Monthly Archives: March 2011

What are whole grains?  Short answer: grass seeds.  Long answer: see below.

Grains are made of bran, germ, and endosperm.  Refined grains are endosperm only (GLUTEN and starch).

Germ is the embryo.  Bran is the shell, lots of fiber & vits.  Has unsaturated fatty acids which can go rancid so bran is removed to improve shelf life of refined grains.

Moving on to the data:

Round 1. Grains et al. vs. mortality

Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial (DART) (Burr et al., 1989)

The Diet And Reinfarction Trial (DART) is one of the most historically important nutrition INTERVENTION studies.  Intervention studies are where investigators actually go into a population and ask them to change something about their diet; they are intended to determine causation and thus the best advice to give the target population.  The findings from DART, in particular, are crucial & too often ignored.

DART included ~2,000 men, ~56-57 years of age, who recently suffered a heart attack and the intervention was simple.  They were randomly assigned to receive one of three dietary recommendations:

1. < 30% dietary fat
2. > 2 servings of fatty fish per week
3. > 18 grams of cereal fibre (whole grains)
4. Control group, received no advice

If you’re dispensing nutrition information, then you are intervening just like these researchers.  It stands to reason that the recipients of your advice might respond similar to the DART subjects.  Pay attention.

Just like real patients, the DART population mostly did what they were supposed to.  The fat group decreased dietary fat intake from 35.3% to 32.1%.  The P/S ratio reflects the ratio of polyunsaturated to saturated fat.  The recommendation was to increase this ratio by either increasing polyunsaturated fat consumption or decreasing saturated fat consumption, which was accomplished.

The fish group increased their fish intake from less than one serving per week on average up to the recommended 2 servings (however, 14%-22% of the patients couldn’t tolerate fish and were allowed to take fish oil capsules instead).  The table is showing EPA as a proxy for fish intake; salmon has about 0.5 – 1 gram per serving.

And the fibre group doubled their cereal fibre (whole grains) intake from 9 up to 19 grams per day.

So remember three things: fat, salmon, and cereal fibre.

Gravitas (see below):

Divide and conquer.

10.9% of the men who were advised to decrease dietary fat intake died within 2 years while 11.1% who received no such advice died.  That is an absolute risk reduction of 0.2% and a relative risk reduction of 2%.

Absolute risk = 10.9% – 11.1% = -0.2%

Relative risk = (10.9% – 11.1%) / 10.9% = -2.0%

9.3% of men who ate more fish died compared to 12.8%!! That is an absolute risk reduction of 3.5% and a relative reduction of 27%.  27% reduced relative risk is huge.  Eat salmon.

Last but not least, 12.1% of men who increased their consumption of cereal fibre died while 9.9% who didn’t died.  IOW, increased cereal fibre caused a 2.2% increase in absolute risk and a 22% increase in relative risk.

In summary, reducing dietary fat had no effect on mortality.  Eating more salmon drastically reduced mortality.  And eating more cereal fibre increased mortality.  Cereal fibre is bad for you?

Cereal fibre comes from whole grains, which are different from other fibrous foods like broccoli and spinach.  Cereal fibre, and whole grains in general, are suspect.  These were men in their 50’s who had a heart attack, so the results may not apply to everyone, but there is another way to look at it.  The DART population had two immediately relevant risk factors: age and a cardiovascular event.  I propose cereal fibre may have been simply another insult to their health profile.  IOW, the mortality risk for increasing cereal fibre might be > 22% for a population with more than two risk factors and < 22% for a population with fewer risk factors. IOW, cereal fibre is bad but won’t kill a healthy person.  Indeed, we see this every day; many people who lead a healthy lifestyle consume whole grains and are fine.  Perhaps the whole grains aren’t what is making them healthy.

Another remarkable finding of this study was the effect of increasing fatty fish intake:

The survival curve: the life-saving effect of increased fish intake are almost instantaneous; by 3 months there is already a noticeable reduction in mortality in the fish group.  That is more substantial than what has been shown in any single trial of statin drugs.  Gravitas.

