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Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Saturday, June 23, 2012

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!





41 comments:

ProudDaddy said...

Help an aging layman out here.

So your cells aren't starving for fat fuel during and shortly after exercise (or for a resting state in the obese, for that matter). How does this translate to not being hungry? Couldn't the elusive obesity mechanism be related to a disconnect between hunger and cellular energy state?

How did this study debunk the idea of impaired mitochondrial function? Did it show that the preobese, obese, and formerly obese burn NEFAs at the same rate as the perpetually thin?

I know I must be misunderstanding a lot of this stuff, but not all of your readers have a degree in physiology. How about dumbing this down for those of us who are at sea?

Regards, as always.

Evelyn aka CarbSane said...

Personally, I don't know if elevated fatty acids influence hunger signals, but if they did, they should stimulate appetite. Why? Because they are highest in the fasted state and during/after heightened energy expenditure. But the "unconventional wisdom" seems to be that carbs make you hungry by stimulating insulin, which traps fatty acids in your fat tissue thereby starving your cells, which makes you hungry and eat more. I haven't gotten to it yet, but this is the scenario Lustig sets up in Part 3 of the Skinny on Obesity series (http://www.youtube.com/watch?v=Yo3TRbkIrow) and Tom Naughton sets out in Fat Head. Made up nonsense that I have no patience for anymore :) So if tipping the TAG/FA cycle towards TAG supposedly starves cells and causes hunger, then tipping it towards FA should bathe cells in energy and assuage it.

"Couldn't the elusive obesity mechanism be related to a disconnect between hunger and cellular energy state?"

I certainly think that's more than possible!

"How did this study debunk the idea of impaired mitochondrial function? Did it show that the preobese, obese, and formerly obese burn NEFAs at the same rate as the perpetually thin?"

It isn't a thorough debunking, but a big stink was made about how in one paper, the so-called preobese and formerly obese had high fasting RQ's that were supposedly indicating some impairment of mitochondrial ability to burn fat. For starters it makes no sense that once obese these dysfunctional mitos magically become super burners (the obese in that paper had rather low RQ's) -- that has nothing to do with this paper. But here these lean young metabolically undamaged men had fasting RQ's averaging 0.92 -- on par with an RQ's of the post obese "damaged" people. And yet with activity, their fatty acid oxidation ramped up nicely -- so it CAN'T be a capacity issue, their mitochondria responded just fine and started burning fatty acids as they became more available (while still burning a fair amount of carb b/c RQ was nowhere near 0.7)

If there's anything else I can explain better feel free to ask and I'm happy to respond. I'm afraid right now my sarcasm gene is overexpressing and I'm in another one of those moods of incredible disbelief about the sheer volume of total made up crapola being passed off as science and high-minded hypothesizing in the low carb community. It is making me sick and making taping the narration for my GT piece difficult -- the last thing I want to do is sound as annoyed as I am! LOL

ProudDaddy said...

OK, I understand your first point as showing something doesn't follow in a flawed theory. As to the obese having the same RQs as the study's healthy thin folks, doesn't that only indicate that the mitochondria burn glucose and fat at the same proportions? Couldn't damaged mitochondria not be burning enough of either substrate in the formerly obese at least?

Nigel Kinbrum said...

I think the theory is that fatty acids only generate ATP via mitochondria whereas carbs can generate ATP via mitochondria and other pathways. Therefore, mitochondrial damage shifts ATP generation away from fats towards carbs using the other pathways, which increases RQ.

Morris said...

Hi Evelyn
An interesting analysis. It seems to me that presenting an energy balance during each phase ie contribution from all sources (plasma NEFA, plasma glucose, muscle TG , muscle glycogen) would be a clearer way of showing how much fat is actually burned. That the authors used a work-around ie re-esterification perhaps suggests difficulty in establishing the contribution from muscle TG’s. Is muscle TG contribution well understood, significant in this case? See Fig 9.9 in Keith Frayn’s textbook at http://bcs.wiley.com/he-bcs/Books?action=resource&bcsId=5402&itemId=1405183594&resourceId=20824 for energy partition at two intensities. The 2 intensities given in the chart are below (25%) and above (65%) the study and also for a shorter period.

