get hungrier faster and more annoyingly so after breakfast, until we start wondering why we’re starving a mere 1-2 hours after a decently sized meal.

In a sense, it’s funny that blood glucose regulation works better in the fasted state, relative to the aforementioned breakfast scenario. It’s understandable when you consider that in the fasted state, you have balance between input and output, which in this analogy would be glucose and insulin. Glucose input to the blood is low and is well maintained with a low level of insulin in an insulin sensitive person.

With breakfast, insulin output is disproportionate to the input (breakfast), due to cortisol. A mismatch that would otherwise not be present under different circumstances (i.e. the same meal eaten later in the day, with low cortisol, or by someone with lower insulin sensitivity).

All of this raises interesting questions regarding the role of the cortisol-insulin connection, or dare I say breakfast consumption, and adaptation (or absence thereof) in the role of human evolution and its consequences for modern man, with his modern meal patterns.

Very interesting indeed, when you consider the events that transpire on a metabolic and transcriptional level once you combine cortisol and insulin. Not to mention the role of cortisol in place preference conditioning, learning, and the fact that even though breakfast-first-thing-in-the-morning is an artificial habit, manufactured by one of the first and possibly largest giant of the food industry (The Kellogg’s Company), it certainly is a habit we learned very fast.

But that’s for another time. Or for another one smart enough to recognize the clues to something big that I just handed them. Assuming they give a shit.


Closing Point

As a closing point, I want to point out that there were a few things that I had to cut out, since this article is long enough as it is. I figure that I should mention them very briefly by stating that there is a high degree of individual variance in the CAR, and that this might affect insulin secretion as well (i.e. a high CAR may have a larger influence on the feeding-induced insulin surge).

Furthermore, there is obviously a big role of food and macronutrient choice in all of this, but the role played may not be one that people typically expect. For example, some protein sources – or should I say, amino acids - are not only highly insulinogenic, but also trigger cortisol secretion. Incidentally, it tends to be the ones often consumed with breakfast.

Perhaps I need not mention that protein triggers a cortisol response, depending on the context (Benedict et al., 2005; Gibson et al., 1999; Slag et al., 1981). Oh, you thought that it was the other way around – that protein lowers cortisol? Well, then you learned another little something new today.

Maybe I’ll talk more about this another day, because there were many related and interesting semi-related parts to the topic of this article that I had skimp on, or cut out. Hopefully, time and motivation permits. I don’t trust myself to give any guarantees for the latter, unfortunately. But for the time and being, I’m back.


Closing Point: Addendum (July 16th)


An important point, which I should have accentuated and expanded upon, is the high degree of individual variability present among the hormonal factors within the equation that might predispose people to post-breakfast hunger. I wrote:

Post-breakfast hunger cannot be explained by differences in food choice, but by certain individual factors, and their interaction with a time-of-day effect of feeding on hormonal profile and metabolism.

More appropriately, my hypothesis states that it's the magnitude of these certain individual factors. Obviously, there are plenty of people who eat breakfast and do just fine. Some of whom probably need to eat breakfast in order to function optimally, and a portion of those that tolerate fasting poorly.

It should also go without saying that leanness and high insulin sensitivity does not inevitably bring about post-breakfast hunger, since there are tons of lean people who do not experience it. High insulin sensitivity are merely one of the factors that I believe plays a key role - and although leanness correlates strongly with insulin sensitivity*, there is a good degree of individual variance at any fixed level of body fat percentage.

*Specifically, visceral adipose tissue - not subcutaneous - predicts insulin sensitivity. However, low body fat means relatively low amounts of visceral fat, if you got to that point with a healthy and wholesome diet (i.e. with a decent fatty acid composition).

What are the other key factors - or variables - that determines the response? On top of insulin sensitivity, there is a very high degree of intra-individual variability when it comes to the CAR. I wrote:

 ...There is a high degree of individual variance in the CAR, and that this might affect insulin secretion as well (i.e. a high CAR may have a larger influence on the feeding-induced insulin surge).

My original article included a much longer section on CAR, in which I mentioned a few factors that should predict a high CAR, which in turn would predispose one to post-breakfast hunger. However, there are so many discrepancies and inconsistent findings on the subject within the scientific literature, that I choose to not delve into in such great detail. It would have been too speculative for my taste. This is also the current consensus on the topic in the scientific literature:

...The CAR literature is so inconsistent with regard to associations with trait psychosocial and health measures. 
...It is likely that different trait factors may be associated with different aspects of the regulatory puzzle, making it very difficult to tease apart.

- Clow et al., 2010.


Insulin sensitivity is easy to predict (body fat percentage), CAR is not - but I know there's some companies that provide kits for measuring salivary cortisol at home, and those are fairly reliable, I think. Anyone who's really interested in knowing their CAR might consider going that route.

There is one fairly consistent finding when it comes to the CAR; it's higher among women (Fries et al., 2009; Clow et al., 2010. Coincidentally, quite a few women have reported to me that they experience post-breakfast hunger - but  the role of CAR in all of this is anyone's guess, as is the relative contribution of each of these factors. After all, all of this is a hypothesis of mine, based on empirical research, endocrinology, and scientific theory.

The third important factor, which unquestionably plays a very important role in this, is food and meal composition, where you would have rapidly absorbing high-glycemic and highly insulinogenic meals (think toast, or cereal and milk) on one extreme end and low-glycemic low-insulinogenic meals on the other. The standard fitcentric breakfast that made me so ravenous for all those years falls somewhere in between. I usually had oatmeal, cottage cheese, whole grain bread, protein shakes, etc, in various combinations.

Someone in comments asked what you should eat if you happen to break the fast shortly after awakening. First of all, you need to ask yourself if you're hungry after whatever it is you're eating right now. No? Then there's obviously no need to start fixing and changing because you read a bunch of yang-yang on Leangains.com. All this theory and speculation, however fancy and educated that speculation happens to be, is always secondary to real life results.

