“A Calorie is a calorie,” uncoupling and collateral estoppel.

Posted: May 16, 2016 in energy metabolism, low-carbohydrate diet, The Nutrition Story, thermodynamics
Tags: , , ,


One of my favorite legal terms, collateral estoppel, refers to procedures to prevent re-litigation of issues that have already been settled in court. From the same root as stopper, that is, cork, it prevents harassment and wasting of the court’s time. The context is the recent flap over a poster presented by Kevin Hall which has started re-trying the case of whether all diets have the same metabolic efficiency, a question which, in my view, has been adjudicated several times. I put it this way because frequently I have made an analogy between evidence-based-medicine (EBM) and evidence as presented in a court of law. My main point has been that, in the legal system, there are rules of evidence and there is a judge who decides on admissibility. You can’t just say, as in EBM, that your stuff constitutes evidence.  My conclusion is usually that EBM is one of the self-congratulatory procedures that allows people to say anything that they want without having to defend their position. EBM represents one of the many corruptions of research procedure now under attack by critics (perpetrators ?) as in the recent editorial by Richard Horton, editor of The Lancet. One thing that I  criticize medical nutrition for is its inability to be estopped from funding and endlessly re-investigating whether saturated fat causes heart disease, whether high protein diets hurt your kidneys, and whether a calorie is a calorie. It seems that the issue is more or less settled — there are dozens of examples of variable energy expenditure in the literature. It would be reasonable to move on by investigating the factors that control energy balance, to provide information on the mechanisms that predict great variability and, most important, the mechanisms that make it so small in biological systems — most of the time, a calorie is a calorie, at least roughly. Funding and performing ever more expensive experiments to decide whether you can lose more or less weight on one diet or another, as if we had never done a test before, is not helpful.

Several bloggers discussed Hall’s study which claims that either a calorie is a calorie or it is not depending on whether, as described by Mike Eades, you look at the poster itself or at a video of Kevin Hall explaining what it is about. Mike’s blog is excellent but beyond the sense of déja-vu, the whole thing reminded me of the old joke about the Polish mafia. They make you an offer that you can’t understand.  So, because this is how I got into this business, I will try to explain how I see the problem of energy balance and why we might want this trial estopped.

I have taught nutrition and metabolism for many years but I got into nutrition research because the laws of thermodynamics were, and still are, invoked frequently in the discussion. Like most chemists, I wouldn’t claim to be a real expert but I like the subject and I teach the subject at some level. I could at least see that nobody in nutrition knew what they were talking about. I tried to show that the application of thermodynamics, if done correctly, more or less predicts that different diets will have different efficiencies (from the standpoint of storage, that is, weight gained per calorie consumed).

But you don’t really need thermodynamics to see this. Prof. Wendy Pogozelski at SUNY Geneseo pointed out that if you think about oxidative metabolic uncouplers, that is all you need to know. “Coupling,” in energy metabolism, refers to the sequence of reactions by which the energy from the oxidation of food is converted to ATP, that is, into useful biologic energy. The problem in energy metabolism is that the fuel, as in many “combustion engines,” is processed by oxidation — you put in oxygen and get out CO2 and water . The output, on the other hand  is a phosphorylation reaction — generation of ATP from ADP, its low energy form. The problem is how to couple these two different kins of reactions. It turns out that the mitochondrial membrane couples the two processes (together called oxidative phosphorylation). A “high energy” state is established across the membrane by oxidation and this energy is used to make ATP. Uncouplers are small molecules or proteins that disengage the oxidation of substrate (food) from ATP synthesis allowing energy to be wasted or channeled into other mechanisms, generation of reactive oxygen species, for example.

BLOG_car_analogy_May_16The car analogy of metabolic inhibitors. Figure from my lectures. Energy is generated in the TCA cycle and electron transport chain (ETC). The clutch plays the role of the membrane proton gradient, transmitting energy to the wheels which produce forward motion (phosphorylation of ADP). Uncouplers allow oxidation to continue — the TCA cycle is “racing” but to no effect. Other inhibitors (called oxidative phosphorylation inhibitors) include oligomycin which blocks the ATP synthase, analogous to a block under the wheels: no phosphorylation, no utilization of the gradient; no utilization, no gradient formation; no gradient, no oxidation. The engine “stalls.”