Evelyn aka CarbSane said...

Thanks for that clarification Nigel ... it still makes no sense to me since as we age we normally tend to become more insulin resistant and our RQ's decline meaning we're burning more fat. If the RQ's cited in that selective (one might say cherry-picked) review are true, somehow we damage our mitochondria with overnutrition but at some breaking point when we become obese (sorry, this notion of "preobese" is confusing) all of a sudden our mitochondria can now burn fat again?

@PDaddy, As I said, this study doesn't debunk that theory fully. But many others have ... thorough reviews of the literature that conclude mitochondrial impairment leading to impaired fat burning is not identified as a cause for obesity. In the formerly obese they had to be fat burning up a storm to become so ... so now they're left with damaged mitochondria as a result? Regain seems far more impacted by lower metabolic rate requiring lower intake be sustained (compared to what the person was used to eating for years prior), metabolic rate may be lower compared to someone who had never been obese due to adaptation, and/or leptin levels may have fallen too low from shrinking fat cells.

In good science one takes observations then formulates a hypothesis, then tests the hypothesis. I'm not aware of any information showing that mitochondrial dysfunction is more prevalent in obesity prone cultures. RQ is very much influenced by diet and energy state. I've seen many papers measuring high RQ in the obese, in direct contradiction to that one paper. Indeed if memory serves, I've yet to find another study that showed obese with substantially lower RQ's than pre/post or lean controls, etc.

Personally I think RQ is irrelevant to weight gain, loss or maintenance -- it only tells you that if you expend 2000 calories in a day maybe 80% comes from carbs and 20% from fat, or 80% from fat and 20% from carbs. At the end of the day, if you've eaten 3000 calories, 1000 of those calories are going to be stored as glycogen or fat.

This notion of being a "fat burner" is a scam! Especially if one is eating a load of fat, because they're not burning all of it and we all know a famous person who regained a lot of weight doing that!

Jim said...

Evelyn, You have clearly established that subtracting fat or carb calories are equally efficacious for weight loss, but the theories of Peter and J. Stanton et al are from people who have low fat mass and are trying to provide a scientific rationale why when you have low fat mass, carb and fat calories are clearly not equivalent. Since you do not personally have low fat mass, you do not see the "common sense" in their position (even though their theories may be scientifically incorrect) which is that different exercise activities require differing amounts of carbs in the diet when you have a low amount of fat mass and wish to prevent gain of fat mass and retain a decent amount of lean mass. Peter and J. Stanton and Mark Sisson obviously do not have the same exercise regime as Anthony Colpo who needs far more carbs in his diet. Can you marshal your research knowledge toward answering why this may be so? It is not a weight loss issue but it is important for avoiding obesity.

Evelyn aka CarbSane said...

Jim, I don't know what my fat mass has to do with understanding common sense, but just so you know, I was not always obese and I'm do not come from a genetic pool of obese people. I have had low fat mass at various times in my life. The reason I can't see the "common sense" in their theoris IS because their theories are demonstrably scientifically incorrect. I don't know Peter or J's lifestyle, but Mark would do just fine I'm sure eating like Stephan Guyenet or Kurt Harris, both of whom currently (unless something has changed for Stephan) consume 40+% carb. I don't accept that carbs would make any of those 3 obese. Entire cultures eat far more carbs than AC and are lean and healthy -- like, for example, Taubes favorite traditional Pima he loves to misrepresent repeatedly, and the Kitivans -- like 80+% carbs and they are lean and healthy. And while I hate to invoke his name in terms of a healthy diet, Durian Rider is almost "excessively" lean. Carbohydrates did not make me fat. Heck, fat didn't make me fat. But considering what foods did make me fat (combination of carb + fat, processed and takeout) I'd say it's a pretty good bet that the fat had more of a hand in it. But that's just me, and I don't hold out my anecdotes as proof of anything.

Evelyn aka CarbSane said...

With any luck one of these days I'll get around to blogging on the lipid droplet stuff I came across over a year ago.