That said, assuming you do seem to be experiencing post-breakfast hunger after breaking the fast in the morning, I would definitely recommend cutting down on carbs in favor for fat and a solid protein source. Solid meaning chewable, meaning meat.

Aside from a change in macrocomposition, I would also consider some common sense fixes depending on needs. Cutting down on caloric density and increasing volume (e.g. by replacing some food items with veggies, ideally crucificerious veggies) is almost always a good idea.


Short addendum, July 17th


I added a quote by Vila (2011) to the article. Nothing new, just a little something in support of what I wrote about the CAR and insulin secretion:



The early insulin response to a meal is higher in the morning than in the afternoon, and this fact can only partially be explained by a moderately increased secretion of incretins. Rapid non-genomic effects of higher cortisol levels in the morning might be, at least in part, responsible for this finding.


Lastly, I should mention that the original article included a few more mechanisms by which breakfast may trigger hunger in some. However, I felt that the article was already too long, and would get way too technical and confusing for most people if I veered off into several directions. Furthermore, the blood glucose mechanism for post-breakfast hunger seemed like the most likely candidate. That said, it's interesting to note that Vila (2011) also demonstrated a direct effect of concurrent glucose and cortisol administration on PYY, a key hormone involved in appetite regulation:

The modulation of PYY plasma levels suggests the possible non-genomic effects of glucocorticoids on appetite-regulatory hormones.

However, in that study they used intravenous glucose, which makes the relevance of these results to real life settings questionable.


P.S.


In case anyone’s wondering where I’ve been, especially those of you used to reading my frequently updated nonsense on Twitter and Facebook, only to see me disappear from the face of the Earth for the last two months.

An “I’ve been busy” type of response won’t do this time around. That would be a disservice to my true and loyal fans, many of who do a terrific job of directing others to the enlightenment they come to discover here. Not to mention an insult to those I’ve had to break important obligations to – you know who you are, and you will hear from me soon.

To make a long story short, an unfortunate chain of events forced me to take time off from everything. Literally everything on the online side of things, which is more or less like saying time off from work.

In either case, I’m back now. I understand that my work here is not yet done, and I shall finish what I started. Or die trying.

A special thanks to those of you who emailed me and wrote about the role I played in your life, development, career choice, inquired about my health, and reminded me of the important role I have come to play for some people. The few times I checked my inbox, it seems that there was yet another email from one of you, and I appreciated every single one of them. Here’s to hoping that I’ll get back to you one day.




Thanks for the support.



P.S. That deadlift video I talked about earlier in the article: deadlifting 600 lbs x 4 on Leangains intermittent fasting. Stay tuned for more videos. You can subscribe to my YouTube channel to be sure you don't miss 'em.

P.S.S. By the way, while you're over on YouTube, you might also want to check out the Hodge Twins talking about Leangains and intermittent fasting. Nothing new if you've read my stuff, but these guys are pretty hilarious. I can certainly appreciate them spreading the good word about intermittent fasting and killing off all these diet myths the way I've done here for years.

Lastly, I thought I'd mention that I'm once again quite active on Twitter and The Leangains Facebook Page. Feel free to follow me and join in the conversation.



Reference List 


Benedict, C., Hallschmid, M., Scheibner, J., Niemeyer, D., Schultes, B., Merl, V., Fehm, H. L., et al. (2005). Gut protein uptake and mechanisms of meal-induced cortisol release. The Journal of clinical endocrinology and metabolism, 90(3), 1692–1696. doi:10.1210/jc.2004-1792

Campfield, L. A., & Smith, F. J. (2003). Blood glucose dynamics and control of meal initiation: a pattern detection and recognition theory. Physiological Reviews, 83(1), 25–58. doi:10.1152/physrev.00019.2002

Clow, A., et al., The cortisol awakening response: More than a measure of HPA axis function. Neurosci. Biobehav. Rev. (2010), doi:10.1016/j.neubiorev.2009.12.011

Dallman MF, Akana SF, Strack AM, Hanson ES, Sebastian RJ. The neural network that regulates energy balance is responsive to gluco- corticoids and insulin and also regulates HPA axis responsivity at a site proximal to CRF neurons. Stress: Basic Mechanisms Clin Implicat 1995; 771: 730±742.

Fries, E., Dettenborn, L., Kirschbaum, C., 2009. The cortisol awakening response (CAR): facts and future directions. Int. J. Psychophysiol. 72, 67–73.

Gibson, E. L., Checkley, S., Papadopoulos, A., Poon, L., Daley, S., & Wardle, J. (1999). Increased salivary cortisol reliably induced by a protein-rich midday meal. Psychosomatic Medicine, 61(2), 214–224.

MAYER, J. (1953). Glucostatic mechanism of regulation of food intake. The New England journal of medicine, 249(1), 13–16. doi:10.1056/NEJM195307022490104

Newport, D.J. and Nemeroff, C.B. (2002) Stress. In: (Ed. in chief), Encyclopedia of the Human Brain, Vol. 4. Elsevier, pp. 449-462.

Shin, I.-Y., Ahn, R.-S., Chun, S.-I., Lee, Y.-J., Kim, M.-S., Lee, C.-K., & Sung, S. (2011). Cortisol Awakening Response and Nighttime Salivary Cortisol Levels in Healthy Working Korean Subjects. Yonsei Medical Journal, 52(3), 435. doi:10.3349/ymj.2011.52.3.435

Slag, M. F., Ahmad, M., Gannon, M. C., & Nuttall, F. Q. (1981). Meal stimulation of cortisol secretion: a protein induced effect. Metabolism, 30(11), 1104–1108.

