las

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!)

Friday, August 17, 2012

Ketone and Fat "Burning" are Not the Same Thing to Your Mitochondria

This notion of being a "sugar burner" vs. a "fat burner" -- with the latter being touted as preferable based on nothing I've seen in the scientific literature -- is getting really out of hand.  This is not a new idea, but it certainly seems to be being pushed more lately, particularly in the area of athletic performance.  There were a smattering of posts about the diets of Olympians about the net and I just have to shake my head at the one that goes something like "just imagine how much better fill in the blank would do if (s)he didn't eat grains" or "ate LCHF" or "went paleo".  C'mon already ... Michael Phelps is a prime offender of all laws and gods nutritional, but will someone please remind me how many medals he's earned and records he's held/broken in his career?  Gawd forbid any of these elite athletes set a bad example by having their face put on a box of Wheaties!  I dunno ... it all seems so silly when Phelps sports one of the leanest torsos on the planet burning sugar.  But I digress ...

But with ketomania in full-blown fad form, there's a new twist on the fat burning meme which is to confuse fat burning with ketone burning.  It is not.  Yes, ketones are produced mostly from the breakdown of fatty acids (they are also produced from some amino acids), so you "burn fat" in your liver to produce them.  If you are in caloric deficit, the source of the fatty acids will be body fat.  However, if you're fueling the other cells of your body with ketones, this is not the same as the mitochondria in those cells "burning fat".  

Below is a schematic of a brain cell mitochondria and the metabolic pathways showing where ketones feed into Krebs (aka the TCA), from:  D-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease (thus it shows the points of issue for these two diseases) 


See there just above and to the right of this sentence?  That's the major ketone that enters the mitochondria and produces an NADH if converted to acetoacetate which is then converted to acetoacetyl-CoA and finally to two acetyl-CoA's.  Acetyl-CoA feeds into Krebs generating the NADH that is put through -- yikes! -- Complex I of the ETC.  Glycolysis to produce pyruvate takes place outside the mitochondria, so if one wants to nit pick, the mitochondria are directly fueled by pyruvate primarily, and alternately by ketones.  It would appear that ketones may work by feeding the TCA intermediates from a point in the cycle other than where the defect occurs glucose metabolism ... but that's not the subject of this post.  
direct image link

Unlike glucose, fatty acid burning, aka beta oxidation in what is commonly referred to as the fatty acid spiral, occurs entirely within the mitochondrial matrix.  First the fatty acids must be activated and transported through the double membrane of the mitochondria into the matrix as shown at right.  The entire mitochondrial transport/metabolism scheme is shown below.  Notice anything?  In addition to ROS which are formed in not the common TCA, and common ETC (though yes, different ratios of ROS from different protein complexes used), we have metabolic byproducts that can build up inside the mitochondria.  When one wants to talk about a "clean burning fuel" it is one that is "burnt" completely.  This is the case for glucose/pyruvate and ketones.  But not fats.  I will go into this in more depth in another post or few with citations, but incomplete oxidation of fatty acids and the buildup leads to lipid peroxidation and so forth.  This particular schematic comes from this paper (I do not currently have the full text, if anyone is so inclined, I'd appreciate a copy carbsane at gmail dot com).  

