Adiponectin supplementation: Body fat loss

Adiponectin is a hormone exclusively secreted by body fat. This hormone has been recently gaining attention from researchers because of some of its functions. Two important ones are the regulation of glucose and fat metabolism.

Elevated levels of adiponectin are associated with increased insulin sensitivity, and increased fat catabolism (i.e., fat burning). And these associations appear to be causal. That is, adiponectin levels do not seem to be only markers, but causes of increased insulin sensitivity and fat catabolism.

In other words, an increase in circulating adiponectin seems to lead to increased insulin sensitivity and increased fat catabolism. Insulin sensitivity is the opposite of insulin resistance. The latter is a precursor to diabetes type 2, and is associated with elevated fasting and postprandial (i.e., after a meal) glucose levels.

Adiponectin also seems to work closely with leptin, another hormone implicated in a number of diseases of civilization. It appears that adiponecting and leptin modulate each other’s secretion and effects in metabolic processes.

So what do we do to increase our levels of circulating adiponectin?

Well, apparently there is only one guaranteed way, and that is to lose body fat!

Adiponectin is unique among hormones secreted by body fat in that it increases as body fat decreases. Other important body fat hormones, such as leptin, decrease with body fat loss.

The figure below (from: Poppitt et al., 2008) shows a graph where adiponectin levels are plotted against body mass index (BMI). BMI is strongly correlated with body fat percentage.

As you can see from the figure above adiponectin levels more than double when BMI goes from 26 to 20. One does not need to be obese to take advantage of this effect, and to benefit from having increased adiponectin levels.

The linear (Pearson) correlation between BMI and adiponectin levels is indicated as a high 0.551. The fluctuations around the line (the "line" looks more like a quasi-linear curve obtained through quadratic regression), which are why the correlation is not 1, are probably due chiefly to two factors:

    - BMI is not a very precise measure of body fat. A very muscular person will have a high BMI and low body fat. That person will consequently have much higher adiponectin levels than an obese person with equal BMI.

    - Adiponectin levels are naturally higher in women than in men. This is another point in favor of adiponectin, as women have always been the evolutionary bottleneck among our Paleolithic ancestors.

Now you know why doctors prescribe weight loss to patients with diabetes type 2.

And, when we look at various hunter-gatherer groups that were apparently free of diseases of civilization prior to westernization, there are only a few common denominators. Diet was not one of them, as Weston Price and others have shown us, at least not in the sense of what they included in their diet.

One of the few common denominators was arguably the fact that those hunter-gatherers typically had relatively low levels of body fat; an almost universal feature among non-westernized hunter-gatherers.

Reference:

Poppitt, S.D. et al. (2008). Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-α, and C-reactive protein to a high-fat dietary load. Nutrition, 24(4), 322-329.

LDL, chylomicrons, HDL, and atherosclerosis: A lazy Sunday theory

Notes:
  - This post is a joke, admittedly a weird one, which is why it is labeled “humor” and is filed under “Abstract humor”.
  - I apologize for this spoiler. Some people probably like humor posts better if they do not know what they are in advance, but several others may think that reading a post like this is a waste of their time. If you are in the latter category, move on to another post! If not, here it goes …

***

Today I was spending some time under the sun, in one of the year’s 364 sunny days in Laredo, Texas. The goal was to see if I could obtain a precise count of the number of advanced glycation endproducts (a.k.a. AGEs) that would form as my skin was exposed to the sun’s damaging rays.

Then I read a post by Peter at Hyperlipid, and inspiration consumed me. A new theory was born regarding the interplay of LDL, chylomicrons, HDL, and atherosclerosis. By the way, Peter is a fat genius, by which I mean a genius regarding all fat issues – who happens to be thin.

A key observation forms the main pillar on which this new theory solidly rests:

The endothelium gaps, which let atherogenic particles enter into the forbidden area and do their damage, are around 25 nanometers in diameter. And what is the typical size of LDL particles? You guessed it, 25 nanometers in diameter! And guess what more, quite a few of the chylomicrons, another group of particles that would elicit immediate revulsion in any normal human being, are even smaller than 25 nanometers in diameter; those atherogenic pests!

So here is the theory, in a nutshell. A 500-page book will clearly be needed to discuss it in more detail.

The Devil created LDL particles to kill us all. But LDL particles were not such effective killers, because the Devil, trying to pack as much killer cholesterol into them, ended up making them too big! At 25 nanometers in diameter, on average, they basically had to squeeze their way into the forbidden area.

Since LDL particles were not doing a good enough job, the Devil also created chylomicrons, and those chaotic pests come in all sizes. In fact, it is well known that the word chylomicron has a Greek origin: chylo = killer, micron = particle (Deth & Disis, 1999; full reference at the end of this post).