Therrien, F., Drapeau, V., Lupien, S. J., Beaulieu, S., Doré, J., Tremblay, A., & Richard, D. (2008). Awakening cortisol response in relation to psychosocial profiles and eating behaviors. Physiology & Behavior, 93(1-2), 282–288. doi:10.1016/j.physbeh.2007.08.019

Vila, G., Krebs, M., Riedl, M., Baumgartner-Parzer, S. M., Clodi, M., Maier, C., Pacini, G., et al. (2010). Acute effects of hydrocortisone on the metabolic response to a glucose load: increase in the first-phase insulin secretion. European journal of endocrinology / European Federation of Endocrine Societies, 163(2), 225–231. doi:10.1530/EJE-10-0282

Sunday, May 15, 2011

Omega-3 Fatty Acids for Muscle Growth: Promising Potential

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Can omega-3 fatty acids boost muscle growth? Well, let's just say that I'm very excited to report about the results from two new studies that sought to answer that question. The results? I will tell you all about in this article.

I don't have time to keep up with the going-on's in the forums, and I don't know if the weight training community has taken note of these studies yet. I hope they will, because these findings are - by far - the most interesting thing I have come across in a long time.

First, I'd like to do a brief review on omega-3 (n-3) fats and how they work. And since we're on the topic, let's also do a quick no-BS review on what they are actually good for.

(This article is somewhat long and I wrote the n-3 health and fat loss review since I thought I'd give myself a refresher course on the topic. I don't talk about the new studies mentioned in the introduction until the latter 2/3 of this review. If you don't give a damn about the effects of n-3 intake on health and fat loss, feel free to skip the first part of the article and go to "Omega-3 Fatty Acids and Leucine Resistance.").


Omega-3 Fatty Acids and Your Cell Membranes 


Since most people's eyes glaze over when someone starts talking cell biology, imagine your cell as an avocado. Picture the avocado with myriads of pins buried in it.





This is your cell. The pins are membrane proteins, some of which are nutrient transporters for glucose, amino acids, and so forth. The dark skin and the edible green flesh is the plasma membrane, which consists of two thin layers made of fatty acids. N-3 supplementation has the potential of altering this part of the cell. Generally speaking, plasma membranes with a higher % EPA and DHA enrichment are healthier; they have the potential of modulating signals in between the white pins/plasma proteins and the avocado core. The "avocado core" is the cell interior, which react in response to signals from the cell exterior.

Pins: are called integral membrane proteins."Integral membrane protein" is a catch-all term for proteins that shuttle nutrients or signals to the cell itself, or the avocado core if you will. Included in these are glucose transporter type 4 (GLUT4) and amino acid transporters, for example. Pretend these pins had the ability to move up and down through the skin and flesh of the avocado. The word for this is translocation, or protein targeting depending on how fancy you want to get.

Skin and edible part: this is the cell membrane, also called the lipid bilayer, or the phospolipid bilayer. A large part of these layers consists of fatty acids and their structure is highly dependent on the fat composition of your diet. This is where n-3 fatty acids exert their effect; by their incorporation into lipid bilayers, n-3 acids can modulate signals between the pins to the cell itself. In particular, it is the omega-3 series members docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) that facilitates these processes. When I talk about "n-3 supplementation/intake", it is often in specific reference to EPA and DHA, and not ALA.

Avocado core: cell interior, where transcription (i.e. muscle protein synthesis) takes place based on feedback from the cell exterior and pins.

Obviously, this is a vastly simplified version of the cell, but I've found the avocado analogy somewhat helpful in dumbing down the cell and its workings.

The fact that n-3 is incorporated into the plasma membrane of all your cells - be it brain cells, muscle cells, and so forth - explains how these fatty acid can have so diverse effects on human physiology and health. Let's take a look at what they do.


Omega-3 Fatty Acids: Effects on Health 

Controlled studies have clearly established the positive influence of n-3 intake on cardiovascular health. The role of n-3 as a modulator of inflammation is also well recognized and the fact that omega-3 fats down-regulate genes involved in chronic inflammation makes it likely that n-3 intake can reduce the risk of atherosclerosis.

Dietary epidemiology have also shown a link between n-3 and mentally debilitating disorders such as Alzheimer's and depression. Furthermore, n-3 may affect the development of many facets tied to brain function, such as intelligence, vision and mood. For example, infants who do not get enough n-3 from their mothers during pregnancy might be at risk for developing vision and nerve problems.

Other epidemiological trials have suggested a protective effect of n-3 on cancer and tumour growth; in particular, prostate, breast and colon cancer.


Omega-3 Fatty Acids: Effects on Body Composition


Freedom from disease and a sharper mind is all good and well, but what what about biomakers related to body composition? Results from studies on n-3 intake and insulin sensitivity are mixed. In summary, people with poor insulin sensitivity (obese) usually see an improvement with n-3, while lean subjects see no or only modest improvements. Keep in mind that "lean" in a clinical context is 15-20% body fat for males and around 25% body fat for females.

What about n-3 and fat loss? I have not seen a single study which shows that adding n-3 alone will generate fat loss in lean subjects, but overweight/obese subjects sometimes see a small - but clinically significant - effect of n-3 supplementation. There are some exceptions to this, i.e. some studies do show a clinically significant fat loss effect in lean subjects, but the sample size and diet design is extremely poor - such as in this widely cited study by Couet, et al.

In combination with exercise, n-3 has been shown to accelerate fat loss in a few studies, but once again the effect is limited to obese subjects.

However, I'll note that it's a profound flaw to look at the effects of n-3 and fat loss in lean subjects and conclude that there is no benefit. Why? Because the effect of n-3 on fat metabolism and adipose tissue is not acute. It takes approximately 4-6 weeks of n-3 supplementation to change the fatty acid composition of the cell membrane, and controlled interventions on n-3 supplementation and fat loss have never been longer than 12 weeks in duration. In the case of Brilla, et al., who looked at fat loss in lean subjects, it was 10 weeks.

