Exercise & Fat Mobilization ... and starving cells & hunger

There's no denying it, TWICHOO is down to a broken toothpick where the science is concerned.  (See here for the toothpick reference if you're a newer reader.)   The remaining claim supporting TWICHOO rests on the action of insulin on the fat cell.  Insulin does indeed act to stimulate esterification and suppress lipolysis, favoring deposition and accumulation of triglycerides in fat cells.  They even teach this stuff in some medical schools I'm told!  So these days it's all about how carbs make you hungry and overeat (although overeating is so inane) because they stimulate insulin which traps all your fat calories in your fat starving the rest of your cells of energy.  Now, that part's not true, but let's for the sake of argument assume it is.  What, then, would cause you to lose weight and not be hungry?  Why anything that favors net mobilization of fat stores -- that is stimulates lipolysis and fatty acid release from fat cells.  This will raise the circulating free fatty acid, NEFA, levels and make them available in abundance to your cells.  Hunger be gone!  It's all about the balance of the TAG/FFA cycle.

Well, if that is the case, then exercise would be THE most effective means of preventing or reversing fat accumulation.  Hands down.  No argument.  Oh ... and it wouldn't make you hungry, quite the opposite, because your body is awash in fatty acids.  Work with me here TWICHOOB's.  If you have your hypothesis, you must fit it or apply it to all situations.  Exercise is the ultimate TWICHOOB miracle weight loss dream.   Because if anything that works to put fat into fat cells is fattening, then anything that works to get fat out of fat cells is de-fattening.



Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise
(I have the full text of this, email me: carbsane at gmail dot com, and I'll share via Google Docs)

So first, a quick recap of the TAG/FA cycles. Below is the augmented diagram from Reshef et.al.  I use the plural because we have an intracellular cycle (inside the fat cell) and an extracellular cycle (liver recycles to VLDL and sends back to the fat tissue).

Let's focus on the internal cycle for a moment.  I've isolated it at right, and labeled the processes involved.  Stored triglycerides undergo lipolysis and are broken down to glycerol and fatty acids.  Fat cells (in humans at least) mostly lack the enzyme required to use the glycerol  as a source of glycerol-3-phosphate for the re-esterification process so it is all released into circulation.  Therefore, glycerol release and blood levels of glycerol in the post-absorptive (fasted) state are regularly used to assess lipolysis rates in adipose tissue.  The fatty acids have two fates -- they can also be released into circulation (green), or they can be re-esterified back into triglycerides (blue).  Thus, the proportion of fatty acids that are mobilized vs. re-esterified can be determined by comparing changes in glycerol levels vs. fatty acid levels.

So in this study, they used radioactive tracers to assess lipolysis rates in response to exercise and in recovery.  Subjects were 5 body-weight and metabolically normal men in their mid-twenties.  The exercise was fairly low intensity (40% max O2 consumption) for 4 hours on a treadmill -- I think this qualifies for "long and slow" -- followed by 2 hours of recovery.  How'd you like to be a volunteer for this?!  When stored triglycerides undergo lipolysis, the glycerol released is not used to re-esterify fatty acids because adipocytes in humans largely lack the enzyme to do so.  In addition to lipolysis and mobilization rates, the rate of fat utilization for energy -- e.g. fatty acid oxidation -- was also measured.

The rate of lipolysis increased 3-fold in 30 minutes and continued to increase to 5-fold of baseline by 4 hours.  Lipolysis decreased rapidly during the first 20 minutes of recovery then the rate of decline slowed, and at 2 hours recovery remained elevated  slightly more than 2X baseline.   Fatty acids in circulation (mobilized) followed the lipolysis pattern (though it would appear more consistently), but interestingly enough there was an "overshoot" spike in levels during the first 10 minutes of recovery after which they rapidly declined for the first hour before stabilizing out during the second hour of recovery -- the 2-hour recovery levels of NEFA look to be approximately 2.5X baseline.

Interestingly the respiratory quotient (RQ) fell slightly during exercise -- from an average of 0.92 to 0.83 -- and remained at around 0.83 during recovery.  Whoa there!  Back up the bus ... see that?  To refresh, the RQ is a measure of metabolic fuel source where an RQ of 1 would reflect total carb burning while an RQ of 0.7 would be total fat burning.  These normal healthy males were burning carbs at rest and even during 4 hours of mild exercise with abundant fatty acids in supply mobilized from fat, and NO dietary glucose, they did become "fat burners", but still were burning some carbs after four hours.   But to the degree they became "fat burners", this is not dependent upon fatty acid availability in circulation, because they kept burning the same proportion of fat for at least two hours after the exercise while fatty acid levels plummeted and leveled off.  Things that make you go hmmmmm.  

It's worth noting that total energy expenditure declined in recovery but remained about 20% above resting for the duration of the recovery period.  The measured fatty acid oxidation rate rose to 10-fold over the 4 hour exercise period, and fell rapidly to about 1.5-1.75X baseline during recovery.  The figure at right shows the measured FA oxidation rate (dark circles) during exercise.