And, needless to say, LDL particles and chylomicrons are fat particles that make the blood kind of taste and smell like butter, a toxic substance often fed to laboratory rats and known for its powerful carcinogenic properties among all living creatures except descendants of Vlad the Impaler. The latter has long been rumored to have been one of the Devil's best buddies, so no surprise there.

Michael the Archangel, who dislikes the Devil, and usually takes a hands-on approach to dealing with those he dislikes, the Devil in particular, gave us HDL particles. If you have any doubts about Michael’s hands-on approach, check the picture below (from: Wikipedia), which clearly shows what Michael had already done to the Devil. And that was over a relatively minor disagreement.

And don’t think about trying to discredit this theory by asking why HDL particles are so small compared with LDL particles and chylomicrons! This is easy. For the same reason that David was small and Goliath big!

But those nasty particles, the LDLs and chylomicrons, weren't only two big bullies, they were two against one. HDL particles were doing a valiant job at fighting the damage done by the Devil’s two evil particles, but not quite enough to save everybody from atherosclerosis.

Michael cried foul, and threatened to give the Devil another lesson. God, seeing this, said: Michael, no, mankind must be given a choice! If men and women want to gorge on the fatty flesh of the beasts they savagely slaughter, let them sin and face the consequences.

And so it was.

This theory probably needs some adjustments and refinements based on analysis of refereed research, especially solid research supported by drug manufacturers, and consultation with the most interesting man in the world. But I am pretty confident it can, after adjustments and refinements, pass the test of time.

The only nagging problem is the Original Sin. To the best of my knowledge, it was not eating the fatty flesh of beasts. It was eating a very sweet apple …

Reference:

Deth, R., & Disis, M. (1999, Feb 31). The origins of killer lipids: An evolutionary-theological perspective. The Lipid Review, 123(7), 77-66.

A trip to Europe: Some health-related routines and observations

Every year I travel to Europe on business, normally once or twice a year. These trips usually involve meetings with engineers, researchers, and project managers from various European countries; often 5 to 10 countries are represented.

Here are some of my notes on a recent trip to Europe. In this trip I spent time in two cities: Amsterdam, Netherlands and Antwerp, Belgium. Below is a set of the photos I took in Antwerp, of a statue depicting the roman soldier Silvius Brabo holding the severed hand of the giant Druon Antigoon.

According to legend Druon Antigoon had terrorized and extorted the people of Antwerp, cutting off the hands of several people and throwing them in the nearby Scheldt River, until the brave Silvius Brabo came into the scene and not only cut off the giant’s hand but also killed him.

This legend has probably been concocted toward the end of the Roman Empire, largely by the Romans, who first established Antwerp as a Roman outpost.

After this small digression, here are some health-related routines that I followed during this trip, and some of my main observations regarding diet and health issues.

On the plane:

    - The meals were a festival of hyperglycemic and pro-inflammatory refined carbohydrates, unhealthy vegetable oils, and sugars – white bread, pasta, various sweets, pretzels, chips loaded with supposedly healthy omega 6 fats, margarine etc. I skipped all of the snacks and one of the meals, the breakfast. At the main meal of each flight I ate only meat, veggies, and some of the fruits.

    - The flights over and back were very comfortable since I was water-fasting most of the time. Not a hint of indigestion or abdominal discomfort of any kind. These were 9 to 10 hour flights, from Houston to Amsterdam and back.

At business luncheons:

    - The idea of having a sandwich for lunch seems to be getting popular in Europe. At least I have been seeing that happening more and more often lately. At these sandwich luncheons, I ate only the content of some sandwiches (basically cold cuts, cheese and veggies), and left the bread slices untouched.

    - Some people noticed that I was not eating bread. I told them about insulin, lectins etc. A few looked at me as though I was insane; others with a disapproving look – dontchano, the lipid hypothesis!? A notable exception was a German gentleman who said that Germans were too pragmatic not to notice that they were getting fat on low fat diets, and are now reverting back to their staple diet of meats, fish, vegetable stews, and cheese.

At restaurants for dinner:

    - This was fairly easy. I ate basically fish or meat dishes with veggies, and enjoyed them a lot. I skipped the deserts; again much to the surprise of some of my European colleagues.

    - Skipping the desserts seems to have helped me cope with jetlag a lot better than I usually do. On my second day in Europe I slept quite well, and was unusually rested on the next day.