If I understand correctly you're wondering what amount of NEFA that is presumed to be oxidized might not have been b/c the muscle TG was used instead (at least partly?). I don't know for sure, but it seems reasonable to presume that muscle TG levels are relatively constant. I wonder if anyone knows of a study where they are measured in adapted low carbers in maintenance. Because high levels are found (and maintained) in trained athletes indicating continual replenishment of these local stores. Therefore it might be reasonable to assume that "net re-esterification" can be assessed by the difference of liberated - oxidized, though the actual re-esterification of the released NEFA may well be higher to replace muscle TG used for fuel. Hope that makes sense.

ProudDaddy said...

I'm still confused. So, what's new, heh? Anyway, it's easy to see that obesity cannot be a result of evil insulin locking fat into fat cells when one's blood is full of fat fuel. But since glucose levels are often also elevated (attendant diabetes or pre-diabetes), a reduced resting energy expenditure cannot be for want of fuel. If we can agree that something goes awry in the body's normally very precise homeostasis mechanism, then it seems to me that the problem has to be that fuel intake is too high because the feedback mechanism isn't measuring the excess correctly or is calculating the requirements incorrectly. This latter explanation would seem to me, the layman, to represent a lower REE / insufficient fuel burning situation. And to simple-minded me, fuel is burned primarily by mitochondria. So, our body temp is a few points lower, or the body subconsciously doesn't move as much, or both, and we get, or stay fat. I'm sure there's a precise scientific definition of impaired mitochondrial function, but to me it would just mean insufficient fuel burning.
So, to overweight me, it makes sense that my mitochondria might be letting me down. The other possibility is that the regulatory mechanism doesn't recognize that there's plenty of fuel in the tank but is still calculating the requirements correctly, or both, and now I'm really confused!

Evelyn aka CarbSane said...

Ahh ... I see part of the problem is confusing RQ which only reflects the proportion of carb v. fat burned for fuel with REE which is the total fuel burned.

I dunno, I'd love to get back to that metabolism series one of these days, but most of what I was finding about the formerly obese was the very short term after dieting. If that Biggest Loser study showed us anything, it was that the REE of the obese is extremely high, and even after weight reduction, it remained quite high despite supposed suppression beyond that predicted by body weight.

More later ...

Jim said...

But Evelyn, the point is that the type and amount of exercise DO correlate to macronutrient intake when your body fat is low. The compulsive always-in-motion types like Durianrider and Colpo need lots of carbs to be lean; the slower and aging Sisson and Peter know they fatten up on carbs. None of these people would be swayed by your "scientific" argument that macronutrient percentage does not matter at all to obesity! And they are all demonstrably successful in maintaining low fat mass! Even the "macronutrient agnostic" Dr. Harris most certainly did not say "I had to do some serious physical labor so I cut carbs and increased fat." So I don't see that maintenance of low body fat while maintaining lean mass, where 99% of the people in the USA fail, is a priori the exact same science as losing weight because you cut calories.

Geoff 99 said...

The following review paper from 2007 discusses some of the issues with mitochondrial function, especially in the obese with high IMTG. The role of IMTG and reduced lipid oxidation in facilitating mitochondrial damage might make one wonder about the long term wisdom of a high fat diet.

In this and in other papers I have seen the argument made that exercise encourages biogenesis of mitochondria - i.e. more exercise equals more mitochondria equals more function.

On the other hand, I haven't found any papers yet studying obese, sedentary people on a prolonged 85% fat diet ( would you get ethics approval for such a diet? ).


"Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise"

http://www.ajcn.org/content/85/3/662.full.pdf

"In contrast, obese persons and persons with T2DM exhibit reduced mitochondrial efficiency and lipid turnover, which may facilitate the build up of deleterious lipid metabolites and encourage lipid peroxidation, which in turn can affect both insulin signal transduction and mitochondrial function (34, 36). Overall, reduced lipid turnover is a necessary component to any apparent lipotoxic effects on insulin signaling that may arise from IMTG accumulation. Under conditions of reduced lipid oxidation, there is an increased load of fatty acids on the mitochondrial membrane facilitating the entrance of neutral fatty acids into the mitochondrial matrix (37), where they are prone to lipid peroxidation. Studies have shown that there is a higher degree of lipid peroxidation within skeletal muscle of obese insulin-resistant persons (36). The peroxide products are highly reactive cytotoxic metabolites that damage DNA and proteins and further hinder mitochondrial oxidative capacity. This constitutes a vicious cycle, and it is currently unclear whether mitochondrial defects lead to IMTG accumulation or whether IMTG accumulation leads to mitochondrial defects."

Evelyn aka CarbSane said...

Please ... if you honestly believe Mark Sisson would become overweight let alone obese eating carbs, there's no discussion to be had. The man is active if not a maniac like AC or DR. FWIW, my mass may not be low fat, but I have managed not to regain fat and even losing some for a short while incorporating more carbs. Many, many others in the LC community have done so as well which is why I mentioned Kurt. Last he posted here about his diet, he mentioned eating 40-50% carbs (don't recall the exact number) and made it a point that he didn't have a problem staying lean. Macro composition of the diet not to gain weight obeys science too. Near as I can figure, Peter is not concerned about weight at all, he's more in it to avoid some skin issues and such and that is not due to carbs per se, but probably some specific foods. Shame he doesn't find out which but rather celebrates his young child shunning a banana but smearing his face with honey sweetened chocolate -- chocolate being a highly processed/refined/decidedly NOT "whole" "real" "food".

Personally I think a sedentary person would probably do better to eat high carb low fat than the other way around. This notion that carbs are only for the super active is another myth I hope to bust through some day. Too many other things on my plate just now ...

ProudDaddy said...

I think if you reread my posts, I correctly noted that RQ represented the proportions of substrate, not the absolute expenditure. Actually, it was my point.

In any event, I'm guessing you subscribe to the notion that we get fat because we eat too much. I'm curious as to why we do so. Homeostasis mechanisms I can understand. The significance of the AMP:ATP ratio, or whatever, is beyond me.

Jim said...

I am in total agreement with you that a low-fat diet emphasizing filling starch such as potatoes is the easiest way to lose fat mass because one suffers much less from the low calorie level that is necessary. Where I disagree is when you extrapolate that to maintenance of fat mass loss. Hopefully, you will have the opportunity to lose fat mass and stop and ask how do I maintain this? At that point I predict you will decide that you must limit carbohydrate to your glycogen usage which may be quite low unless you exercise intensely; otherwise the calorie level will be uncomfortably low and lean mass will shrink--or else you will just gain the fat mass back when you give up.

Steven Hamley said...

I think 'mitochondrial dysfunction 2011' missed the mark. It's not so much being a fat or sugar burner, it's more about aerobic vs anaerobic. A cause of the metabolic acidosis in T2Ds is high production of lactate and poor aerobic respiration (mitochondrial dysfunction).

The study of the healthy young men and RQ knocks the idea of burning glucose = a sign of poor health and of de novo lipogenesis playing a major role in metabolism. If someone thinks it's only healthy to burn fat at rest then a thought hurdle is the idea of what happens to the carbs after ~2 hours, because you couldn't possibly be burning that many carbs then.

It could be more accurate is to say 'healthy is good aerobic metabolism, whether that comes from carbs or fat is irrelevant'. Low carb diets can facilitate that adaptation if you've got IR/T2D/etc, but afterwards it doesn't matter.

Let me know what you think and thanks for the interesting post Evelyn.

chintillo said...

More than 1 hour of exercise reduce leptin levels, this could have some impact in some parts of the study results.

And is impossible to be a sedentary and go to a high carb diet without a dieting plan. You are hungry all the time. That is why people cannot eat high carbs without becoming obese or having high sugar levels or go to the gym.

If you eat high carb you cannot be 5 hours without eating. If you do so, you start to be terrible hungry and disconcerted.

In Greece, due the economic situation, some fathers cannot afford breakfast for their children. The result is that some children fain in class.