So, back to the TAG/FA cycle.  At rest, 70% of fatty acids released from triglyceride undergo re-esterification.  SEVENTY PERCENT.   There can be no doubt that lipolysis is NOT rate limiting for utilization of fatty acids for fuel.  Now of that 70%, about 17% is re-esterified within the fat cell in the rested-fasted state (the article states it is 20% of the fatty acids released therefore by my math this means of 1/6th of FA's created by lipolysis, however 20% makes more sense for the other math in the article.  I think this is because they mix between percents of amounts vs. percents of rates.)

Now the open circles on the plot represent a calculated rate of fatty acid oxidation if the re-esterification rate remained constant during exercise.  In other words, if the increased lipolysis resulted in the same proportion -- roughly 83% -- of liberated fatty acids were mobilized, and of those 57% were recycled extracellularly leaving 30% to be oxidized.  The difference (shaded area) was because exercise markedly altered the re-esterification rate:  rest = 70%, 30 min exercise = 25%, next 3.5 hours exercise = 35%.  In recovery, the body goes into recycling overdrive to stop the flooding of blood with NEFA.  Re-esterification jumped to 90% during the first 30 minutes before settling back down to near resting values, 75%, by the 2-hour mark.  The overshoot of excess mobilized fatty acids no longer needed to sustain activity apparently stimulates, in some fashion, the re-esterification pathway.   Overall, as stated in the caption, the changes in re-esterification rate account for 50% of the difference between calculated oxidation rate and the oxidation rate actually measured.    Lipolysis and even mobilization does not dictate "fat burning".

The authors address intracellular vs. extracellular re-esterification.  During exercise, the intracellular rate of re-esterification more than doubled, but accounted for only ~ 12% of fatty acids liberated by lipolysis due to the even greater increase in lipolysis rate.  The intracellular recycling rate remained reduced in recovery.  This is important folks, because post exercise your fat cells don't "go wild" to trap fats within, rather almost 90% of the recycling occurs outside the fat tissue.    Comparing rates, the extracellular recycling was 62% of mobilized NEFA at rest, 20-25% during exercise, 72% first 30 min recovery, and fell to 65% during remaining recovery.

Thus most of the change in the percentage of released fatty acids that were reesterified during exercise and recovery could be attributed to changes in extracellular cycling.

If I were going to take a myopic view of this, exercise is amazingly effective to reduce fat tissue mass.  It mobilizes the heck out of fatty acids, and when the time comes to re-esterify them, they are re-esterified outside the fat tissue!  Ahhh ... but the liver does eventually "return to sender" in the form of VLDL.  Got another figure for you.  The open circles are the rate of fatty acid "delivery" to circulation and the dark circles are the rates of fatty acid oxidation.  This graphic makes it perfectly clear that fatty acid availability does not dictate fat burning.  Furthermore:

At all times there was more than enough plasma FFA available to provide all substrate for fatty acid oxidation....

... even in these "metabolically inflexible" men with high fasting RQ's who must have been voraciously hungry as their cells starved.  But while we're on carbs, let's talk glucose levels for a moment.  Plasma glucose levels were 5mm baseline (90 mg/dL), decreased steadily during exercise to 4mm (72 mg/dL), and remained lowered in recovery.

At rest almost all of the glucose released from the liver is metabolized (<15% recycling ), so that changes in availability of glucose during exercise must entirely result from changes in the rate of production. 

Low grade exercise reduces glucose output from the liver.  Interesting that.   OK, some excerpts from the discussion, with apologies that some of these are repetitive:

At rest, ~70% of all fatty acids released during lipolysis were reesterified.  During the first 30 min of exercise, that value dropped to 25%, whereas total fatty acid release via triglyceride hydrolysis tripled (Figs. 3 and 5).   This coordinated response allowed a sixfold increase in FFA availability for oxidation. By itself the sharp decrease in percent reesterification effectively doubled the number of FFA available for energy metabolism in working muscles during exercise and could account for more than one-half of total fatty acid oxidation (Fig. 4).   Immediately at the cessation of exercise almost 90% of fatty acids released from lipolysis were reesterified.  This dramatic increase in percent reesterification was a major reason for the rapid fall in FFA concentration.

Firstly, this is huge!  This demonstrates that the level of fatty acids is determined by the balance of two processes that are controlled separately -- lipolysis & re-esterification -- and in times of high demand, moreso by drastic reductions in recycling (or "fixing") back to triglycerides than by lipolysis.

Although an increase in NEFA for energy is required during activity, the changes in lipolysis do not appear to be the ultimate controller of the "rapid response".  As the authors note:

Had the percentage of fatty acids reesterified in the recovery period stayed at the value during exercise (25-30%), plasma FFA concentration would have risen to a level that would have far exceeded the binding capacity of albumin.  

