Calories-in-calories-out, substrate cycles and diesel engines

Posted: April 1, 2017 in energy metabolism, TAG-fatty acid cycle, thermodynamics, triglycerides

Discussions on energy balance and diet have not improved over the years. Most of social media and even the medical literature pretty much conform to what is called, in communications, half-duplex, and tends to generate, as they say, more heat than light. What remains interesting, however, are the scientific points associated with metabolic inefficiency,


Many biological reactions function in a steady state cycle of synthesis and breakdown. In adipocytes (fat cells), for example, there is a continuous cycle of synthesis of fat (triacylglycerol, TAG) and lipolysis (break-down) that goes on all the time. The overall reversible reaction:    3 fatty acid + glycerol ⇌  triacylglycerol + 3 H2O

Fatty acid from the hydrolysis of TAG (or fatty acid from the circulation) is processed for energy(ATP is generated).BLOG_TAG-FA_CYCLE_OxidationFA

The lipolysis (breakdown) step goes by itself but to re-synthesize TAG constitutes an uphill reaction (requires energy) — it’s easy to break stuff. If you want to make things, it costs you. So to put the fat molecule back together, you have to transform the fatty acid and glycerol molecules to make them more reactive. The actual substrates are glycerol-3-phosphate and fatty acyl-CoA which are more chemically reactive but you have to get the energy from someplace, so the synthesis of these compounds requires ATP. This is how fat becomes stored from fatty acid coming into the adipocyte. Glycerol-3-phosphate can be made in the liver from the glycerol from a previous round of lipolysis but, in adipose tissue, the glycerol-3-phosphate comes indirectly from a series of reactions. It is currently believed that the main one is glyceroneogenesis, the truncated form of gluconeogenesis, although some may come from glycolysis.

“glycerol” (different sources of glycerol molecule) +  ATP  → glycerol-3-P + ADP + H2O.

fatty acid + CoA-SH +  ATP → fatty acyl-CoA  + AMP + 2 phosphate +  H2O.BLOG_FA-TAG_TAG_SynthThere is thus a steady-state that continuously readjusts levels of fat and fatty acid. The process will drift in the direction of oxidation when stored fat provides energy to other cells and will tend in the opposite direction — toward synthesis — when fat is stored. The important point is that the steady-state, like an equilibrium state, does not mean that everything has stopped. It means that the forward rate of breakdown is equal to the resynthesis rate. Every time there is a cycle, TAG → FA → TAG,  however, energy is wasted — synthesis of TAG requires ATP, lipolysis is spontaneous and no ATP is re-syntesized. Why would such a thing evolve? The common name of the process is substrate cycle but because each cycle wastes ATP and accomplishes nothing — you get back the substrate that you started with — it has been referred to as a “futile cycle.” Why would the adipocyte waste energy in this way?

The energy in the TAG-fatty acid cycle is not really wasted even though it looks that way on paper. It improves overall efficiency. The cycle regulates the availability of energy to the body. As such it must be able to respond to differing conditions rapidly. Regulation is easier if competing reactions are maintained in a cycling steady-state and then biased in one or another direction. This becomes, in the end, more efficient  than starts and stops in response to different conditions. The TAG-FA cycle :

BLOG_TAG-FA_LOOPDiesel engines

I usually describe, as an analogy, how, if you walk past a bus station, you might see that the buses are parked with their engines idling. Probably less common now than it used to be, the explanation was that it is difficult to start a diesel engine and it is more efficient to let it idle and then put it in gear. Fuel costs and engine designs have changed since the analogy first occurred to me so I checked on line. There is now some controversy and some of the discussion is reminiscent of Marissa Tomei’s testimony in My Cousin Vinny but it is still true that it is common to let diesel engines idle when parked for reasonable periods of time. Diesel engines don’t have spark plugs and depend on high compression and generate high temperatures. It is costly to start and stop the engine repeatedly.  The analogy is that is more efficient to run a cycle of metabolic reactions and then readjust which direction you want it to go in than to start and stop.


The point is that you will store different amounts of fat depending on how many cycles you run in a given amount of time. For weight loss, of course, you hope to run as inefficiently as possible (relative to fat storage. The “wasted energy,” however, is less than if you had a lot of starts and stops.