Summary of DART: Eat salmon, not grains.  And dietary fat doesn’t matter.

Support for the theory that whole grain consumption is simply a habit of healthy people, not what actually makes them healthy:

Whole grains, bran, and germ in relation to homocysteine and markers of glycemic control, lipids, and inflammation (Jensen et al., 2006 AJCN)

This paper includes data from the Health Professionals Follow-Up Study, a huge epidemiological study on food intake data and a variety of endpoints.  HPFS = >50,000, all male doctors, established circa 1986

Divide and conquer.

Table 1: lifestyle and dietary characteristics

The table above is divided into three columns.  On the right are people with low grain intake (4.9-11.9 g/d).  Middle is intermediate grain intake.  Rightmost column is high grain intake (38.6 – 50.9 g/d)

Healthy people eat a lot of whole grains (and exercise more, maintain a healthier body weight, smoke less, eat more fiber, eat less trans fats, and eat more vegetables).  All of those factors are directly correlated with the consumption of whole grains.  IOW, scientifically, this makes it very difficult to differentiate true health-promoting effects of grains because there are a lot of bona fide confounding factors.

For example:

1)      low insulin levels are good.

2)      People who eat a lot of grains are all-around healthy

3)      There is a good inverse correlation between grains and insulin level, suggesting that grains may actually be healthy and not something that is coincidentally ingested by healthy people; note the high degree of significance (“0.01,” red arrow)

BUT once the data are statistically corrected for confounding lifestyle factors such as smoking, body weight, and exercise, the association between grains and insulin gets weaker (“0.06,” middle row, red arrow)

And when the data are further corrected for confounding lifestyle and dietary factors such as vegetables and sugar, the association is no longer significant (“0.13,” bottom row, red arrow):

So in some cases, like with insulin, high grain intake is most likely a marker for a healthy person; the grains themselves aren’t what makes these people healthy, it is the lifestyle and dietary things that healthy people do.  In hindsight this shouldn’t have been too unexpected, because foods high in grains are carbohydrate-rich, after all, and carbohydrates drive insulin secretion.  So we shouldn’t be terribly surprised that higher carbohydrate consumption is not associated with lower insulin levels.

Moving on.

C-reactive protein (CRP) is a general marker of inflammation and an excellent marker for an assortment of morbidities and mortality… (IMHO CRP a better marker than LDL).

Note the similar trend: There is a strong correlation between CRP and grains (top row, last column, “0.03”).  But the correlation is weakened by controlling for lifestyle factors (middle row, “0.32”) and further weakened by controlling for diet (bottom row, “0.63”).  Thus, while someone who eats a lot of grains also has relatively low systemic inflammation, the grains are most likely not playing a causal role.

So where does this leave us?  The things that were true in 1989 and 2006 are probably still true today.  Eat salmon, not grains.  And fat doesn’t matter.

Will whole grains kill a healthy person?   No.

Whole-grain intake is inversely associated with the metabolic syndrome and mortality in older adults (Sahyoun et al., 2006 AJCN)

This was a population of >500 healthy people, 60-98 years of age, established circa 1981.

The usual suspects:

Same as above, people who eat more whole grains smoke & drink less, exercise more, eat less saturated fat; all things that are common amongst “healthy” people (but may or may not actually be what is making them healthy).

But to make a long story short:

Hey!! They are the only data I want shown!

This was a much smaller study, but supports the theory that grains may only be detrimental to people with more serious risk factors (like a previous cardiovascular event [e.g., heart attack, etc.]).

DART was an intervention study, and therefore was more powerful and meaningful. The other studies were observational.  Will you still recommend whole grains?

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Brown adipose tissue (BAT) has classically been thought of as a thermogenic tissue in rodents, infants, and to a small degree in adults.  BAT is brown because of its rich vascular supply; it’s not a fat storage organ like it’s cousin white adipose tissue.  BAT burns fat and wastes the energy as heat.  Cold temperature activates BAT, which we know is true for humans

Cold-activated brown adipose tissue in healthy men (van Marken Lichtenbelt et al., 2009 NEJM)

BAT in humans, the dark areas represent regions of brown adipose tissue (BAT).