The implication of this is that the study, or studies, on n-3 intake and fat loss in lean subjects might be too short in duration to show a clinically significant effect. The n-3 supplements simply didn't "kick in", if you will, until the passing of several weeks. Furthermore, any greater weight loss, as a percentage of body weight, is always harder to spot in lean subjects in comparison to obese subjects, unless you have a large sample size (Brilla, et al., used only 8 subjects in the fish oil + exercise group). 

In conclusion, there simply aren't any good trials on n-3 supplementation and their role in fat loss yet. Oh sure, there are studies looking at fish intake and so forth, but I'm talking controlled interventions without a bunch of variables (fish protein, outpatient trials with poor control, etc.).


Omega-3 Fatty Acids: What We Know So Far


In summary of a vast area of research on n-3 and health, the scientific evidence is indisputable for a positive effect on cardiovascular health and chronic inflammation. These are things you can measure and track, and find a clinically significant effect on within 12 weeks; i.e. improved blood lipids and lower TNF-a (tumor necrosis factor-alpha, an inflammatory marker).

Furthermore, research is also highly suggestive of a positive effect of n-3 on brain function and several disease processes, ranging from cancer to the metabolic syndrome. Keep in mind that it's impossible to provide hard data on these aspects of human health. You can't put people in a lab, give some of them some fish oil pills, and look at who got Alzheimer's or cancer 8 weeks later.

Instead you look at things like fish consumption in thousands of individuals, sometimes over several years, and compare the disease trends relative to fish or seafood consumption. When you do this, you often see positive associations between n-3 saturation of the phospholipid membranes and greater health.

This positive association seems independent of other factors that affect health; meaning that, in an imaginary scenario where we compare two people with the exact same stats, such as body fat percentage and lifestyle habits, with the exception of n-3 intake or fish intake, the person with a higher n-3 intake will be healthier.

A striking example of this, is the fact that fat Eskimos have significantly lower rates of Diabetes Type 2 compared to equally fat Americans (3.3% vs 7.7%). Not a completely valid comparison, due to the inherent problems of dietary epidemiology, but it illustrates the point I'm trying to make, as these health trends are seen across the board in many different populations.

It's safe to say that n-3 is good for us. The Western diet contains too little omega-3 relative to omega-6 fats for optimal health, and our low n-3 intake might certainly be an independent factor influencing the disease trend amongst Westerners compared to other populations with high n-3 intake (e.g. Eskimos, etc.).

Now finally, what about those new studies on n-3 and muscle protein synthesis? 



I saw that Michael Rennie, a hot shot in protein research, was among the authors so I very was excited to read it. The results were very interesting.

This study was carried out on older adults, aged 65 and above. The elderly population is a high-priority group in protein research and there are probably more studies looking at optimizing protein intake for the elderly than there are studies looking at how to make young guys or athletes ripped and swole. How come?

As we age, we encounter a phenomenon called "anabolic resistance". This is a catch-all term for an overall crappier response to weight training and dietary protein.

A fancier sounding word for anabolic resistance is "sarcopenia". But this is just a made-up word that researchers use to get funding for studies. Sarcopenia sounds better than anabolic resistance, I guess.

In terms of dietary protein, "leucine resistance" describes the phenomenon in regards to how the response to feeding is altered. The amino acid leucine is the primary amino acid responsible for triggering muscle protein synthesis. Elderly folks need higher concentrations of leucine to get the same response as young folks. Various feeding strategies that overcomes this problem include:

1. "Protein pulse feeding", which means eating infrequent meals higher in protein and leucine (in contrast to frequent meals). There is a threshold level of leucine needed to consume in each sitting to maximize muscle protein synthesis and this threshold is raised with aging. Larger meals cause leucine to hit that threshold, which triggers muscle protein synthesis. Leucine resistance is similar to insulin resistance in the sense that more leucine and insulin is required to trigger the same response.

2. Supplementing with whey protein or amino acids (EAA, BCAA or leucine). There are many practical advantages of this strategy, i.e. the hassle-free process of drinking whey protein or taking free-form amino acids.

3. Simply eating enough high-quality protein in each meal. This might seem like a no-brainer for us, but with aging comes a loss of appetite. When was the last time you saw a 70-year chew down a big steak? Achieving a high leucine concentration in the blood is mainly about eating enough protein. In the case of elderly folks, faster protein sources - such as well-chewed meat or whey protein - is preferable. This is first and foremost due to absorption kinetics; i.e. leucine concentrations will rise fast and the threshold will be easily reached with 20-30 g protein.  

So that's that. As a side-note, I detest faux diet gurus who cite studies on protein supplements for the elderly to sell leucine supplements. It makes zero sense for a young guy on a high-protein diet.

(Context is crucial. The supplement industry flourishes because no one cares to read or question their claims. Here's some advice: take a second or two to actually read and reflect on studies that are cited in order to validate a claim ("Leucine increases muscle protein synthesis by 537%!"). If it sounds too good to be true, it is too good to be true.)

Anyway, so this one study I mentioned earlier showed that 8 weeks of n-3 supplementation lead to a significant increase in muscle protein synthesis in response to feeding. The same experiment was repeated with younger subjects and the results were released a few weeks ago. 

Below, I'll do a detailed review of the newly released second study and talk a about the results.


Omega-3 Fatty Acids and Muscle Protein Synthesis


Here's the study I'm going to talk about now:

"Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperaminoacidemia-hyperinsulinemia in healthy young and middle aged men and women."


Introduction

...we have recently demonstrated that LCn-3PUFA supplementation (4 g·d-1 of Lovaza®) in older adults (≥65 y) significantly increased the rate of muscle protein synthesis during hyperinsulinemia-hyperaminoacidemia, most likely because of greater activation of the mTOR-p70s6k signalling pathway


This is in reference to the first study on a group of elderly subjects that I mentioned earlier. There have also been other studies, prior to that one, which suggested that n-3 supplementation spared muscle mass when added to a tube feeding formula during cancer treatment

...feed enriched in menhaden oil, a fish oil rich in EPA and DHA, doubled the insulinstimulated
non-oxidative whole-body disposal of amino acids (a marker of increased whole-body
protein synthesis) and increased the activation of the mTOR-p70s6k signalling pathway in
muscle of young and still growing steers...

