Monday, May 02, 2016

On Stephen Phinney and an RQ of 0.62

There is an update on this post here
****End edit****

Now, oxidising long chain saturated fat gives you an RQ of 0.69. Lower than this needs a supplementary process of some sort. In the last post I had Table II from Stephen Phinney's 1980 paper. There are RQs below 0.69 all over the place and even the mean RQ of the 6 week fasting exercise test was 0.66,  with some individuals down at 0.62.

So how can we manipulate RQ values?

This is a graph taken from that nice paper on ketogenic diets for rats. The black line is the RQ of the chow fed rats. They are on 17% or so calories from fat, 64% of calories from starch and the rest is protein. Grey zones are night, white zones are daytime. Ratties are nocturnal, they eat their high carbohydrate diet at night. While they are eating they run their metabolism on glucose. This should give an RQ of 1.0 but we can see the RQ is greater than 1.0 during the times at which the rats are feeding:

We've seen this before during an OGTT in massively weight reduced people. Show them some glucose and they will immediately convert it to lipid and store it. After a mere 75g of glucose during an OGTT, these post obese ladies will develop an RQ over 1.0, see the top dashed line:

This is de novo lipogenesis, either routine in the rats on a 64% carbohydrate or pathological in the post obese ladies. Glucose arrives as an oxygen rich molecule. During the reorganisation to a very oxygen poor molecule oxygen is provided without it needing to be taken up through the lungs. Smaller oxygen flux per unit CO2 produced gives an RQ greater than 1.0.

So it's pretty easy to get a RQ above 1.0. How easy is it to get an RQ below 0.69?

As we all know, acetoacetate is unstable, spontaneously decarboxylating to acetone and CO2. On its own this isn't fast enough to be useful so we have acetoacetate decarboxylase to speed the process up. You find it in the liver and in the brain, mostly. The sorts of places where glucose might be useful.

Apart from being exhaled, what is the fate of acetone in the body? I can't imagine that we are deliberately forming the stuff enzymatically just to breathe it out... Well, here's a pathway I cribbed earlier, can't remember from which paper but one on basic acetone metabolism:

Soooo theoretically ketone bodies, via acetone and oxaloacetate , are glucose precursors. If you radio label acetone with (14)C, where does it end up?

"Radioactivity from (14)C acetone was not detected in plasma free fatty acids, acetoacetate, beta-hydroxybutyrate, or other anionic compounds, but was present in plasma glucose, lipids, and proteins".

Ketones to glucose. How much?

“On the basis of our specific activity data, we have calculated that 4-11% of plasma glucose production could theoretically be derived from acetone”.

The 11% was calculated for 21 day starved humans.

The most logical explanation for an RQ of 0.62 is that the person is performing a significant conversion of fat to glucose. This is completely plausible via acetoacetate, acetone and oxaloacetate. The exact steps are unimportant. What matters is that there will be an increased consumption of oxygen per unit CO2 produced. The RQ is just a ratio so increasing oxygen use will make it drop, possibly below that 0.69 of saturated fat oxidation.

Summary: We already know that total O2 consumption must and did drop on fat adaptation. We know from simple arithmetic that CO2 production drops even more that O2 usage when fat (vs glucose) is oxidised, to give us that normal RQ of 0.69.

If there is a further usage of O2 in the process of converting ketones derived from fat in to glucose, this would explain an RQ of 0.62.

Despite this "waste" of oxygen you still use less O2 per ATP from fat oxidation, even if doing some gluconeogenesis. We know this from the absolute VO2 measurements combined with the RQ values in Phinney's Table II and my back of envelope calculations.

I sit in awe of fat oxidation. We carry fat as long term energy storage for use in times of need. Under those conditions of privation this long term energy store allows very efficient ATP generation per unit oxygen, at the same time as reducing CO2 production, at the same time as generating a significant amount of glucose. Fatty acids and beta oxidation, with ketones thrown in, are just awesome.

I'm also hugely impressed by how far ahead of its time Stephen Phinney's paper was and how well it still stacks up against modern papers.



E-S said...

I could see a very successful future for any substrate that could drop a human's need for O2 to zero for a few hours, in the diving industry as well as aerospatial exploration.

raphi said...

