All Roads Lead Through Krebs ~ True Keto Clarity & The Truth About Fat Burning Beasts

Summary:

BUMPED January 26, 2018

This post was written around three and a half years ago, and through some bizarre twist of dietary fate, somehow ketogenic diets are still trending on Google for everything from weight loss to hang nails.  So I thought I'd bump this post which was my attempt at dispelling some myths regarding ketosis and the role of dietary protein in the mix.  

In the end, and some of these points are not made specifically in this post but I'll make them here:

• Carbohydrate restriction is the greatest determinant of ketogenesis 
• Protein (various amino acids) can feed into the Krebs Cycle and attenuate the reduction in oxaloacetate that favors ketogenesis from fatty acids.
• Ketogenesis represents a conversion of fat energy to ketone energy but it is not evidence of the ultimate usage of that energy.  
• Like glucose, ketones will be burned for energy before fatty acids, so ketogenesis is not an indicator of actual fatty acid oxidation ("fat burning")
• Type 1 Diabetics have elevated ketogenesis and gluconeogenesis.  This is evidence that gluconeogenesis does not "kick one out of ketosis"!
• The availability of gluconeogenic substrates is an unlikely cause for any elevation in blood glucose levels by stimulating gluconeogenesis.
• Ketogenesis occurs in all of us at low levels, moreso when fasted and in caloric deficit.  But significant levels generally require significant metabolic dysregulation (e.g. Type 1 diabetes) or carbohydrate restriction.  The exception to this is high intake of MCTs.
• Exogenous ketones are not "ketogenic" any more than eating a banana is "gluconeogenic".  Both simply directly supply the energetic substrate vs. creating it in the body.

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ORIGINAL POST August 8,  2014

As Jimmy Moore embarks on his whirlwind Keto Clarity tour, I've decided at this point to take a pass at reading/reviewing the book.

I do, however, think it's time to inject some biochemical facts into this discussion to combat the misinformation train wreck that is Mr. Moore.  Specifically: 

• Excess protein is turned into glucose
• Ketones are magic molecules

In his podcast interview with Primal Man of Science Mark Sisson, Jimmy repeated what is clearly becoming a mantra of his, is part of his now "canned" speech on nutritional ketosis, and apparently is discussed in the book.  After mentioning that "long word" -- gluconeogenesis -- Jimmy launches into his discussion of where people who are low carbing go wrong over the long term:  they are eating too much protein.  This sabotages ketogenesis, spikes blood glucose, and stalls weight loss according to Jimmy.

The entire podcast is enlightening (though not for the reasons Sisson and Moore would hope) but I excerpted this clip for you which I found to be particularly informative (direct link):

In general chemistry we learn the various factors that determine reaction rates, among them is the concentration of reactants.  The more reactants there are, the faster the reaction will occur.  In biochemistry, this general rule almost never holds true.  Why?  Because:

• Most reactions are under the control of "living catalysts" more commonly referred to as enzymes and will not occur without the enzyme in active form with all necessary co-factors.
• Many reactions (e.g. synthesis reactions) are not thermodynamically favored.  That is they proceed in the opposite direction of that which is spontaneous.  This is accomplished by coupling with another reaction with favorable energetics thereby harnessing the energy required.

As a result, metabolic pathways are usually not regulated by the substrate per se.  I was recently discussing here the hierarchy of macronutrient metabolism.  This is important as it manages these energy containing molecules in such a way as to store those that are most efficient at storing, and utilizing first those which cannot be stored at all or stored efficiently.  If the presence of fatty acids meant we burned them for energy -- whether we needed that energy or not -- there would be no saving the energy for a rainy day, or even an overnight fast.  

Most who are familiar with low carb diets have long been aware of gluconeogenesis.  The liver maintains blood glucose levels in the post-absorptive state ("fasted") by producing glucose, and it does this by either breaking down glycogen or making glucose via the gluconeogenesis pathway.  In reality, likely a little bit of both occur at all times, though depending on the diet and/or nutritional status, one may rely more heavily on once source or the other.