The characteristic of BAT introduced in this paper is that of a Hoover sucking lipids out of the blood, but instead of swirling around in the Windtunnel, they are disposed of into a region of space in which nothing, not even light, can escape (except maybe heat).  For those of you at home, this means if you spend the day swimming in a cold pool or the ocean and then consume a fat-rich meal, virtually all of the lipids will be diverted into BAT where much of their energy will be dissipated as heat.

Brown adipose tissue activity controls triglyceride clearance. (Bartelt et al., 2011 Nature Medicine)

This paper had such an astounding umph…

Below is the profile of plasma lipids from fasted mice at either room temperature (control) or after 24 hours at 4C (39F):

Figure 1a: mice at 22C or 4C.  Cold mice have much lower triacylglycerols (TGs) and moderately lower glycerol.

Problem #1.  Less glycerol generally means lower lipolysis; cold mice should have more glycerol because: cold -> sympathetic nervous system activation -> catecholamines -> lipolysis -> more glycerol and FFAs (?)

It’s so early in the post, but here is the gravitas.  The meat and potatoes.  Cold mice experience virtually no lipemic response to an oral bolus of 100uL olive oil.

I love the author’s choice of dollar signs to denote statistical significance.

Problem #2.  ³H-triolein was mixed in the olive oil, and accordingly plasma ³H rose in parallel with TG’s in control mice.  But plasma ³H also increased in cold mice despite no increase in TGs.

Plasma ³H mirrors TGs in control but not cold mice.

The lipid profile of plasma ³H 2 hours after the gavage is shown below (Figure s3)

In the controls (normal mice at room temperature, open circles), most of the ³H is recovered in TRLs (chylomicrons and VLDL) and HDL.  The only ³H recovered from the plasma of cold mice was in the flow-through.  For some reason the authors are calling this fraction “degraded oleate,” but in my experience everything that’s left in the sample dumps out together in the end, including free fatty acids. The authors claim this “degraded oleate” is comprised of partially oxidized (chain-shortened) ³H-fatty acids and ³H₂0, which it could be, but it could also be unmetabolized ³H-oleate.  More importantly, however, is that it was similar in both groups.  So the cold didn’t enhance the appearance of these mysterious ³H molecules.  IOW, there is still a lot of ³H unaccounted for…  So, where did it go?

Divide and conquer

Figure 1e.  2 hours after the oral gavage, tissues were collected and checked for radioactivity

As expected, liver and muscle took up the most.  Liver should have a higher fractional uptake, but muscle takes up more overall simply because it is a much bigger organ….   Enter: BAT.

Problem #3.  Figure 1e is showing uptake per total tissue, and given the authors claim that both liver and BAT are of equal weight (1.4 grams), that is a ridiculously high fractional uptake in cold BAT.

Suspicions confirmed:  when expressed as fractional uptake, it is ridiculously high in BAT:

Figure s4: As expected, liver is higher than most tissues, except for BAT, which exhibits a phenomenally high fractional uptake in both control and cold mice.  If it’s true that BAT really clears more TG than any other tissue, even at room temperature, then I learned something shocking today.

Problem #5.  Why have I never heard of BAT’s role in clearing chylomicron TGs?

Inconsistency (or Problem #6):  Figure 2d.  Tissue distribution of ³H 15 minutes after i.v. injection of ³H-triolein-labeled chylomicrons.  Note cold liver and BAT are approximately equal at around 5,500 cpm per total tissue.

Below, they tested lean and obese mice in the same type of experiment:

Figure 4i.  Cold liver is about 3x higher than cold BAT.  The units are different, first experiment is cpm per total tissue, second is cpm per gram (“c.p.m. x g” ?) or fractional uptake… but from the first two figures 1e & s4, total and fractional uptake is higher in BAT than liver.  Why is this result flipped around?  Actually, the values for BAT are pretty much the same in both experiments.  But the value for liver is almost 10x higher when corrected for the “weight of the excised tissue.”  The experiment was the same, the data are expressed differently (which is OK), but the results seem different.