I really like your blog but no matter how many chemicals pathways you post but is not possible this is a good diet.

Mike said...

"If you eat high carb you cannot be 5 hours without eating."

Then why can all the people who eat tons of carbs go 8 hours or more every night without dying in their sleep or waking up halfway through to top off their glucose stores?

Evelyn aka CarbSane said...

Sorry if I misunderstood. OK, let's try this: Are you saying that mito dysfunction --> reduced REE --> weight gain? I don't think how much "fat burning" goes on is directly related to metabolic rate -- not from dietary manipulation anyway.

If reduced obese eat too much and regain, leptin seems the likely culprit there, as it does for the reduction in REE for that matter. Leptin increases metabolic rate and suppresses hunger. Deflated fat cells --> reduced leptin --> reduced met rate and increased appetite. I'm not saying that IS what happens, but that this is plausible and supported by what we know about leptin, etc.

Evelyn aka CarbSane said...

Sounds good Steven. Whoo boy, that word "lactate" just jumped right off the page at me. Something I've been looking at on the side is DNL in the adipocyte to generate palmitoleic acid. This MUFA has even been described as a lipokine or "hormone" of sorts with insulin sensitizing properties. Diabetics apparently have impaired aDNL. Excess glucose is mostly converted to lactate in their dysfunctional adipocytes (if I read that right, I'm having a hard time remembering where I read that, hopefully I'll remember to poke around later this week).

There's been a lot of discussion about which mito complexes are used for carbs vs. fats. These discussions ignore the action of UCP3 which seems to be more of a transport protein than an uncoupler to prevent FA buildup and peroxidation. I guess we could call this MD 2012 ;-)

Evelyn aka CarbSane said...

I lost around 100 lbs of fat mass in 2007-8, and I can lift and hold a 55 lb kettle bell in an upright row position for several seconds, NO weight training. Eating more carbs over the past year and a half has not turned me into some ravenous fiend ... indeed maintenance is easier than just strict VLC.

I'm not the extrapolater here (not saying you are either). But those who point to Sisson and say just going from SAD to Primal will turn a 300 lb man into him ... those are the extrapolaters.

ProudDaddy said...

To the best of my knowledge, fat is not the only fuel we burn, and I didn't say anything about only fat burning or dietary manipulation. All I'm saying, and I know that it's oversimplification, is that we either consume too much energy, or don't burn enough, or both. Since mito do the burning, I don't understand why they can't be part of the problem. Are there studies in humans who are NOT weight stable, with ad libitum diets, that somehow their mito are chewing up fuel as well as thin weight stable people?

P2ZR said...

My memory may be concocting things, but remember that much-vaunted HIIT study where the HIIT exercisers burned fat at 9x the rate and/or for 9x as long compared to steady-state exercisers? Was that eventually debunked (how I can't stand that term anymore!) due to this very issue of mobilized but not used up (actually 'burned') FA's, so it was much ado about lipolysis that merely led to re-esterification?

Galina L. said...

I think that being able to tolerate hunger is the mark of a healthy metabolism. I couldn't practice IF and used to be hungry on scale one to 10 right at 10 mark in 2 - 3 hours after eating a mixed meal. I needed to start LC diet to resolve that issue (and some more). However, I personally know people who could comfortably fast even on a high-carb diet.
In case if you are guessing, I usually live comments in the defense of LC way of eating, but I don't see LC approach to a diet in a simplified way. Probably, people who faint from the lack of breakfast are not adopted to fast, but not everybody needs such adaptation.

MD said...

Using men who are naturally thin (Sisson, Harris, etc) might not be the best way to look at this. Peter has mentioned in his early blog archives that he started eating OD to lose some weight. He also has a pretty active lifestyle. His child looks happy and healthy and they use very high quality chocolate with very little sugar. I wouldn't take the posts that he's done on food he's made for special occassions as indication that that's the only thing he eats.

High carb low fat seems like a recipe for disaster except for those who are naturally thin and / or athletic. Most dieters, even those using CICO end up eating moderate carbs and low fat to save calories. I read the blogs of many personal trainers and fitness pros, nearly all of them eat moderate carb levels to stay thin, especially the women.