At the hotel:

    - The breakfast buffets were a mix of: (a) breads, pastries, sweetened cereals, sugary items, and fruits; and (b) meats (often cured), some fish, cheeses, eggs, nuts, and some veggies. There were also fruit juices. I had solid breakfasts with (b)-type items, with a few fruits added (cantaloupe and berries). I had regular coffee with cream and no sugar, and stayed away from fruit juices.

    - I did not use soap, shampoo etc. at the hotel; just plain water. Occasionally the soap used in hotels is very caustic, or rich in other chemicals, causing rashes. I stuck with showers and had no baths, as sometimes the bathtubs are not properly cleaned after their last use.

    - At the end of my trip I took a train from Antwerp to Amsterdam, and stayed at a hotel near the Schiphol Airport (which has its own train station) since my flight back to the U.S. was in the morning. I had dinner by myself at the hotel, which was easy. I stopped at a place called Food Village at the Airport (visible from the Airport’s main entrance) and bought a water bottle, a piece of Gouda cheese, a can of sardines, and a box of seaweed. That was a very good dinner, and cost me about 6 euros.

The outcomes for me:

    - I had no hint of indigestion at all throughout the trip, in spite of eating way more cheese than I normally do. The cheese that I ate was natural, aged cheese, not the processed kind.

    - I had no need for more or less use of the bathroom than I usually do, and remained “regular” throughout the trip. No sign of constipation at all.

    - I had no body odor (at least none that I could notice), even though I used no soap. My hair was fine too; I used no shampoo or conditioner.

    - Jet lag problems were less pronounced than they usually are when I travel to Europe. The time difference is about 7 hours from Texas. Usually, I tend to feel very sleepy in the afternoon and wide awake around 3 am. Not this time.

    - In spite of not exercising for about 7 days, except for walking, I was able to lift slightly heavier weights at a workout the day after my return than I did before my trip.

    - According to the scale, I lost 1 pound during this trip. I do not know whether this was body fat or just water. It is unlikely that there was any muscle loss.

From what I could see, Europeans are generally thinner than Americans (particularly Texans), and also seem to be healthier. None of the people I met, not one, was clearly obese. On the other hand, the majority seemed to be somewhat overweight.

My impression was that the Europeans consume lesser amounts of refined carbohydrates and sugars than Americans, on a weekly basis, even though they currently consume more of those items than they should, in my opinion.

Consumption of vegetable oils other than olive oil is also lower than in the U.S; consumption of butter and cheese seems to be a lot higher.

From my conversations with several people during this trip, it seemed that the health of Europeans, like that of their American counterparts, is strongly correlated with the extent to which they are overweight. The more body fat, the more common was to hear complaints about pain here or there, fatigue, degenerative diseases, or talk about surgeries.

Interesting Articles in the AJCN

I just received an RSS alert for the American Journal of Clinical Nutrition's latest articles. This upcoming issue is full of very interesting material:

1. Dr. Neil D. Barnard reviews food consumption patterns in the US from 1909 to 2007 (1). This is something I've written about a number of times. The most notable change is that industrial seed oil use has increased by more than 3-fold in the last 40 years, and even more in the last 100 although he doesn't provide those numbers. Butter and lard use declined sharply. Meat consumption is up, but the increase comes exclusively from poultry because we're eating the same amount of red meat we always have. Grain consumption is down, although it peaked around 1900 so it may not be a fair comparison with today:

In the late 1800s, wheat flours became more popular and available due to the introduction of new [high-gluten] wheat varieties, [low extraction] milling techniques, and transport methods, and during this time new breakfast cereals were introduced by John Harvey Kellogg, CW Post, and the Quaker Oats Company. Thereafter, however, per capita availability of flour and cereal products gradually dropped as increased prosperity, improved mechanization, and transport (eg, refrigerated railway cars) increased competition from other food groups. [Then they partially rebounded in the last 40 years]

2. Dr. S.C. Larsson published a paper showing that in Sweden, multivitamin use is associated with a slightly higher risk of breast cancer (2).

3. Soy protein and isoflavones, which have been proposed to do everything from increase bone mineral density to fight cancer, are slowly falling out of favor. Dr. Z.M. Liu and colleagues show that soy protein and/or isoflavone supplementation has no effect on insulin sensitivity or glucose tolerance in a 6 month trial (3). This follows a recent trial showing that isoflavones have no effect on bone mineral density.

4. Dr. Ines Birlouez-Aragon and colleagues showed that high-heat cooked (fried and sauteed) foods increase risk factors for diabetes and cardiovascular disease (insulin resistance, cholesterol, triglycerides), compared to low-heat cooked foods (steamed, stewed) in a one-month trial (4). The high-heat diet also reduced serum levels of long-chain omega-3 fatty acids and vitamins C and E.