image link 

Caption from article:   Lipotoxicity evokes mitochondrial dysfunction by affecting organelle-associated protein phosphorylation. Illustration of the proposed consequences of lipotoxicity on mitochondrial protein phosphorylation: (i) fatty acid overload exceeds the oxidative capacity of the mitochondria, resulting in enhanced radical production that is accompanied by generation of lipotoxic derivates. ROS can affect constitutive matrix kinases and/or phosphatases, yielding deleterious changes in the mitochondrial phosphoproteome. (ii) Upon excess substrate flow, various enzymes and/or kinases are activated (e.g. Nox, JNK and/or PKCβ), leading to phosphorylation of protein mediators, such as p66Shc, that translocate to the mitochondria and trigger organelle dysfunction. (iii) During the onset of lipotoxic responses, cytoplasmic kinases are activated and associate with the inner mitochondrial membrane to affect ion-transporter activity by reversible phosphorylation, causing mitochondrial dysfunction because of an ionic imbalance. Abbreviations: I, II, III, IV, complexes of the respiratory chain; Cyt c, cytochrome C; acyl-CoA, acyl-Coenzyme A; GPDH, glycerol-3-phosphate dehydrogenase; IMM, inner mitochondrial membrane; JNK, c-Jun N-terminal kinase; mtHsp70, mitochondrial heat-shock protein 70; NADH/H+, reduced nicotinamide adenine dinucleotide; Nox, (plasma) membrane-bound NADPH oxidases; OMM, outer mitochondrial membrane; p66Shc, Src-homology-2-domain-containing transforming protein 1; PKCβ, protein kinase C-β; PTP, permeability transition pore; Q, uniquinone; ROS, reactive oxygen species.
Missing from the schematic is UCP3 - uncoupling protein 3.  I have a lot of information on UCP3 and it's role in preventing fatty acid overload.  Much of the current literature makes a case that UCP3 is misnamed as it appears to be less of a true uncoupling protein and more of a transport protein facilitating fatty acid transport out of the mitochondria.  Mitochondrial dysfunction in diabetes is linked to defects in the genes encoding UCP3 -- a deficiency in the ability of mitochondria to essentially expel the "dirty" byproducts of burning fatty acids as fuel.  More details to come ...

Bottom line, certain cells of the "fat burning beast" may be operating more efficiently -- those that normally burn glucose and there's evidence that ketones can improve cardiac muscle efficiency (as does insulin!).  But the cells being forced to burn more actual fat for fuel?  If you've got dysfunctional mitochondria, this isn't going to make the situation better.  I don't know that it will make it worse, probably not in caloric deficit/weight loss, but nobody really knows in caloric balance, especially in the obese or overweight state.  

21 comments:

Charles Grashow said...

http://www.ajcn.org/content/88/5/1419.long

Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies

Conclusions: The meta-analysis shows that fructose intakes from 0 to ≥90 g/d have a beneficial effect on HbA1c. Significant effects on postprandial triacylglycerols are not evident unless >50 g fructose/d is consumed, and no significant effects are seen for fasting triacylglycerol or body weight with intakes of ≤100 g fructose/d in adults.

Tsimblist said...

Will you eventually explain how glucose gets changed into pyruvate? I am under the impression that it is a stressful, inefficient cascade with its own fallout.

Sanjeev said...

that is truly, TRULY SERIOUSLY WHACKED.

It occurs, with variations, in nearly all organisms, both aerobic and anaerobic. The wide occurrence of glycolysis indicates that it is one of the most ancient known metabolic pathways.[3] It occurs in the cytosol of the cell.

that blurb is from here:
http://en.wikipedia.org/wiki/Glycolysis
or click

but from my memory of all my coursework (admittedly pretty old now) that claim is way, way "out there" ... any stress from this is a STANDARD, unavoidable stress that comes with living.

Sanjeev said...

> that is truly, TRULY SERIOUSLY WHACKED.

IOW whoever convinced you of that was either joking or misguided

Tsimblist said...

I agree. I am confusing glycolysis with post-glycolysis anaerobic respiration which creates lactate.

Here is another blurb from your source:
"This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen, or in infarcted heart muscle cells. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time."

Evelyn aka CarbSane said...

I'm not aware of it being stressful. It requires 2 ATP to doubly phosphorylate glucose, then it's split in half, and produces 4 ATP and NADH when dephosphorylated to pyruvate.

I'm seeing a lot of BS how glycolysis is (more primordial) anaerobic while fatty acid oxidation is aerobic. Perhaps confusing that there are two glycolysis pathways? Dunno.

If I come across anything I'll be sure to post.

Evelyn aka CarbSane said...

Lactate feeds well into various pathways. I haven't had a chance to digest this one yet, but http://carbsanitylibrary.blogspot.com/2012/05/lactate-metabolism-new-paradigm-for.html

Tsimblist said...