Steven Hamley said...

Another factor in the glucose>lactate thing could be adipose tissue hypoxia (ATH)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650750/?tool=pubmed

I haven't delved into the topic, but this study discusses the role of ATH in insulin resistance, inflammation, lactate overproduction, MD and ER stress and that ATH is due to poor blood flow from too much fat (and atherosclerosis?).

Evelyn aka CarbSane said...

I don't recall that study, but there've always been studies about how this or that exercise is better for "fat burning" than some other exercise. I think any argument about weight loss that is based on lipolysis or RQ is, frankly, a hoax. Performance and body composition/fat distribution is another story, but many of those arguments appear to be largely based on conjecture.

Evelyn aka CarbSane said...

Welcome chintillo! I have to be more careful about this too, but the absolutism -- e.g. you WILL be hungry all day -- really has got to go! Many low carbers will report days where they are just hungry all day long and no amount of LC food seems to do the trick, it's happened to me a few times. When I started eating oatmeal again, I was quite surprised just how filling it is, and for how long. Sometimes I can't even finish the bowl at 10am and I'm not hungry again until 6pm. I only make it with almond milk so it's pretty low fat too. Yes, that's just me, but I think many who have psyched themselves into this carb=hunger meme would find themselves equally surprised.

Evelyn aka CarbSane said...

That one's a keeper! Some of what I've come across lately boggles my mind -- that it's all been out there, in many cases for 10 and even 20 years, for quite a while and I never came across it before. This fits right in with that and I'm going to have to make time to look at this further!

The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity.

This jumped out at me from the abstract ... for obvious reasons given my near obsession with fatty acids ;)

Evelyn aka CarbSane said...

Are those posts about special occasions? It doesn't seem so. There are tons of babies who look happy and healthy noshing on Cheerios.

High carb by percent is not a recipe for disaster. It's how Americans used to eat before this obesity epidemic, and how the Pima used to eat despite what Taubes misleads people to believe. No need to even invoke remote cultures like the Kitivans.

Evelyn aka CarbSane said...

@PD: Forgive me for intertwining what "they" say in with this discussion. The overarching point of the post is that using the mechanisms of Taubes' theories, exercise would be THE most effective means for fat mass loss. It mobilizes fat like crazy and most of it is re-esterified outside the fat cells. As to mitochondria, there are animal models of impaired mito function leading to obesity, but this cannot explain the obesity epidemic, so to the line in Geoff's paper where it's unclear what is cause and what is effect, the evidence seems to come down on the side of effect. Since mitos are regenerated, it also doesn't seem to be permanent damage -- which is good news. My point of raising the RQ issue was best re-expressed by Steven:

"The study of the healthy young men and RQ knocks the idea of burning glucose = a sign of poor health."

Mitochondria "burn" carbon-based molecules for fuel when fuel is needed. The fact that any of us can ever do more than sit around all day speaks to that we have more than enough mitochondrial capacity. Hope that makes sense.

Nice find Geoff!

Nigel Kinbrum said...

You mean Impact of exercise intensity on body fatness and skeletal muscle metabolism?

Unknown said...

I think that logically there has to be a connection between exercise intensity and increased rate of fat loss, of course that is offset by the fact that there is an inverse relationship between intensity and exercise duration, so the less intense exercise may well yield superior fat loss (due to higher duration).

Most people don't do much of anything though, and those who do often fool themselves about the intensity of their efforts, so the point is probably moot for 98% of the population.

ProudDaddy said...

I should have made it more clear that I have no problem with the main points of your post. It was just the next to last paragraph on mito dysfunction that I couldn't follow, especially after having just read Rogge, 2009. I am really looking forward to a Carbsane post on miti function in the preobese (the arm of an RCT of participants who are gaining weight vs the weight stable, if there's ever been such a thing). I just don't believe studies of weight stable obese or the formerly obese can explain much about how we got fat in the first place, both as a nation and as individuals.