Furthermore, animal studies have also hinted at an anabolic effect of n-3 enriched feedings. Based on the aforementioned studies, the researchers speculate that the mechanism by which n-3 can increase muscle growth is via activation of the mTOR-p70s6k signalling pathway in response to feeding. The exact mechanism is unknown.

The mTOR-p70s6k signalling pathway is commonly used as a marker for muscle anabolism and protein synthesis, and by measuring the phospholyration rate (activity) of p70s6k, you can get an idea of the anabolic rate in the muscle.

For example, in the study I reviewed in "Fasted Training Boosts Muscle Growth", they found that p70s6k increased more after fasted training. Though they did not measure muscle protein synthesis, it is reasonable to assume that MPS increased in concert with p70s6k. (Keep in mind that this does not necessarily mean that fasted training is superior to fed-state training. Measurements were made during a fairly narrow time-period. Read the article for my thoughts on the topic).

The purpose of the present study therefore was to determine the effect of LCn-3PUFA supplementation for 8 weeks on indices of muscle protein anabolism in human muscle in young/middle aged adults.

Examining the activity of the mTOR-p70s6k signalling pathway and muscle protein synthesis (MPS) in response to n-3 supplementation was the purpose of this study.


Method

Nine healthy individuals (5 men and 4 women; age: 39.7 ± 1.7 y; BMI 25.9 ± 1.0 kg/m2; body fat determined by dual X-ray absorptiometry: 25 ± 3 %; means ± SEM) participated in this study.

Note that "young" in a clinical context is not necessarily young as we tend to think of it. The average participant was almost 40-years old. Clinical standards are somewhat different than those used in everyday speech. For example, "lean" usually means 15-20% body fat, "high protein" tends to be used liberally and for almost any diet regimen with >0.8 g protein/kg (FDA standard), and a 30 g protein meal is considered a "high protein meal", and so forth. 

After obtaining baseline values for anabolic signalling pathways (mTOR-p70s6k) and muscle protein synthesis, the participants were given 4 g n-3/day for 8 weeks.

8 weeks of dietary supplementation with 4 g·d-1 of Lovaza® (GlaxoSmithKline, Research Triangle Park, North Carolina, USA) containing 1.86 and 1.50 g·d-1, respectively of the ethylesters of eicosapentaenoic acid [EPA; 20:5n-3] and docosahexaenoic acid [DHA; 22:6n-3]).


It should be noted that the addition of 4 g n-3/day was the only intervention made in this study. Participants were instructed to not change their usual diet and activity pattern for these 8 weeks.


Important: Note that the n-3 dose totalled 1.86 g EPA and 1.5 g DHA, which is a lot higher than what you will get from your average fish oil supplement. 

Looking at the n-3 supplement I'm using, the 3 g/day I've been taking only gives me a total of 0.54 g EPA and 0.36 g DHA (and 0.15 g ALA). That's really bad. Take a look at yours. A good n-3 brand should contain no more than 50% filler, but this one I'm taking is 65% filler ( in stark contrast to Lovaza, pharma-grade n-3, with only 15% filler). I haven't noticed this until now and will be more stringent with my n-3 intake. More information on good n-3 supplements at the end of the article. Let's carry on with the study review now.


Infusion Protocol


First, a brief description of the procedure on the day when the results were obtained. I'd normally skip this tedious section in my study reviews, but there are some crucial details here that will become important later on  in the article.

All participants ate a standardized meal at 8 PM on the day prior. A 6-8 AM the following morning,  they arrived at the laboratory, where they were infused with tracers for four hours.

Without going into technical detail, tracer infusion is a technique for tracking the passage of nutrients, i.e. amino acids and glucose, through the body. This is always done prior to infusion of amino acids; e.g. you can see how much of the amino acids that ended up in muscle if you infuse tracers, followed by amino acids, and lastly take a muscle biopsy (and that's exactly what they did here).

After fours hours of tracer infusion, participants were then infused with a mixture of amino acids and insulin for  three hours. The amino acid dose was determined to 105 mg/kg lean mass, which with these participants in mind amounts to ~5-6 g amino acids/hour.

A one-time "priming dose" of 35 mg/kg lean mass, or ~2 g amino acids, was given prior to the 3-hour infusion; this is often done in order to stabilize blood concentrations prior to steady-state infusions of this kind.

Important: Adding the aforementioned numbers together, 17-20 g amino acids were infused over a 3-hour period. This might seem like a fairly trivial amount, but the the amino acid mixture, Travasol 10%, was of a very high quality. 20 g of it yields 1.4 g leucine, 3.8 g BCAA (leucine, isoleucine, valine) or 13 g EAA (BCAA + 5 essential amino acids). I'll discuss the implications of this later on.

During the infusion protocol, blood samples were taken with regular intervals. Three muscle tissue samples were obtained, one prior to the amino acid infusion, and two towards the end. Based on these values, the researchers were able to obtain relevant data points for comparison against the ones obtained 8 weeks prior (the same procedure was performed before the n-3 intervention).





I just treated myself to an n-3-intervention. I don't eat a lot of fish, but when I do it's usually salmon with cottage cheese. I find that the salty salmon fits nicely with the cool creamy cottage cheese. Perhaps you would like it too.