In teaching metabolism, I usually use the analogy of an automobile where the clutch connects the engine to the drive train . The German word for clutch is Kupplung and when you put a car in neutral your car is uncoupled, can process many calories of gasoline ‘in,’ but has zero efficiency, so that none of the ‘out’ does the useful work of turning the wheels. Biological systems can be uncoupled by external compounds — the classic is 2, 4-dinitrophenol which, if you are familiar with mitochondrial metabolism, is a proton ionophore, that is, destroys the proton gradient that couples oxidation to ADP-phophorylation.  There are natural uncouplers, the uncoupling proteins, of which there are five, named UCP-1 through UCP-5. Considered a family because of the homology to UCP-1, a known uncoupler, it has turned out that at least two others clearly have uncoupling activity. The take-home message is that whatever the calories in, the useful calories out (for fat storage or whatever) depends on the presence of added or naturally occurring uncouplers as well.

This is one of many examples of the mechanisms whereby metabolic calories-out per calorie-in could be variable.  The implication is that when somebody reports metabolic advantage (or disadvantage), there is no reason to disbelieve it. Conversely, this is one of the mechanisms that can reduce variability.

In fact, homeostatic mechanisms  are usually observed. You don’t have to have a metabolic chamber to know that your intake is variable day-to-day but your weight may be quite stable. The explanation is not in the physics which, again,  predicts variation, but rather in the biological system which is always connected in feedback so as to resist change. However strong the homeostasis (maintenance of steady-state), conversely, everybody has the experience of being in a situation where it doesn’t happen. “I don’t understand. I went on this cruise and I really pigged out on lobster and steak but I didn’t gain any weight.”  (It is not excluded, but nobody ever says that about the pancake breakfast). In other words, biochemistry and daily experience tells us that black swans are to be expected and, given that the system is set up for variability, the real question is why there are so many white swans.

So it is physically predicted that a calorie is not a calorie. When it has been demonstrated, in animal models where there is control of the food intake, or in humans, where there are frequently big differences that cannot reasonably be accounted for by the error in food records, there is no reason to doubt the effect. And, of course, a black swan is an individual. Kevin Hall’s study, as in much of the medical literature, reported group statistics and we don’t know if there were a few winners in with the group. The work has not been reviewed or published but, either way, I think it is likely to waste the court’s time.


  1. wabmester says:

    Great tutorial on uncoupling, but wouldn’t that come into play for overeating? Hall’s study was hypocaloric (even though intention was apparently eucaloric).

    And I don’t agree at all with the estoppel suggestion. I think Hall’s ultimate goal is to refine his computer model of metabolism, and this should give him a bit more data to tweak the model, but more experiments are needed. To me, this was just a preview of coming attractions.

    In terms of mechanisms, I would think the inefficiency of GNG is a better fit for the increase in EE he saw. Didn’t it correlate with the increase in protein catabolism he also saw?

  2. Tom Welsh says:

    This article is very interesting, and many of us will read it with satisfaction and relief. But I also suspect that the great majority of the “calorie is a calorie”, thermodynamics-spouting crew are merely good examples of the Dunning-Kruger syndrome.

  3. I get the reasoning and call for the estoppel regarding ATP and oxidation, but what about results during sustained metabolic shifts into a comprehensive use of ketones for fuel, i.e. long fasts and ketogenic diets? Does that not produce a differing caloric payoff and expenditure than is experienced on the NADH pathway?

    • rdfeinman says:

      I am not sure what you mean. Ketone body metabolism uses NADH. What should be estopped is continuing to try to prove or disprove that only calories count.

  4. Vicente says:

    I just can’t see the physiological relationship between the energy balance terms and fat accumulation in an adipocyte. The energy paradigm gives us no clue whatsoever about the causes or possible solutions for obesity.

    How do I increase the energy stored as muscle mass in my body, according to the energy paradigm?

    Regarding obesity, talking about energy is the problem.

    • I’m not sure that the energy paradigm is supposed to give us clues as to the direct solutions for obesity. But if we view different diets (ratios of CHO:Pro:Fat) on the energy efficiency scale as Richard and others describe, the we can start to unravel it and make sense. I think downstream hormonal and neurotransmitter activity driven by evolving obesity creates havoc with satiety regulators. And much of the problem seems to have its origin with chronically spiking insulin levels with high carb diets leading to a “more efficient storage” (anabolic oriented) per calorie consumed. I’ ve not analyzed the methodology of this study but it is fascinating look at the set point (homeostasis) that a human body is capable of when it comes to “burning” vs conserving energy for vital metabolic functions. http://www.vox.com/2016/4/28/11518804/weight-loss-exercise-myth-burn-calories

  5. puddleg58 says:

    Why didn’t the physics teacher marry the biology teacher?
    Because the chemistry wasn’t right.