I don't suppose Sisson has ever heard of the LoBAG diets.  (Perhaps the spy minion should read some of the posts while he/she is here).  That link is to a blog post of mine, with additional commentary added more recently, but is from the early days of the Asylum.  

LoBAG stands for Low BioAvailable Glucose and though carb content varied from 20 to 40% on different versions of the diet, protein was doubled in all, from 15% to 30%.  Furthermore, since these were not calorie restricted weigh loss diets, the absolute protein consumption effectively doubled from baseline.  As an example of where absolute amounts matter more than percentages let's say one begins on 2400 cal/day of a 50C/30F/20P diet (roughly 300g C, 80g F, 120g P).  If this person switches to consuming 1200 cal/day of a low carb diet 10C/60F/30P (roughly 30g C, 80g F, 90g P), he has actually cut carbs and protein while keeping fat intake constant.  And yet this is often described as "upping fat and protein".  So

In LoBAG studies, because they did not cut calories, they doubled the absolute amount of protein in the diet.  In diabetics no less.  And guess what?  HbA1c improved because endogenous glucose production (EGP) in the liver decreased.

These subjects, whose metabolisms are "primed" for excessive glucose production (hyperglycemia in diabetes is due to unchecked gluconeogenesis), didn't respond to protein increases with the expected increase in EGP.  Jimmy Moore can go home now ... And yet Mark questioned Jimmy (paraphrase):

Does Dr.Westman had an explanation for the body so readily making glucose when it has been so finely keto-adapted?

Perhaps he should spend his next relaxing work day actually cracking open a biochemistry text rather than worrying about whether he'll look more cool in the papasan chair or on the cabana bed for the next video.   After all, Sisson has a degree in Biology from Williams College, so presumably he is capable of researching this for himself.   That is his job, after all.  Well, that's what he told the audience repeatedly at PaleoFX this past April.

Krebs though ...

I want to back up to the title of this post.  I have been beating this drum for a very long time in the carbs vs. fat debate.  MOST of the energy produced from either one is produced from Krebs on forward (e.g. the electron transport chain), and the common entry into that pathway is acetyl-CoA.  Don't believe me, how about this opening summary quote from Chapter 20 of Marks' (obviously not Mark'S) Medical Biochemistry p. 360:

The TCA cycle (tricarboxylic acid cycle [Krebs]) accounts for over two thirds of the ATP generated from fuel oxidation. The pathways for oxidation of fatty acids, glucose, amino acids, acetate, and ketone bodies all generate acetyl CoA, which is the substrate for the TCA cycle.

I'm going to get to protein in a minute, but I have altered the diagram I often use here to show where amino acids feed into the Krebs cycle to demonstrate the point about converging pathways.  (Note that this version of the cycle is incomplete in the intermediates of the cycle shown.)

I like to liken the Krebs Cycle to a giant revolving door  with many entrances and exits about the rotation at which people can get on and off.  We can also imagine that nobody gets in the main entrance (around 2 o'clock in the diagram) unless there are some people in the compartment to help pull them in. When the "door" is filled with people in each compartment, it revolves around and the coordinated "pushing" of all the people imparts a momentum to the door itself, while any single person can pretty much be swept along and round and round without even trying.  In your "balanced metabolism", there are lots of people in each section of our imaginary door.  Glucose is converted to pyruvate which is readily converted to acetyl-CoA for entry into Krebs.  Meanwhile fatty acids are broken down more or less directly to acetyl-CoA for entry into the very same Krebs cycle.  

The "fat burns in the flame of carbohydrate" saying, that Sisson dismisses as mythology later in the podcast, actually has a basis in the biochemistry of Krebs.  When there is glucose around, the different compartments remain relatively full of passengers at every point around the rotation.  When glucose is scarce, emergency workers are dispatched to pull people out of the revolving door at the oxaloacetate opening (around 10-11 o'clock).  Biochemically, oxaloacetate gets depleted. When that section or the door comes around to 2 o'clock, there aren't enough people in the compartment to pull in new passengers.  