Results


After these 8 weeks of 4 g n-3/day, EPA and DHA enrichment of the cell membranes had increased dramatically. This confirmed that compliance was good and that the n-3 supplementation was effective. For those interested in some raw numbers:

EPA: 0.66% vs 2.57%

DHA: 1.91% vs 4.05% 

Values are expressed as percentage of the total fatty acid composition of the phospholid membrane. It's interesting to note that n-3's displaced n-6 and monounsaturated fatty acids (MUFA) in the membrane. These were significantly lower (~50% vs 46% and ~8% vs 6%) after 8 weeks. Saturated fatty acid composition remained stable at 36-38% (increase by ~2%, not statistically significant).

What did this result in? Let's start with some health markers:

As expected, the concentration of inflammatory markers in plasma was low in this healthy
cohort of subjects and there were no differences (all P ≥ 0.33) before and after LCn-3PUFA
supplementation in the plasma concentrations of CRP (0.61 [0.39, 1.03] vs. 0.73 [0.17, 1.23]
mg·l-1, respectively), TNF-α (0.30 ± 0.02 vs. 0.31 ± 0.02 pg·ml-1, respectively) and IL-6 (1.49 [1.05, 3.25] vs. 1.34 [0.98, 1.47] pg·ml-1, respectively).
LCn-3PUFA supplementation had no effect on whole-body glucose kinetics.

These results are not all that surprising. Recall what I said earlier about n-3 supplementation and metabolic status. Overweight and obese people often see meaningful improvements in these markers with n-3 supplementation, but in these normal weight subjects, n-3 supplementation did not do much in terms of reducing inflammation or altering glucose tolerance.

Glucose rate of disappearance, which shows glucose tolerance but can also be seen as a rough marker for insulin sensitivity, was unchanged. Then again, 8 weeks might also have been too short of a time to see any significant improvements in this area.

The basal muscle protein FSR (calculated by using the muscle free phenylalanine enrichment
as the precursor enrichment) was not different before and after LCn-3PUFA supplementation...

Basal muscle protein FSR (fractional protein synthesis rate) denotes muscle protein synthesis (MPS) in the fasted state. I will use MPS instead of FSR to avoid confusion, and it's basically the same thing.

Why "fractional synthesis rate" you ask? Muscle protein is made out of three fractions; 2/3 myofibrillar protein and 1/3 sarcoplasmic and mithocondrial protein (around 15% of total muscle volume each).

Without derailing the topic too much, I'll note that an increase in MPS usually mean that synthesis in all these fractions increase equally in proportion to their volume. Weight training tends to increase synthesis of myofibrillar protein slightly more, relatively speaking, while endurance training increases mithocondrial protein synthesis specifically.

Anyway, MPS in the fasted state was unchanged, which is to be expected. Meaningful changes in MPS are always seen in response to feeding. For example, weight training boosts MPS in response to amino acids in the blood (via pre-workout and/or post-workout meals), but does not alter basal FSR, assuming concentrations of amino acids in the blood are not elevated.

Basal MPS is only altered in some disease states (the severe kind, burn injury, sepsis, etc.) and - of some modest interest - with anabolic steroids. Steroids exert their effect by boosting basal MPS much more than MPS in response to feeding, which I find somewhat interesting. It also appears that sleep deprivation has the potential of lowering basal MPS.

Once again, I find myself ranting like a mad man and going off-topic, so let's proceed with the study review now.

Insulin and amino acid infusion led to a marked increase in the muscle protein FSR (P < 0.001) and the anabolic response (i.e., the increase from basal values) was ~50% greater after LCn-3PUFA supplementation (0.042 ± 0.005 %·h-1 vs. 0.027 ± 0.005 %·h-1; P = 0.01). Consequently, the muscle protein FSR during insulin and amino acid infusion was significantly greater (P < 0.01) after than before LCn-3PUFA supplementation.

Important: Now this is the interesting part. In response to the amino acid infusion, MPS was dramatically increased after 8 weeks of n-3 supplementation. Some raw numbers below.

MPS before n-3 (FSR % / hr)

Basal: 0.037
Amino acids: 0.062 (+68%)

MPS after n-3 (FSR % / hr)

Basal: 0.042
Amino acids: 0.083 (+98%)

These numbers were estimated from a graph when they were not reported in the text. As you can see, the increase in MPS was ~50% greater post-n-3 supplementation (+ 68% vs +98%) in response to the 20-gram amino acid infusion. I'm pointing this out specifically to differentiate it from a +50% absolute increase (i.e. +118%), which it could easily be mistaken for from the quote.

A 98% absolute increase in MPS in response to such a modest amount of amino acids is unheard of. Let me give you some data points to provide some perspective on MPS in response to feeding and training:

Typical MPS increase in response to 20 g amino acids: +50-70%. See MPS values pre-n-3 supplementation.  Bohe, et al., used a similar dose and saw an increase of +57%. Similar values (+51%) were obtained after consumption of ~20 g beef protein.

Maximal MPS noted after high-protein meals or amino acid intake: +88-100%. Bohe, et al., for example, saw an increase of 88% in response to ~50 g amino acids infused over 3 hours. Other studies, such as this one, showed a ~100% maximal increase in response to 10 g EAA (~25 g mixed amino acids).

Maximal MPS noted after weight training and high-protein meals or amino acid intake: +170-200%. These values denote the highest absolute increase in MPS seen within 36 hours following weight training. Some data points are available in this text for those interested.

Important: The key point here is that MPS increased much more in response to feeding after n-3 supplementation, and that this increase is on par with the maximal increase seen after intakes of much higher doses of amino acids. The 20 g amino acids gave a boost in MPS that was comparable with a boost that would normally only been seen after intakes of 25-50 g protein.

...mTORSer2448 and p70s6kThr389 concentrations increased by ~50%

The activity (phospholyration rate) of anabolic signalling pathways increased similarly as MPS.

Very, very interesting. Now let's see what the researchers said about these results in the discussion that followed.



Discussion



These data compliment and extend the results we recently obtained in older adults and demonstrate that LCn-3PUFA supplementation not only alleviates the muscle protein anabolic resistance associated with old age but can actually boost the anabolic response to nutritional stimuli in healthy muscle from young and middle-aged adults.