So many things are whizzing through my head after reading this post...Ok, 2 things in particular jumps to mind:

1) in the paper <>, Hetlelid et al say "During increased glycolytic flux, lactate accumulation in the contracting muscle moves to the extracellular fluid and increases [H+], which is buffered by [HCO3−]. This excess (non-oxidative) CO2 is excreted through hyperpnoea, elevating the VCO2. As a result, indirect calorimetry overestimates CHOox and underestimates FATox during high-intensity exercise". So this is 1 reason why FATox's contribution to ATP during 'glycolytic levels of activity' may be underestimated.

2) might this underestimate of FATox also partially stem from humans "performing a significant conversion of fat to glucose"?, i.e., because glucose is the substrate 'counted' as being oxidized, despite the starting substrate being fat?

And down the rabbit hole we go.... :)

Peter said...

raphi, Phinney measure plasma lactate and it more than doubled. Has to be a consideration...


raphi said...


right, glycolysis is certainly well in play then. I wonder if that Carbon-14 4-11% estimate is meaningful in terms of contribution to glycolytic performance on a ketogenic diet...maybe this is where 'individuality' comes in.

Zachary said...

Kevin Hall at it again..

I looked over his previous paper and can't figure out WTF the participants were actually eating. The diets were designed by dietitians (cough) using ProNutra software. Bet you $5 they weren't feeding them lard and butter...

Peter said...

raphi, am I correct that the elevated CO2 from bicarbonate loss during lactic acidosis would occur at as the threshold in to lactic acidaemia was crossed and would cease once a steady state was achieved? It's a change in the buffering which liberates CO2, there is no extra CO2 being produced per se. We only have lactate post exhaustion here and RQ 10 mins in to exercise averaged with just before cessation, so a bit wooly data. I'm struggling to get a handle on how big this lactate/HCO3-/CO2 effect might be. 0.69 to 0.62 seems enormous to me. BTW Exercise physiology reminds me of nutrition research when you try to read the papers! "ketogenic" diets generating 0.15mmol/l BHB, 4 times the value on a mixed diet!!!!

Zachary, yes, had vaguely heard. Might have a think about it at some stage.


Unknown said...

I'm thinking out of the box here. If millions of people became fat-adapted, would that make a huge impact on atmospheric CO2 levels? That could possibly help with global climates?

E-S said...


I would guess switching mankind to lipids would also mean switching agriculture to fat-producing crops instead of the grains, and I suspect the former is a bit less efficient at extracting CO2 from the atmosphere and into complex organic chemistry than the latter. So it would be mostly a wash.


raphi said...


Yes, that's correct as far as i can tell. I dug around a bit and found Stringer et al "The VCO2/V02 relationship during heavy, constant work rate exercise reflects the rate of lactic acid accumulation" ( They say..."Underestimates or overestimates of the metabolic production of CO2 during non-steady state exercise conditions may occur when: (1) tissue PaCO2 increases at the start of exercise, (2) bicarbonate decreases in response lactic acid buffering, and (3) hyperventilation of pulmonary capillary blood occurs".
They've got interesting graphs plotting VCO2, VO2, lactate and HCO3- during and after moderate, heavy & very heavy exercise intensities.

Overall, it seems that lactate accumulates exponentially upon reaching the lactate threshold, lots of HCO3- gets used up there & thus 'liberates' CO2; this is the origin of the increase in CO2 you point to.

Figure 5.12 from "Exercise & Sport Physiology 5th Ed (2011)" shows how muscle pH quickly decreases from a baseline of 7.1 to 6.5 during a sprint, and returns smoothly to baseline within 30-35min. They go on to note that "even when normal pH is restored, blood and muscle lactate levels can remain quite elevated. However, experience has shown that an athlete can continue to exercise at relatively high intensities even with a muscle pH below 7.0 and a blood lactate level above 6 or 7 mmol/L, 4 to 5 times the resting value".

Given how some level of glycogen breakdown is needed for the producing NADH used to maintain the ETC, might that fat=>oxaloacetate=>glucose be geared towards ETC maintenance? This is totally speculative so please squash the idea if you think it silly.

Nutrition will always take 1st place for least scientific field of biology given its religious components, but exercise physiology is a close second (it's flooded with "broscience" after all).

karl said...

There are way to many papers that ignore the adaption effect - Not sure if this was the first paper to talk about it.

I looked at this paper when I was trying to understand T4 => T3 . This is of interest to heart patients - there is a correlation of low T3 and heart disease.