The  "empty compartment" (oxaloacetate depletion) causes two things to happen.  

1. Pyruvate is diverted to the left towards gluconeogenesis, and 
2. Acetyl-CoA (now from fats mostly) is diverted into ketogenesis.

As fewer passengers are taken on as acetyl-CoA, and lost to oxaloacetate with each turn, the Krebs cycle "door" slows.  The cycle is never just one molecule that goes along for the ride throwing off reducing equivalents and ATP.  It is always a bunch of each species around the loop that keeps the revolving door turning, pulling people in from various doorways and generating energy as it churns around.

So, first things first:  there is no real "elaborate metabolic machinery" involved in producing ketones.  And as you can see, the biochemistry (in a physiological context) is quite simple.  Most importantly, gluconeogenesis and ketogenesis go hand in hand.  They don't really compete!   Oh ... and they are both unequivocally associated with "starvation" metabolism.  

In the liver, when glucose is scarce, other sources of pyruvate are shuttled into the gluconeogenesis pathway rather than acetyl-CoA production.  When fat is metabolized  in this metabolic condition, there is no "carb flame" to ensnare it into the Krebs "revolving door", thus this acetyl-CoA is shunted to acetoacetate rather than a spin around the cycle.  Here's an interesting little biochem tidbit given recent discussions as well (the note about ethanol toxicity):   

 The AA can be converted back to acetyl-CoA as we'll see, or ...

The NAD+/NADH status of the liver cell, which is governed by the sum total of metabolic activity in the cell, is what really determines the fate of the acetyl-CoA to Krebs vs. "ketone 1" (acetoacetate) and then subsequently to BHB or acetone.  By the way, all of these "ketone bodies" are in various body fluids, it is simply that different tests measure different species (urine is AA, breath is acetone, and blood testers measure BHB).

Primary Metabolism thus far ...

Carbohydrate ► Glucose ► Pyruvate ► Acetyl CoA ►►► CO2 + H2O + ATP

Fatty Acids ► Acetyl CoA ►►► CO2 + H2O + ATP

There are some differences in the production of ATP and reducing equivalents (NADH or FADH2) up until the point of Acetyl-CoA, but after that we're talking about the same metabolic pathways for the majority of energy production.

How Does Protein Factor In?  

If you read some of my older blog entries, you will see my understanding "evolve" a bit.  It is easy to fall into the trap that protein is only used for energy after first being converted to glucose.  Although I took two biochemistry classes in college -- one in the bio department, and one in chem -- I honestly don't recall either spending much time on how protein fits into the picture for energy production.  In bio, we focused on the cycles themselves more, the regulation of the various pathways and how this integrated into physiology.  In the chem course, we focused tediously on the mechanisms of the various reactions and the chemical structures of intermediates and enzyme active sites.



But, just because we didn't focus on it doesn't mean it wasn't all there in the textbooks or ignored entirely.  So, as it turns out, amino acids feed into Krebs and associated pathways at various places.  I've referred to this diagram many many times.

It seems odd to talk about "protein" being glucogenic and anti-ketogenic, when in fact some amino acids (in the white boxes) are ketogenic, while others are solely glucogenic, and many can be either depending on the situation and where they are fed into the cycle.

So one of the roles amino acids play in metabolism is in keeping the revolving Krebs door filled with people so that it keeps going around.   It is this, preventing "oxaloacetate drain", that is the most likely mechanism by which dietary protein blunts ketosis by allowing fatty acid derived acetyl-CoA to enter the cycle and be metabolized to completion.  In the process, the amino acids that feed into Krebs produce ATP and/or reducing equivalents depending on their points of entry.  

Some (actually only a few!) can provide substrate directly for the gluconeogenesis pathway.  It should also be pointed out that other substrates for this pathway include glycerol (from the backbone of  triglyceride fats),  lactate from anaerobic respiration, and some short chain fatty acids.   At least in the adipocyte, glycerol released in lipolysis (breakdown of triglyceride to FFA + glycerol) cannot be used to provide the glycerol backbone to esterify/re-esterify FFA back to triglycerides. 