I should note that the results from the prior study on older adults were even more impressive, relatively speaking. The increase in MPS in response to amino acids were ~120% greater after n-3 supplementation (vs ~50% greater for this sample.).

...the effect was probably mediated via one or more alternative pathway(s), which have yet to be determined (but may include e.g., Rheb or vps34).

Rheb is a cell membrane protein and vps34 can roughly be described as a nutrient sensor. Both of these are involved in activation of the anabolic cascade that follows amino acid sensing outside the cell.

Furthermore, weight training also activates these anabolic triggers, which has the effect of increasing MPS more than normally, i.e. the cell takes up more amino acids from the same amino acid dose if Rheb/vps34 expression is increased from weight training. The speculation above revolves around whether n-3 supplementation has the potential to alter Rheb/vps34 expression.

Considering the observed changes in skeletal muscle phospholipid composition, it is also possible that LCn-3PUFA supplementation modulated key substrates along the anabolic signalling cascades by affecting membrane lipid composition and/or fluidity.

Another potential mechanism, albeit very poorly and unprofessionally formulated in my opinion. Amino acids do not simply diffuse and move through the cell membrane; "fluidity" should not affect uptake of amino acids in that sense.

However, n-3 enrichment of the membrane has the potential of affecting nutrient transport via modulation of the integral plasma proteins. Go back and read about the avocado if you don't follow. Look at the white pins. Some of them are amino acid transporters.

I believe one potential mechanism for the increase in MPS post-n-3-supplementation is altered amino acid transporter expression. Amino acid transporters  are in contact with the cell membrane, and can translocate to the membrane surface in response to amino acids in the blood plasma. It's possible that an n-3 enriched membrane sensitizes, increases, or somehow alters transporters such as System-L, which is primarily responsible for uptake of leucine.

(Interesting side-note: paradoxically, transporters also increase during amino acid deprivation; i.e. starvation - presumably for transporting amino acids out of the cell interior, or to allow rapid resynthesis of muscle protein once amino acids become available again.).

A second hypothesis of mine, albeit somewhat remote and vague, is that increased blood flow supplementation might have something to with it. I do not have enough insight into hemodynamics to provide an informed opinion, but perhaps n-3 supplementation affected blood flow in such a way that hyperaminoacidemia occurred faster.

However, this would only alter the temporal pattern of MPS, and not the absolute rate. That might be a desirable effect for the elderly population, but not necessarily great for younger folks.

It is unlikely that the beneficial effect of LCn-3PUFA on muscle protein synthesis was related to their antiinflammatory properties because our subjects were young and healthy and we did not detect any treatment-induced changes in inflammatory cytokine concentrations in plasma – most likely because the concentrations were very low to begin with.

One hypothesis was that MPS could be negatively affected by inflammation. Since these subjects were healthy, there was no meaningful relationship between MPS and these markers. However, low-grade inflammation is often present in metabolically challenged individuals and there are studies which suggest that MPS is impaired in these cases.

Lowering inflammation, i.e. via n-3 supplementation, might be beneficial for restoring MPS in inflammatory states, such as obesity or illness. I don't think any human studies have confirmed this as far as obesity goes, e.g. lowered inflammation with n-3 and seen increases in MPS, but it's a theory.

Lowered inflammation with n-3-enriched tube feeding was posed as a possible mechanism for greater muscle retention in an earlier study on n-3 and cancer (a highly inflammatory disease state.).

...we infused amino acids and insulin at rates close to those used to achieve the half-maximal amino acid induced increase in muscle protein synthesis...

This is in reference to the choice of the amino acid dose to achieve a 50% increase in MPS, which is typical of that dose, based the response seen in other studies. This was done to avoid the "ceiling effect".

The "ceiling effect" is also referred to as the "muscle full" phenomenon and denotes the point where MPS falls back to basal values. In the Average Joe, this ceiling is reached in the third hour in response to an infusion rate of 10 g amino acids/hour, which amounts to about 2 g leucine total. After that, MPS becomes refractionary. A logical response. Had MPS not fallen back to basal values, we'd all look like Ronnie Coleman times ten.

Simply put, there is a limit to how much amino acids the muscles require for maintaining normal function, and they will not take up more aminos than what is required for muscle homeostasis.

We made our measurements of muscle protein synthesis during a 3-h infusion of insulin, amino acids and glucose because the rate of muscle protein synthesis rises quickly (within <30 min) in response to increased amino acid availability but then returns to basal values after ~2.5-3.0 h.

Important: This is a crucial aspect of this study that might make the results less than fully applicable. In fact, I think the researchers have made a critical error here.

It seems that they choose the amino acid infusion rate (105 mg/kg/hour) based on the assumption that MPS becomes refractionary in the third hour, regardless of the infusion rate, which is not the case at all. Bohe et al., showed that the refractionary response occurred in response to an infusion rate of 162 mg/kg/hour. Meaning that they had no grounds for limiting themselves to a 3-h infusion.

But why is this important then? Because the short time-period vastly limits the conclusion that can ultimately be drawn from the results. For example, recall that MPS increased by 68% in response to amino acids pre-n-3 supplementation. After n-3-supplementation, the same dose caused a 98% increase.

However, nothing can be said about the temporal pattern during these 3 hours. What if MPS would have become refractionary in the 4th hour after the second experiment, whilst remaining elevated after the first experiment?

We can only say that the absolute increase in MPS was greater within the narrow time-period of the study protocol. However, recall what I said about the "muscle full" scenario. It might be that n-3-supplementation simply increases the rapidity of amino acid uptake for any given dose; e.g. by altering amino acid transporter expression, which would then result in greater MPS within a shorter time-period.