Finally, here's an off topic obersvation regarding ELMM. When I was a kid, long before you were, there was only one "fleshy" lady in my known universe. A sedentary village lady? Nope, a farmer's wife. Everyone was always baking up a storm, except for a brief period of sugar rationing during WWII. Yet even said farmer's wife was not obese by today's definition. When you next visit the subject, I'd really be interested in your possible explanations.

ProudDaddy said...

Please forgive the spelling errors. It's not dementia yet (I think). I'm using a tablet which is not a touch typist's or editor's dream to use.

P2ZR said...

I'm not sure; to be honest, I don't know if I even came across the original study at some point. I know that the punchline of '9x rate of fat burning' was repeated ad nauseam by fervid HIIT proponents. It *was* mentioned that the actual kcal used in exercise was fewer for HIIT (thus helping to build to the 'mindblowing' conclusion of greater total 'fat burn' over the course of the day), but I'm not sure if they actually measured skinfolds. For a long time, I had filed it in the 'how does this even make sense?' folder.

P2ZR said...

The takeaway of the study I'm thinking of was, 'kill yourself for 15 minutes, and you'll burn a zillion times more fat than in a moderate 1-hour effort.' Very true that people think that by the mere act of going to the gym, they are killing themselves--even if it's just reading a magazine on the recumbent bike.

Craig in CT said...

I am currently reading the latest book in the "New Rules of Lifting" series of books. This one is subtitled "for Life". The basic thrust is how to train and avoid injury when you are middle age or older. They also offer some advice about diet, nutrition, and weight loss.

On the subject of exercise and weight loss, they spend a couple of pages on this particular study:

"Dual-process action of exercise on appetite control: increase in orexigenic drive but improvement in meal-induced satiety1,2,3,4" by Neil A King, Phillipa P Caudwell, Mark Hopkins, James R Stubbs, Erik Naslund, and John E Blundell

http://ajcn.nutrition.org/content/90/4/921.full

As per the NROL4L summary: The study put several dozen overweight and obese people on a 500 calorie per day, 5 day per week exercise program, then tracked food consumed, weight changes, and body composition changes over a 12-week study.

On average, the participants lost 7 lbs, mostly from fat. But the range of the results was large. One extreme responder ate 1000 calories per day less and lost 31 lbs, without reporting any issues with hunger. In the middle, some responders ate more, but still managed to lose weight. And one of the unlucky nonresponders ate so much more that he/she gained 7 lbs.

So exercise worked for some of these people, and failed miserably for others. The $64K questions is Why? Unfortunately, the referenced article did not offer a clear answer.

But then the NROL4L author's mention another review paper by the same group of scientists which 'hints' at a possibility. Unfortunately, this review paper wasn't referenced clearly, so I couldn't find it. But I will repeat the NROL4L interpretation, which was that it might be due to differences in the proportions of fat and carbohydrate burned during (and after) exercise: they speculate that nonresponders tend to burn more carbs in response to exercise than the responders. Since the body can store a lot more fat than carbohydrate, it will more strongly defend carbohydrate depletion than fat depletion. So if you derive a relatively high proportion of your exercise calories from carbs, you will end up hungrier than if you derive a relatively high proportion of the extra calories from fat.

It seems like a tidy explanation. But I am guessing from your comments in this thread, you'd probably say it was BS, just more bad science??? Or is their interpretation of poor metabolic flexibility different than what you are referencing?

ProudDaddy said...

Don't you just love scatter plots? They ought to be mandatory in all studies.

I was disappointed to see that measurements of satiety stopped at the 4hr point. My hunger compendation after long intensive exercise always occurs the next DAY.

Any further explanations for the responder/non-responder differences that you can flush out would be greatly appreciated.

Tomas said...

Maybe also the type of fat can influence tendency to either glycolysis or oxidative metabolism

Glycolysis inhibition by palmitate in renal cells cultured in a two-chamber system.
http://www.ncbi.nlm.nih.gov/pubmed/9374661

and this one is from the glucose > lactate department
Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia
http://cardiovascres.oxfordjournals.org/content/59/1/143.abstract
in swines that is:)

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