"Perhaps confusing that there are two glycolysis pathways?"

Yep, I think that was my problem.

Unknown said...

In the Paleo-sphere your thoughts on the matter do not count unless at some point in your life you were an elite triathlete.

/proud Carb Burning Beast who is a non-elite athlete


bentleyj74 said...

...and if you were an elite athlete but are not LC Paleo your thoughts are disqualified from submission.

Standards people. Standards. :)

P2ZR said...

As icky as all this is (sorry, Evelyn!), it's still less icky than photosynthesis, at least as I remember it.

Wait. Plants are autotrophs. Autotrophs don't need glucose--they produce all the glucose they need. If we go back far enough in evolution, we were ALL (unicellular) autotrophs. Therefore, we all at one point didn't need glucose because we could produce all our own! Ta-da--the marriage of LC and paleo!

Oh, wait again. I think I hurt Jimmy Moore's feelings. See, we were autotrophs a few billion years ago. But the earth is only 6,000 years young. And we were Created fully formed upon it. Darn, this doesn't work. Back to the drawing board....

Charles Grashow said...

http://wholehealthsource.blogspot.com/2012/08/ancestral-health-symposium-2012.html#more

The "safe starch debate" was kind of entertaining. There was a panel of people basically debating whether or not starch can be part of a healthy diet, moderated by Jimmy Moore (who I think did a good job). The fact that this debate even took place is absurd—this is the kind of thing that makes it so hard to get research funding to study the Paleo diet. But in the end, thanks to Chris Kresser and Paul Jaminet, carbs prevailed. One of the most surreal moments happened right after Kresser brought up the Okinawans, the longest-lived culture and one of the healthiest in the world, and cited a paper showing that their traditional diet was ~85 percent carbohydrate, mostly from sweet potatoes. Shanahan and Rosedale decided, based on thin air, that the Okinawans actually didn’t eat much carbohydrate, and Shanahan even went so far as to say “I don’t believe you”, even though Kresser was staring right at the citation on his laptop! This is the kind of head-in-the-sand approach to science that we need to move beyond in the ancestral community. It was also amusing to watch Rosedale proclaim that we should get over our obsession with the Kitavans, to scattered applause. I suppose if there were a culture that was lean and healthy eating cake for breakfast and driving from the house to the mailbox to get the mail, I might want people to stop talking about it too.

Jeff Rothschild said...

Why is 'fat burner' vs 'sugar burner' in dispute? When I hear those terms I think of what percentage of fat/carbs someone is burning, and for athletes we can see measurements of RQ during incremental exercise tests. There is a wide variety, with some people burning mainly fat up into some very high heart rate zones.

Unknown said...

It's too ridiculous to even bother addressing.

Swede said...

If Michael Phelps and Usain Bolt both ditched grains and dairy, and also ate paleo, they would both be guaranteed to get gold in the next two Olympic games!

Josh said...

Nah you've got it all wrong. They'd only be able to do that if they went vegan like Carl Lewis - "Lewis credits his outstanding 1991 results in part to the vegan diet he adopted in 1990, aged thirty. He has claimed it is better suited to him because he can eat a larger quantity without affecting his athleticism and he believes that switching to a vegan diet can lead to improved athletic performance."

Jeff Rothschild said...

Are you saying that at a heart rate of 150bpm, everyone is using the same fuel? That's absurd.

Tomas said...

I am a tad confused here. Ray Peat seems to use a bit different terminology where glycolisys equals conversion of glucose to lactic acid.

Aerobic glycolysis, the conversion of glucose to lactic acid even in the presence of oxygen. The presence of oxygen normally restrains glycolysis so that glucose is converted to carbon dioxide instead of lactic acid.

Anaerobic glycolysis, the increased conversion of glucose to lactic acid when the supply of oxygen isn't sufficient, which is a normal event during intense muscle action.
http://raypeat.com/articles/articles/lactate.shtml
The third way of how carbs are metabolized would be a process where lactic acid is not produced it seems...

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