However, once "muscle full" is achieved (after the absorption of ~2 g leucine), it should theoretically become refractionary. In contrast, sans n-3-supplementation the absorption would be slower, resulting in lower MPS that becomes refractionary at a later stage.

The key question here, which in my opinion remains unanswered, is whether n-3-supplementation has the potential of increasing the absolute capacity for MPS in response to a fixed amount of amino acids; similar to what weight training does. There is some indication that this might be the case:

There was a trend for an increase in the RNA-to-DNA ratio, the cell capacity for protein synthesis, but the difference did not reach statistical significance (P = 0.13).

Important: If this is the case, n-3-intake would be one of the most important dietary components for body composition. I am not much for hyperbole, but this is a very exciting study - even if it's limited by its short infusion protocol.

Therefore, we assume that the increase in the anabolic response after LCn-3PUFA supplementation was due to an increase in the magnitude of the anabolic response. However, we cannot rule out the possibility that the effect was due to an increase in the duration of the anabolic effect of nutritional stimuli.

Yes, as I noted before, they cannot say much about the temporal pattern. I'm disappointed in Rennie for his lack of critical reflection around the short infusion protocol, which was chosen based on erroneous assumptions in regards to the refractionary state. Then again, even the best make mistakes.

This study could have been vastly improved if they had chosen the infusion rate (162 mg/kg/hr) required to reach a "muscle full" scenario within three hours and used a 4-hr infusion protocol. They would then compare MPS pre- vs post-n-3-supplementation. Had they then seen that MPS was higher post-n-3-supplementation, their conclusion...

In summary, we have shown that LCn-3PUFA supplementation in healthy 25 - 45 y old individuals increases mTOR signalling and the anabolic response of muscle protein synthesis to hyperinsulinemia-hyperaminoacidemia, which resulted in increased muscle cell size (protein-to- DNA ratio) and protein concentration.

...would have been a lot more valid.

The specific mechanism(s) by which LCn-3PUFA act on the muscle protein synthesis process remain mostly unknown.

And the mechanism by which omega-3 fatty acids affects muscle protein synthesis remains shrouded in mystery.





Here's the reason I don't eat much fish. I have nothing against fish, but there is no protein source I would rather choose over roast beef. Perhaps one day we might also uncover the anabolic potential of roast beef. But until then, I'll make sure to supplement my fat intake with EPA and DHA. I suggest you do so too, if you don't eat fatty fish on a regular basis.



Final Thoughts and Recommendations


Even though the conclusions that can be drawn based on this study are somewhat limited due to the infusion protocol, I find the results promising enough to make changes to my own diet. Consequently, I will personally increase my daily n-3 intake to achieve a similar EPA/DHA saturation of the plasma membranes. I will also make this a mandatory part of the diet templates for my clients.

This means that I recommend an intake of 2 g EPA and 1.5 g DHA per day, and it means that you should pay closer attention to the EPA/DHA amounts you get from your fish oil supplement.

As I mentioned earlier, a 1-gram fish oil capsule does not yield high amounts of EPA and DHA, as most of it is filler. The 3 grams of fish oil I have been taking up until now yields a trivial amount of 0.18 EPA/0.12 DHA per capsule. I'd need about 10 of those capsules to reach the amounts required.

Which fish oil supplements contain satisfactory amounts of EPA/DHA? I don't feel like chewing on 10 of those capsules, so I will explore other alternatives. I've looked around for a bit and have found these high-EPA/DHA-brands:

NutraSea Original Liquid.

Cost of daily dose required (3 tsp/15 ml liquid) to reach 2 g EPA/1.5 g DHA:  $0.99. (500 mL bottle.)

Ultra Omega-3

Cost of daily dose required (4 softgels) to reach 2 g EPA/1.5 g DHA: $0.44. (180 g softgels.)

Swedish readers: "Omega-3 Forte" from Pharbio seems to be the best choice. You will need 6 softgels to meet the EPA/DHA-requirements. Daily cost: 9.4 SEK. You can order Omega-3 Forte from Svenskt Kosttillskott

The aforementioned brands are good and affordable alternatives for meeting the daily EPA/DHA requirements. Softgels are always cheaper, but some people can't stand fish oil capsules, in which case a liquid solution might be a more attractive alternative. So that's that.

If you eat fatty fish on a regular basis, a stringent EPA/DHA-protocol might not be required. You can check the EPA and DHA content of fish here. Example: your average store-bought salmon yields 0.7 g EPA and 1.4 g DHA per 100 g. Do the calculations based on your average weekly intake. Keep in mind that the amounts can vary depending on the breeding of the fish, e.g. farm-raised vs wild salmon.

Read more about supplements you might actually find useful in this article.

---

Where have you been? 

Some readers might wonder why there haven't been any updates for more than a month. I blame this partly on my new laptop crashing. I bought it for myself as a Christmas present, but it came with an unfortunate defect in the HDD which caused my laptop to crash.

The process of sending it back and forth to repairs took about three weeks, during which I had to used my old laptop (which is ridiculously slow). When I write, I always work with several tabs open, since I need to do frequent fact-checking for the studies I cite, and so forth. I couldn't stand doing that on my sluggish old laptop. My work and motivation suffered.

Once I received my new laptop in return again, I had fallen out of the groove of writing and just got lazy and complacent. But I'm back on track now, it seems. Hopefully, you won't have to wait another 5 weeks for the next update.

I hope you found today's article interesting. I apologize for the ranting, the technical detail, and the length of the study review. I think the results are truly interesting, and perhaps revolutionary as far as supplements goes. I was eager to give you the full scoop without dumbing it down too much.

If you enjoyed the article, or any other article on my site for that matter, perhaps you might consider a donation in show of support of my writings and the time I put into them.

That's all for today, folks.




My name is Martin Berkhan and I work as a nutritional consultant, magazine writer and personal trainer.

Welcome to the Internet's leading resource on intermittent fasting and all things related.


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