Saturday, January 21, 2012

If a High Fat Diet was a Pill, the Lay Press Would Celebrate it as "Exercise in a Pill": Two days on High Fat Diet Increase the Activity of Irisin Releasing Transcription Factor PGC1-α

Image 1: If a high fat diet was a patentable pill, I guess BigPharma would already be selling it.
It's crazy, whenever I go to the groceries, there are new products popping up with colorful slogans like "fat free", "diet", "particularly low in fat", "fat reduced", "only 0.1%" etc. What is yet all the more disturbing is that these products are "placed" right next to a more recent "invention" of the industry - products with a "reduced sugar content"... I could now go on a rampage on how the Kellog's and co. just replace table sugar with other sugars in order to be able to put these stickers on their products, but I actually want to make a different point today. If you stand still for a moment and watch the people pass by, there are two things you will notice.
  1. The healthy and lean (and not anorexic) will pass by without even noticing the great "0.00001% fat, reduced sugar whatever" with the Weight Watchers sticker on it.
  2. The hungry-looking slightly overweight to morbidly obese people will pick up the aforementioned "0.00001% fat, reduced sugar whatever" with the Weight Watchers sticker on it, look at the price-tag, sigh and put three packets of that stuff into their cart.
Now, if we, for the time being, disregard that these products are full of chemicals and hidden sugars and just focus on the notion that eating a product that is both low in carbs and low in fats will help you lose weight we have identified what, at least in my humble opinion, is the #1 reason that many self-perceived "low-carbers" stop losing weight after they dropped the initial few pounds of water: A low carb, low fat diet that - irrespective of their protein intake - is telling their bodies that they are in the midst of a famine, where you better hold on to your fat and burn the wasteful muscle tissue so that you can survive for another few weeks...

Please understand: Low carb = high fat! And high fat burns, not stores fat.

I guess, I better stop preaching now and get to the nitty gritty of the latest study on the effects of a high fat vs. low fat diet on short-term (2-days) metabolic adaptations in lean (BMI 19-25kg/m²) and obese (BMI 30-40kg/m²) human subjects.
Figure 1: Relative energy content of the low and high fat diets the lean and obese study participants were fed (data adapted from Bergouignon. 2012)
As you can see from the data in figure 1, the scientists designed the study in a way that facilitates a direct comparison of high fat (50%) vs. low fat (20%). This is different from high carb vs. low carb, because the high fat diet (35% carbs vs. 65% in the low fat diet) is by no means so "low" in carbs as the average low-carber would have it. That the metabolic adaptations were still pretty profound - after only two days - is something, I personally would not have expected.
Figure 2: Total 24h kcal expenditure (left axis) and protein, carbohydrate and fat oxidation (right axes) in lean and obese subjects on the low and high fat diets (data adapted from Bergouignon. 2012)
Both, lean and obese subjects showed almost identical responses with regard to their 24h kcal expenditure and substrate utilization (cf. figure 1). Most prominent among these was the profound increases in 24h fat oxidation (+88% in the lean and +109% in the obese subjects) in the high fat groups that was yet accompanied by a -26% (lean) and -37% (obese) reduction in carbohydrate oxidation. The overall caloric expenditure was thusly "the same" - unless you still believe that 50kcal per day would make a difference ;-)
Figure 3: Free fatty acid and triglyceride levels (24h AUC in mmol/dl and mg/dl, right axis) and free fatty acid to triglyceride ratio (left axis; data calculated based on Bergouignon. 2012)
If we now take a look at the blood lipids (cf. figure 2), i.e. the free fatty acid (FFA) and triglyceride levels, on the different diets, we see a "phenomenon" low-carbers know all to well. After only a few days on a low-carb diet, triglyceride levels start to plumed. The amount of free fatty acids that are released into the circulation from the liver and the adipose tissue, on the other hand, rises. This time with a significantly greater FFA response in the obese individuals (p=0.04), which does support the hypothesis that a significant amount of the FFAs came from the well-stocked adipose tissue of the obese study participants.
Figure 3: Total mRNA expression in vastus lateralis muscle of study participants expressed relative to the subjects in the lean low fat group; please note the discontinuity of the axis between 200% and 600%, which became necessary to fit the data into the graph (data calculated based on  Bergouignon. 2012)
The most intriguing changes this two-day high fat "challenge" induced took yet place on a transcriptional level in the skeletal muscle tissue of the subjects. However, of the changes in total mRNA expression, only the increase in CD36, a protein which regulates the fatty acid uptake of skeletal muscle, and pyruvate dehydrogenase kinase isozyme 4 (PDK4), which reduced the oxidation of glucose, reached statistical significance.

Is a high fat diet exercise in a pill?  ...

If we discard the statistical shenanigan for a moment, you may yet notice the "non-significant" +33% increase in Sirtuin 1 (Sirt 1) expression in both high fat diet groups. The intelligent and well-read SuppVersity student you are, you will also remember that this protein, which is downregulated in states of insulin resistance, has been identified as one of the key players in the anti-cancer effects of compounds such as resveratrol and the longevity effects that have been ascribed to low-calorie diets. And as if that was not enough, Sirt 1 also plays a key role in the beneficial adaptations that come with exercise, where it is part of a triumvirate of AMPK + SIRT1 + PGC1-alpha,  which is induces the production of irisin the purported "exercise hormone" that is supposed to "brown your adipose tissue" (meaning to convert the sluggish white into the metabolically more active brown fat) has gotten quite some attention in the lay press as of late (eg. LA Times).
Figure 4: Skeletal muscle mRNA expression (in au) of acetylated (=inactive) PGC1-alpha and phosphorylated (=active) AMPK in lean and obese subjects subjects on low and high fat diets (data adapted from Bergouignon. 2012)
So, if we fell for the, in my book, stupid idea that a single cellular messenger, in this case irisin, would work like "exercise in a pill" (think about it - how often have you heard that in the last years?) and acknowledge that an increase in PGC1-alpha activity in skeletal muscle will increase the release of this myokine (i.e. a messenger protein that is released from the muscle; compare "adipokine" like leptin, which is a messenger protein that is released from adipose tissue), the logical conclusion would be that a high fat diet works like "exercise in a pill". Why? Because the data in figure 4 shows that the active, i.e. de-acetylated amount of PGC1-alpha (which is obviously the exact opposite of what the scientists measured) in the muscle of the subjects who consumed the high fat diet increased (p < 0.05) - ah,... and did I mention that this is human data, while the irisin craze is based solely on rodent studies?

... it sure looks like that!

In combination with the increase in phosphorylated AMPK (p-AMPK, click here to learn more about the "mTOR/AMPK Seesaw"), which was likewise statistically significant, the short-term adaptation to high fat feeding in lean and obese human beings shares two of the main characteristics of the "healthy endurance training" the same Dr's who warn their patients about the dangers of a high fat diet usually prescribe to their patients. Now tell me, is the voice in your stomach still telling you that low-carb may be good, but that eating a high fat diet is not an option? Well, in that case I guess you are beyond help... go buy some low-fat sugar reduced cornflakes ;-)