The rapid changes in re-esterification are critical to keep NEFA levels in check.  Normally, something like a tenth of a percent of fatty acids in circulation are actually "free", as even what we refer to as "free" are bound to the protein albumin.  If we exceed that capacity, then there would indeed be more "free" fatty acids that have markedly lower solubity in water and could present problems (albumin bound fatty acids are technically a lipoprotein, to consider these dissolved is technically incorrect, but a reasonable simplification for the discussion of lipid transport in circulation).    Further to the importance of changes in re-esterification rate:  (note I subbed "lipolysis rate" for "Ra glycerol" as glycerol release is the marker for lipolysis rate)

Although the initial lipolytic response to changes in energy requirements at the onset of exercise and recovery was rapid, the maximum adaptive response lagged behind.  [Lipolysis rate] continued to rise throughout exercise despite a constant rate of energy expenditure after the first 10 min.  At the beginning of recovery the percentage decline in [lipolysis rate] was much less than the percentage decline in energy expenditure, and 2 h after stopping [lipolysis rate] had not yet returned to the resting level.

Bottom line, it appears NEFA levels are far more tightly controlled at the recycle point than the supply point.  At rest and during exercise:

... the rate of [extracellular] recycling appears to be predominantly passively regulated, reflecting the balance between the actively regulated processes of lipolysis and oxidation.

By passively regulated they are referring to the fact that re-esterification in the liver seems to correlate directly with the fatty acid concentration/flux through the liver whereas fatty acid levels are the result of the difference between lipolysis and oxidation rates.  I would note that this was a 1990 paper, a period where glyceroneogenesis was flying under the radar, and as stated in the article, glucose was considered to be the necessary source of glycerol-3-phosphate for esterification.  Indeed despite the fact that re-esterification rates within the fat cells more than doubled as glucose levels decreased during exercise, they remark that the low percent of re-esterification in the fat cells is due to the low glucose supply.  What we now know to be the case, is that the same hormones that stimulate mobilization in adipose tissue also regulate glyceroneogenesis in adipose tissue and the liver to sustain the degree of re-esterification required.  In any case at the time of this article:

In contrast to the situation described for rest and exercise in which the liver may passively reesterify a constant fraction of delivered FFA, during recovery both the absolute and relative rate of reesterification of released fatty acids increased dramatically, despite a decrease in the delivery of FFA to the liver as plasma concentration fell.   One plausible explanation is thatthere was accelerated clearance and reesterification of FFA in peripheral adipose tissue, but the signal for this type of peripheral clearance and reesterification is unclear.  It is also unclear why clearance and reesterification of plasma FFA by adipose tissue would occur at an accelerated rate in the absence of a change in the rate of intracellular TG-FA recycling.  Thus an increased efficiency of reesterification within the liver cannot be excluded.

To be honest, I'm not entirely sure what to make of that paragraph.  I'm tempted to largely ignore the "thinking out loud" given how much more is now known about the TAG/FA cycle. In the next paragraph, however, they lay out a case for the obvious -- something even Taubes acknowledges in his lectures -- re-esterification is "regulated" by the need for it, and the need for re-esterification is "regulated" by the energy state of the organism.  If mobilized fatty acids are not needed and used for energy, they are recycled.  Simple.

Lastly, the TAG/FA cycle is a "futile cycle" of sorts.  It requires energy to convert fats from esterified form to free form back to esterified form, rinse and repeat.  An interesting "metabolic advantage" of exercising might be the energy cost of this cycle.  Note at rest it's quite low, it approximately doubled with low intensity exercise, but increased almost 6-fold in recovery.  Not a lot, but considering this was the type of exercise (would be interesting to see what happens with shorter bouts) that could otherwise be "NEAT" movement, it could add up to something at least as significant as the metabolic advantage calculated for gluconeogenesis requirements with low carbing.

OK .... this is getting long, but one cannot come across a study such as this and not comment on the various theories circulating out there in the paloleo community (this is what I'll call the low carb faction in the paleoish community).  

To all TWICHOOB's who still believe in lipophilia, this study demonstrates that more than anything else, exercise should make you lean and keep you lean.  It clearly tilts the balance of the TAG/FA cycle to the release side, and the majority of the recycling occurs outside the fat tissue.  Whether it is taken back up, then, depends on the energy state of the organism.   I've got some very recent work by Keith Frayn's group that shows VLDL does tend to be taken up for longer term storage by gluteofemoral fat ... and this may well explain why women tend to have better clearance of these particles.

Then you have the Peter/Hyperlipid, J. Stanton/Gnolls and Taubes theory that you're not hungry on low carb diets because your cells are "eating" fatty acids that are available in abundance to your cells due to low insulin.  If that is the case, then how is it that (paraphrase) "exercise is useless for weight loss and it only makes you hungry"??  At the very least, IF your cells were starving before, because of all the locked up fat, they aren't during exercise, and they remain "well fed" for at least two hours afterwards.    By their theories, exercise should blunt hunger.

And lastly we have the whole metabolic flexibility, wanna be a fat-burner, mitochondrial dysfunction crowd spearheaded by J.Stanton & Peter D.  I'm not going to go into that theory which just has no basis in the science or common sense.  Suffice it to say this study can be added to the heap of evidence against impaired mitochondria causing obesity ... or do I have that theory wrong?

Is there anything actionable in this post?  Well, exercise and don't consume excess energy the rest of the day, and your fat cells will empty out!