It is not gluconeogenesis, however, that puts the brakes on ketogenesis.   

Look at the pathways above again, and realize that it is a deficiency of oxaloacetate that favors ketogenesis rather than processing of acetyl CoA through Krebs.  Gluconeogenesis "drains" OAA.  Protein puts the brakes on ketogenesis because it keeps the Krebs revolving door going around and generating energy the old fashioned way.   If amino acids fill the revolving door, fatty acid derived acetyl CoA is going into Krebs!   

Ketones in Starvation ...

I am including this screenshot from Cahill & Veecht to show the adaptation in starvation to a fat and ketone burning metabolism.  

The free fatty acids rise almost immediately but rise only slightly more after a few days.  (Note that the y-axis can be misleading as these are concentrations of the number of molecules, fatty acids contain much more energy per molecule than glucose,  AA or BHB).  The ketones rise sharply for a bit longer before leveling off, and it would appear that the BHB formation is the "adaptation" that "preserves" this energy.    Below are also from C&V and demonstrate how ketogenesis is glucose sparing mostly for fueling the brain.  

I would note the use of the thickness of the arrows to denote the relative contributions of the fuels for energy.  Obviously, stored fat is the major fuel but the body effectively converts some to a glucose substitute to fuel the brain while sparing lean muscle mass (protein).

Perhaps I'm missing something, but can someone please point out to me how minimizing dietary protein so as to supposedly prevent gluconeogenesis, is a good idea for fat loss and lean mass retention???

What Becomes of the "Ketone Bodies"?  

Here is where I can't help but remind the low carb hucksters of what the man himself claimed.  Yes, the "late great" one.  Dr. Robert Atkins.    Atkins' claim was that ketones were the result of incomplete metabolism of fatty acids, and that they were excreted unused in the urine.  A CICO man through and through.  

It is also why Jimmy's desperate attempts to claim that Atkins wasn't a ketogenic diet are disingenuous at best.  Most folks went to the diabetic supply section of their pharmacy to purchase ketostix when they tried Atkins for the first time.  And the reason why being knocked out of ketosis elicited despair was that Atkins made it sound like ketosis really was the magic pathway so that you could eat endless fat and pee out most of the calories.  Indeed as you "climbed the rungs" after induction, you were to add in 5g/day at a time of carbs until you could figure out how many carbs you could "get away with" and remain in this magical metabolic state.    It's all right there in the original 1972 book.  

I don't know why, with my background, I never thought to do the math on this back when, but they've looked into these claims (and one can do rough calcs using average urine volumes and ketone levels for estimates) and we're talking like 20 cal/day tops here.  Over the long term such "energy leakage" could really add up, but this most certainly cannot be the reason for greater short-term weight loss on Atkins or other low carb plans.

As it turns out, the ketones ... drumroll please ... feed into Krebs!  

So the above biochemistry is from the same link as given previously and you can find more detailed reactions here.

And lastly, though redundant (and I had to switch up the missing intermediates from the original diagram), I've worked ketone metabolism for energy into the cycle below.   My point in bothering with this is to show that acetoacetate basically gives the Krebs revolving door a push in the process of creating the precursor of acetyl CoA to feed in as usual for energy production.

Bottom line:  ketones are a "detour" in the fat burning path -- like getting off the wrong exit on the highway, and going round the loop-d-loop and getting back on going in the same direction.  [FWIW, as far as calories go, yes, you waste a little "gas" accounted for in calories out. ]   IF Atkins had been correct about peeing out quantitatively significant acetoacetate molecules, although the fatty acids were completely oxidized to make acetyl CoA, excreting AA would represent incomplete extraction of energy from the fatty acids, or "incomplete fat burning".  Major calories out (see Marks' Med Biochem quote above) .  Too bad it's not true ... and equally bankrupt of the current bearers of the Atkins torch to make up new (unfounded) ideas to replace the disproven.

And just to beat that horse but good and dead and kill it again.  From Marks'

So now here's a thought regarding dietary protein ...