There were also a number of papers looking at effects of LA changing the effect of T3 (the active form of thyroid) apparently blocking activity of lipogenic enzymes. Seems that this would screw with BG levels as well.

There is a certain amount of T4 => T3 conversion that happens in the liver as well - I'm not sure if it is for internal use or body wide.. Really hard to see the whole system. Or as they used to say "It will never sell; it has too many moving parts."

karl said...

LA update - Stephan has a new post about his paper:

Should add a line to the graph for obesity.. At some point this is going to get hard to ignore..

karl said...

The type of fat may also control the lipogenesis here via T3:

Inhibition of triiodothyronine's induction of rat liver lipogenic enzymes by dietary fat.

So what happens if LA blocks lipogenesis ? My guess is BG goes up.

Peter said...

karl, that's disturbing....


JohnN said...

"Despite this "waste" of oxygen you still use less O2 per ATP from fat oxidation, even if doing some gluconeogenesis"

I can also think of further waste of oxygen/ATP from fat adaptation (not a complaint on my part, far from it): heat produced from uncoupling activities.

IMO, despite this apparent drawback on paper physical activities performed in reduced oxygen environment, high altitude, fat metabolism still provides a net benefit. I'm thinking of better use of uncoupling heat, reduced dehydration, less AMS...

George Henderson said...

The other side of this is, that the conversion of acetoacetate to glucose via pyruvate and oxaloacetate is supplying a metabolic regulatory mechanism for inhibiting ketogenesis itself. When glucose can be made from ketones, the risk of ketoacidosis at times of high glucose demand is lessened.

George Henderson said...

@ Zachary,

someone commenting on Hall's last study parsed macros at 20% LA. Seems a little hard to swallow but even Jeff Browning's low carb NAFLD study used 15% E PUFA.

So maybe the 20% LA is 20% of fat, which would make 16%E.
Whereas Browning's NAFLD case study had fat of 57% SFA, 35% MUFA, and 8% PUFA, supposedly based on Dr Atkins Diet Revolution (which I would expect to give more MUFA than SFA, but anyway, good call).

ItsTheWooo said...

Interesting series of posts as usual!

I hope you comment on hall's study, eades early rebuttle to his media propaganda is quite great however.

Peter said...

George, nice negative feedback!

Woo, I have a bit to say about Hall but Mike has covered the psychiatry and a lot of the biochemistry. I'm more interested in UCPs, FFAs, ketones and ATP as applies to the set up in Hall's project, to Phinney's 1980 paper and to a paper I found on acute fasting and ETC function (it's f*cked). There's a lot going on at the moment so not sure when it will pan out. MOT on the MX5 tmrw and some paddling with friends coming up. And the kids seem to have lost 2/3 of their PE kit and that's an evening trip to ASDA. All takes time...


karl said...

@George Henderson
Triglyceride levels (different but related to liver Trigly) are an associated risk factor for CAD. What most people don't seem to get is 'normal reference range' mean average - not really normal as in healthy.

If you look at young, healthy kids or athletes or primitive peoples not eating western crops - they have trgly around 50 - similar to low-carb dieters. (Some low-carb MDs use Trygly levels as a test for diet compliance).

So my take is that a normal trygly level probably is around 50. It is quite possible that the correlation with CAD is due to confounding variables, say sucrose consumption? The fructose in sucrose spikes trygly levels ( Something that was published and ignored from back in the 1960's).

I don't think our bodies evolved to handle average levels ( 150 or more) - I'm not a palo nut (I would have a hard time eating all those insects), but I think it is prudent to try to go with what we have evolved with.

Tyrgly is a confounded variable in it self as it can be made up of different fatty-acids - so is it really a independent risk-factor or not? - don't think we know.

GoBears said...

Hi Peter,

Excellent analysis and very interesting!

You've previously stated that one should eat some protein, not too little.

Approximately how much protein do you find optimal on a mostly fat and severely CHO restricted diet?

Recently Ron Rosedale has been pushing 0.7g / kg LBM, while Attia seems to be pushing about the same. Many others hover around 1.0 g / kg LBM, and yet others are in the range of 1.5 to 2.0.


js290 said...

Converged on similar understanding through my own metabolic discovery. Discovered Krebs Cycle and the glucose and fat substrates. Find out more ATP from fat than glucose. Deduced from my own scientific training that Nature was not ever going to waste or misuse a better fuel. Lipophobia lies somewhere between religion and propaganda.