5. Dr. Katharina Nimptsch and colleagues showed that higher menaquinone (vitamin K2) intake is associated with a lower cancer incidence and lower cancer mortality in Europeans (5). Most of their K2 came from cheese.

6. And finally, Dr. Zhaoping Li and colleagues showed that cooking meat with an herb and spice blend reduced the levels of oxidized fat during cooking, and reduced serum and urinary markers of lipid oxidation in people eating the meat (6).

More on the Harvard study on saturated versus polyunsaturated fats

This is a follow up on this post, which addressed the main argument put forth in a recent BBC article. The BBC article argued that people should replace saturated with polyunsaturated fats to reduce their risk of heart disease.

Let us take a look at the actual Harvard study itself (i.e., the study discussed in the BBC article). The Harvard study is linked here.

This post, by Stephan Guyenet, already pointed out several problems with the study. Stephan actually reviewed the studies used in the meta-analysis, and also some that were excluded in the meta-analysis and that he believes should have been included.

Here are a few other problems, in addition to the ones already pointed out by Stephan:

One thing that looks suspicious about this Harvard meta-analysis study is that they say that: “Statistical evidence for substantial between-study heterogeneity was not present (Q-statistic p = 0.13; I2 = 37%).”

A meta-analysis is a study that essentially summarizes, in a statistically sophisticated way, a bunch of other studies (the “sourced” studies). Too much between-study heterogeneity (i.e., widely disparate results among sourced studies) is undesirable, because it can bias the results.

The problem is similar to that of trying to summarize net worth figures (e.g., by calculating their average) in a middle class neighborhood that happens to have a few billionaires living in it. The heterogeneity in wealth may lead to a wildly overestimated average.

Now, we know that p values go down with sample size, and are usually high with small samples unless the effect measured by the statistic is very strong, regardless of the statistic used.

Well, with a sample of only 8 studies, their p value (associated with the Q statistic) is close to being significant at the 0.05 level!

If this sample of sourced studies were a little higher (say, 20), there would be significant between-study heterogeneity, which would call the meta-analysis into question. This is a big problem, since a good meta-analysis is expected to include a large number of studies (e.g., greater than 100), and this one included only 8 studies.

Moreover, to the best of my knowledge, the Q statistic is not very reliable when used with small samples, due to its low power as a test of heterogeneity. This makes the p value reported even more problematic.

Finally, the sourced study with the largest sample (n = 9,057; thus possibly the most credible), indicated as “Minnesota CS” on Figure 2 of the Harvard study, found increased risk of heart disease associated with increased consumption of polyunsaturated fats and reduced consumption of saturated fats.

Reference:

Mozaffarian, D., Micha, R., & Wallace, S. (2010). Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS Med., 7(3): e1000252. doi: 10.1371/journal.pmed.1000252.

BBC article's advice: Replace saturated with polyunsaturated fats

The BBC article is here. It is based on meta-analysis of eight previous studies conducted by Harvard researchers, which the article states cover more than 13,000 people. The article also says that: “… [saturated] fats raise the levels of bad cholesterol that block the arteries to the heart.” They are of course referring to LDL cholesterol as the "bad cholesterol".

Sourcing bias is a notorious problem with meta-analyses (i.e., the choice of studies to use in a meta-analysis). Another problem is that you cannot tell what the studies sourced controlled for. Consider a study that compares health markers for smokers and non-smokers, where the smokers eat more saturated fat than the non-smokers. This study may confuse the effect of smoking with that of saturated fat consumption. To be reliable, the study must analyze the effect of saturated fat consumption, controlling for smoking habits.

There are other statistical issues to be considered in meta-analyses. For example, some of the sourced studies may take nonlinear relationships into consideration and others not. In multivariate analysis studies, nonlinearity may lead to significantly different results from those obtained through more conventional linear analyses.

Finally, reaching misleading results with sound statistical analyses is not that hard. As my age went from 1 to 20 years, my weight was strongly correlated with the price of gasoline. Yet, neither my weight caused the price of gasoline, nor the other way around. When you look at an individual study, not a meta-analysis, you can at least try to identify the possible sources of bias and mistakes.

Having said that, a solid refutation of the main argument in the article can be made from many angles. Here is a simple refutation based on what I would call the “HDL cholesterol angle”, with links to posts and various refereed publications:

- Increasing HDL cholesterol levels, especially beyond 60 mg/dl, dramatically decreases the risk of heart disease; and this is an almost universal effect in humans. This reduction in risk occurs even for people who suffer from diabetes and familial hypercholesterolemia. The latter is a genetic condition that is associated with very elevated LDL cholesterol and that is rare, typically afflicting 1 in 500 people in its heterozygous (and most common) form.