If we "starve" Krebs in the liver so as to promote ketogenesis, what does that do to Krebs in all of the other cells?   These cells rely on Krebs processing the acetyl CoA from all substrates to generate the bulk of the energy needed to live.  Is it any wonder that these keto-obsessed athletes -- like Ben Greenfield -- resort to supplementing with oxaloacetate when they need to actually burn fat or ketones for energy?

Fat Burning or Ketone Fueling?

I'm going to finish the biochemistry and metabolism part of this post with this discussion, and it relates to a common misconception perpetuated by the likes of Jimmy Moore.   Being in ketosis is NOT an indicator of overall fat burning.  

Fat burning is the break down of fatty acids all the way down to CO2 and H2O.  This happens all the time in the unstarved state.  

Being in ketosis is NOT an indicator of net BODY fat burning.

Case in point, the medium chain triglycerides, aka MCTs.  Coconut oil and CO derived MCT oil (the shorter of the MCTs) are favorites for the ketogenic crowd.  For good reason, because if ketones are the objective, these will force your liver to make them, pretty much regardless of one's nutritional status.  MCTs are metabolized preferentially in the liver as we do not appear to have the enzymatic machinery to elongate these for storage from this starting length.  This rapid acetyl-CoA production exceeds the capacity of Krebs and ketones are produced and sent out into circulation for use elsewhere.  When this happens, long chain fatty acid oxidation -- aka from body fat or other dietary fats -- is reduced.

Furthermore, if someone is eating hundreds of grams of dietary fat, there is no net body fat burning going on.  And don't look now, but Jimmy Moore has inadvertently demonstrated via his second nutritional ketosis experiment that it is indeed possible to be a fat burning beast and gain substantial amounts of body fat.  (EDIT Jan 2018:  Initially I identified this post NuttyK to be May 2013 to present.  His 2018 "present" finds Jimmy at an undisclosed weight, that by all appearances is well over his pre-NuttyK weight.  This statement holds up!!)

Because calories matter ...

Which Leaves Us With Therapeutic Uses:

The only proven uses for ketogenic diets that I am aware of, have been with neurological diseases.  Let's go back to the Cahill & Veech paper.  It is entitled Ketoacids?  Good Medicine?  In the abstract they write:

Recent studies have shown that D-ß-hydroxybutyrate, the principal "ketone", is not just a fuel, but a "superfuel" more efficiently producing ATP energy than glucose or fatty acid. 

That's because it's not a fair fight!  These ketoacids are but a redox step plus one from acetyl CoA -- the primary "fuel" our metabolic power plants.  They also have an advantage over glucose and pyruvate in that they do not require transporters into cells or the mitochondria where most of the neuronal issues seem to arise.  They are therefore a ready source of acetyl-CoA from which to produce energy.  Peter Attia spoke hopefully of development of ketone precursors as an alternative to ketogenic diets.

Aside from this, and the less promising possibility that diet can manipulate cancer at a metabolic level (the results of these have been way overhyped, and in a short time here we'll have Jimmy leading a panel at #AHS14 discussing this "for sure"), we're left with ketosis for weight management.  Although some experience appetite suppression -- especially in the early going -- from ketosis, this is not universal or necessarily lasting.

Jimmy Moore has claimed that the calories will work themselves out when you're in nutritional ketosis.  He, himself, has demonstrated this not to be true.  

Meanwhile ...

• There are no examples of human cultures in chronic ketosis
• There are no examples of human cultures consuming upwards of 60% fat for any length of time (e.g. lifelong and all members)
• There is no evidence that the few human cultures consuming high fat diets are ever in ketosis except during periods of famine
• There are no long term RCTs in humans of the effects of THIS diet (not Atkins, not "low carb") at weight maintaining caloric levels.
• We only have the n=1 examples .....

But this guy says it's backed by the science!

This was 2004.  Back when Jimmy Moore was eating lean meats on his Atkins diet, hitting the treadmill/elliptical daily, losing 180 lbs, and actually improving his health in the process.