    – actual joke read in The Coffee News.

  6. Razwell says:

    Hi Professor Feinman,

    You are right. The body is involuntarily controlling this carbon atom flow . People can nudge it in the right direction by paying very close attention to true hunger , working with the body, but ultimately this identified system is at work whether or not people are aware of it. This system has an accuracy, when working correctly, of 98 or 99%.

    Many people remain remarkably body composition/fatness/muscularity stable over a decade, as Dr. Jeffrey Friedman, the pioneer from Rockefeller University , emphasizes during his many lectures.

    . Novody can concsciously account for every last carbon atom they took in vs. excreted. It is involuntarily regulated to a very large degree -we have limited say short term. Short term the system may be overrided,mjust as we can hold our breath. Especiwlly if we do not go way past out set points. But this involuntary system is largely the dominamt factor and regulates our fatness over the very looooooong term. Many years.

    The calorie people are dogmatists. Energy is not , itself, anything. Mass and energy are not things at all, they are properties of actual stuff (chairs, apples, atoms) etc.

    Take care,

  7. Razwell says:

    Hi Dr. Feinman,

    You are also very wise in pointing out that fat accumulation is a complex chemical cascade, as is muscle gain. Ungodly biochemistry is involved.

    If two people have a carbon arom surplus, why does “person 1 ” gain muscle mainly, and “person 2” gains all or mostly fat tissue-even when they both lift weights etc? Genetically gifted people like Arnold Schwarzenegger were extremely prone to add muscle. Whereas people who struggle with obesity and gene defects gain fat tissue specifically at the drop of a hat. So easily.

    I am sure genetics plays a big role, but it is totally valid to bring up the totally open question that various chemical compounds in our various foods could predispose what this (food, fuel, ingested and absorbed matter) turns into-fat tissue, repair of wounds, muscle etc.) Partitioning of this ingested food is a huge central issue. Disease states, age, overall health, medications, genetics, gene defects, possibly viruses and microorganisms, gut flora, in utero nutrient exposure-all are factors in obesity.

    The calorie people are totally wrong is they do not admit many open questions exist. Very good point, Dr. Feinman, about biochemistry and complexity. It is definitely an open question if the quality and chemistry of various foods during a moderate carbon atom surplus situation is more likely to be laid down as fat tissue and partitioned there. Looking into that is good creative science.

    The calorie people cannot see the poor science behind their stance. All the physicists that I ever communicated with at MIT said obesity is a biochemical and medical issue and that hucksters are exploiting physics if using physics to *explain* it .

    Best wishes,

  8. Twitchy says:

    Thank you for explaining coupling/uncoupling so simply. Now I can reread the recent Hyperlipid posts with more understanding.

  9. Craig says:

    That seems to be an admirable form of transport.

    Nothing seems to fly in the face of the cico hypothesis as much as the observation that people fail to prosper when fed the same sweet meadow hay that makes cattle so plump, they lack the necessary apparatus. But you may invoke double jeopardy here, the case has already been disproven and nolle prosequi.

  10. […] “A Calorie is a calorie,” uncoupling and collateral estoppel. […]

  11. […] whatever the calories in, the useful calories out (for fat storage or whatever) depends on the presence of added or naturally occurring uncouplers as well […] The implication is that when somebody reports metabolic advantage (or disadvantage), there is no reason to disbelieve it (ver) […]

  12. […] There is a lot of carefully planned marketing around clean eating. Lots of fitness companies, individuals, even Registered Dietitians market themselves on the power of clean eating and how it can transform your life. “Abs are made in the kitchen” or, “You can’t outrun a bad diet” are popular phrases used to bolster its promises. I’m not saying these are wrong, or bad. I can personally say that eating more lettuce and chicken will result in a leaner frame, whereas eating more pizza and beer and wings won’t. What I am saying is these phrases, if thrown about carelessly, can lead to some unhealthy relationships with food, and with the way you view your body. (If you would like further reading about calories, and how a calorie is not a calorie for every body, this is a great read) […]

Leave a Reply to Proteínas desacopladoras | No vuelvo a engordar Cancel reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s