Moving on.  Maybe I’m just nit-picking but there are definitely some anomalies that warranted at least a brief mention.  For example,

1. what are those tritiated molecules that are lurking in the cold plasma (figure s2)?

It’s not exclusively “degraded oleate” (whatever that means).  Perhaps some of it is degraded oleate, of which ³H₂0 and chain-shortened ³H-fatty acids are possibilities, but it could also be native ³H-oleate (or ³H-di- or mono-acylglycerol?).

2. In what form is the ³H remaining in BAT after 15 minutes?  I suspect it is ³H-fatty acids (but from other data they present it could actually be intact ³H-triolein). 15 minutes is too soon for the bulk of it to be ³H₂O, which would reflect an extremely high fatty acid rate considering the position of the label is [9,10-³H]oleate.

3. And WHAT about at 2 hours??? 2 hours is way too long for any of the ³H to still be in fatty acids, 15 minutes maybe, but 2 hours? This is BAT after all, isn’t it supposed to be oxidative especially at 4C?

3a. It shouldn’t be ³H₂O either because water doesn’t accumulate inside of adipose tissue of any color.

3b. Membranes?  But why would BAT suck fat out of the blood membranes remodeling (especially when it’s so cold!)

4. Does BAT really weigh as much as liver?  Given their densities, this would mean the brown adipose tissue depot is significantly larger than the liver.  It seems like these guys would be walking around with little humpbacks (like a camel), especially after a bolus of olive oil in the cold!

Anyway, the data are staring me straight in the face, but I’m still having trouble swallowing this new characteristic of BAT.  In the meantime, flashback 1957:

TISSUE DISTRIBUTION OF C¹⁴ AFTER THE INTRAVENOUS INJECTION OF LABELED CHYLOMICRONS AND UNESTERIFIED FATTY ACIDS IN THE RAT (Bragdon et al., 1958 JCI)

The fate of ¹⁴C from [¹⁴C]palmitate-labeled chylomicrons in rats.  The time point in this study is 10 minutes; in the Bartelt BAT study above it was 15 minutes, but that shouldn’t matter too much.

Total tissue uptake.  Most of the ¹⁴C was recovered in the liver, in agreement with Bartelt’s Figure 2d, but a significant amount is also recovered in muscle and fat, which is not the case in Bartelt’s Figure 2d.

Uptake per gram of tissue (fractional uptake).  These results are drastically different than Bartelt’s.  Liver, heart, and spleen exhibit the highest fractional uptake.  In Bartelt’s figure 4i it’s all liver.  Is this difference due to a rat/mouse thing? 10 vs. 15 minutes?  In any case, both papers agree that a lot of dietary fat/chylomicron-fatty acids end up in the liver.  In mice, maybe it’s liver and BAT, in cold mice maybe it’s all BAT, but in rats maybe it’s liver, heart, and spleen.

In humans, at least from one paper, it seems like fractional TG/FA uptake is approximately equal in fat and muscle (in agreement with mice but not rats where fat takes way more than muscle).

Preferential uptake of dietary Fatty acids in adipose tissue and muscle in the postprandial period. (Bickerton et al., 2007 Diabetes)

This study utilized the arterio-venous balance technique to measure the fractional uptake of [U-¹³C]palmitate from a mixed meal across subcutaneous stomach fat and a forearm muscle.  However, in Frayn’s Biochemistry textbook adipose is said to take up 4-5 times more than muscle overall which is more on par with the mice and rats cited above.

And in this rat study, whole tissue adipose uptake of 14C-oleate was higher than muscle and liver at 2 hours: Trafficking of dietary oleic, linolenic, and stearic acids in fasted or fed lean rats. (Besseson et al., 2000 AJP)

I guess I’m just trying to keep my mind off of the whole BAT thing.  Come to think of it, I’ll just do the experiment myself (in mice) to see if BAT really plays such a large role in TG clearance.  will post the results.

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