- Increasing consumption of saturated fats (present in: lard, fatty meat, coconut oil) and dietary cholesterol (from: fish, organ meats, eggs), while decreasing consumption of refined carbohydrates (e.g., pasta, white bread) and sugars (e.g., table sugar, high fructose corn syrup), significantly increases HDL cholesterol for the vast majority of people. Neither omega-6 nor omega-3 polyunsaturated fats lead to the same results. Omega-3 fats do reduce triglycerides, and increase HDL somewhat, but their effect on HDL pales in comparison with that of saturated fats. Excessive consumption of omega-6 fats is associated with chronic inflammation and related health problems.

- With the exception of cases involving familial hypercholesterolemia, there is no conclusive evidence that LDL cholesterol levels are associated with heart disease. Two widely used online calculators of risk of heart disease, based on the Framingham Heart Study and the Reynold Risk Score, do not even ask for LDL cholesterol levels to estimate risk. And that is not because they calculate LDL cholesterol based on other figures; they do not ask for VLDL cholesterol or triglycerides either.

After reading the BBC article again, it is clear that they are re-stating, in general terms, Rudolph Virchow’s mid-1800s lipid hypothesis. And they do so as if it was big news!

New Review of Controlled Trials Replacing Saturated fat with Industrial Seed Oils

Readers Stanley and JBG just informed me of a new review paper by Dr. Dariush Mozaffarian and colleagues. Dr. Mozaffarian is one of the Harvard epidemiologists responsible for the Nurse's Health study. The authors claim that overall, the controlled trials show that replacing saturated fat with polyunsaturated fat from industrial seed oils, but not carbohydrate or monounsaturated fat (as in olive oil), slightly reduces the risk of having a heart attack:

These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD.

Looking at the studies they included in their analysis (and at those they excluded), it looks like they did a nice job cherry picking. For example:

• They included the Finnish Mental Hospital trial, which is a terrible trial for a number of reasons. It wasn't randomized, properly controlled, or blinded*. Thus, it doesn't fit the authors' stated inclusion criteria, but they included it in their analysis anyway**. Besides, the magnitude of the result has never been replicated by better trials-- not even close.
• They included two trials that changed more than just the proportion of SFA to PUFA. For example, the Oslo Diet-heart trial replaced animal fat with seed oils, but also increased fruit, nut, vegetable and fish intake, while reducing trans fat margarine intake. The STARS trial increased both omega-6 and omega-3, reduced processed food intake, and increased fruit and vegetable intake. These obviously aren't controlled trials isolating the issue of dietary fat substitution. If you subtract the four inappropriate trials from their analysis, which is half the studies they analyzed, the significant result disappears. Those four just happened to show the largest reduction in heart attack mortality...
• They excluded the Rose et al. corn oil trial and the Sydney Diet-heart trial. Both found a large increase in total mortality from replacing animal fat with seed oils, and the Rose trial found a large increase in heart attack deaths (the Sydney trial reported total mortality but not CHD deaths).

The authors claim, based on their analysis, that replacing 5% of calories as saturated fat with polyunsaturated fat would reduce the risk of having a heart attack by 10%. Take a minute to think about the implications of that statement. For the average American, that means cutting saturated fat nearly in half to 6% of energy, which is a challenge if you want to eat a normal diet. It also means nearly doubling PUFA intake, which will come mostly from seed oils if you follow the authors' advice.

So basically, even if the authors' conclusion were correct, you overhaul your whole diet and replace natural foods with industrial foods, and...? You reduce your 10-year risk of having a heart attack from 10 percent to 9 percent. Without affecting your overall risk of dying. The paper states that the interventions didn't affect overall mortality.


* Not even single blinded.  Autopsies were not conducted in a blinded manner. Physicians knew which hospital the cadavers came from, because autopsies were done on-site. There is some confusion about this point because the second paper states that physicians interpreted the autopsy reports in a blinded manner. But that doesn't make it blinded, since the autopsies weren't blinded. The patients were also not blinded, though this is hard to accomplish with a study like this.

** They refer to it as "cluster randomized", which I feel is a misuse of that term.  The investigators definitely didn't randomize the individual patients: whichever hospital a person was being treated in, that's the food he/she ate. There were only two hospitals, so "cluster randomization" in this case would just refer to deciding which hospital got the intervention first. I don't think this counts as cluster randomization.  An example of cluster randomization would be if you had 10 hospitals, and you randomized which hospital received which treatment first.  It's analogous to individual randomization but on a group scale.