To determine lipolysis in the adipose tissue, you can measure the appearance of fatty acid in the blood. If the process is simple, that is, if only lipolysis is going on, then the stoichiometry (balance of reactants and products) should be 3:1, three fatty acid molecules for every glycerol released.  If, however, the fatty acid is re-processed, more or less fatty acid will appear in the blood compared to the amount of glycerol that is produced. You can then calculate the rate of cycling = 3x (rate of glycerol appearance) – (rate of FA appearance).

The rate of cycling is increased by feeding, turned on by adrenergic stimulation (norepinephrine), turned on by glucagon and turned off by insulin.BLOG_FA-TAG_CYCLE_MAR_29

Whether, and to what extent this figures into metabolic efficiency and CICO seems like a good question. Anyway, here’s picture of the main inputs and outputs:


  1. oscaretu says:

    Richard, I liked a lot the idea of “substrate cycle” and the analogy of a diesel engine.

    Could we relate this “substrate cycle” with hibernation? While I was reading the article “Waking From Hibernation, the Hard Work of Spring Begins” in The New York time the idea came to my mind…

    • rdfeinman says:

      Substrate cycles are really a particular focus on a steady-state or equilibrium state which opposes changes in either direction. Hormones shift (and the substrates if high enough) will shift the steady-state.

      • oscaretu says:

        I suppose the hibernation has to be triggered by hormonal shifts and, in that case, the behaviour is to slow down the “diesel engine”, to decrease the waste of energy during hibernation. And it is compatible with the semi-lethargic behaviour (lasting several weeks) posterior to the end of hibernation, until the “diesel engine” heated enough to get the “right temperature” again.

  2. Marilyn says:

    Thank you for this! The concept of steady-state or equilibrium is at the same time profoundly complex and profoundly simple. I know next to nothing about the details of biochemistry, but your portrayal of the dynamic, equilibrium-seeking system is clear and helpful — good to keep in mind when I read articles about this, that, or the other detail about our metabolism.

  3. Will Wilkin says:

    If my layman’s understanding of this article is correct, you are describing a process of simultaneous synthesis and breakdown of fats in the adipose tissue, wherein the variation in their respective rates creates either a homeostasis or an imbalance with a net effect in one direction or the other, and that imbalance would amount to adding or burning off body fat. Do I have that much right? And to the extent that may be a correct understanding, I wonder if these varying rates are controlled by hormonal signals (such as the rise and fall of insulin depending on the diet, and no doubt exceeding complex symphonies of other signals as well) to change that net direction, creating what is commonly called a higher (faster) or lower (slower) metabolism. If so, it would explain the mysterious process by which a long-term dietary change of calorie restriction (relative to a previous diet) causes initial weight loss but then plateaus as the metabolism adjusts to do the same amount of work as before but “more efficiently.” Which would help explain why what you eat probably matters more than how much (calorically-speaking) you eat. In other words, is this cycle you’re describing of simultaneous synthesis and breakdown of fats in an ever-changing net balance of rates, the crux of why “a calorie is not a calorie,” ie, why the quality of the diet and the hormonal signals thus produced is more important that counting calories?

  4. Dan says:

    Thanks for this. You said that the “rate of cycling is increased by feeding” – can you point us to some data on this? Feeding usually reduces glucagon and increases insulin, so it seems counter-intuitive.

  5. Eric says:

    Time restricted feeding research from the Salk institute lab of PhD watching panda is yet more evidence a calorie is not a calorie. How else to explain feeding the exact same food in the same amounts results in fat sick mice when fed adlibedium vs time restricted to 8 hours. And since most calorie restricted studies involved time restricted feeding the calorie reduction needs more study to see how much was time restricted feeding vs calorie restricted. Eric

  6. Vicente says:

    Hi Dr Feinman,

    I read in an article of yours that “weight reduction clearly requires a negative energy balance: calorie expenditure must exceed intake” (source). It is from 15 years ago, so may be you have changed your mind about this. Or may be you agree with me that this statement is open to misinterpretation.

    My key point is that the “negative energy balance” is not a requisite for weight reduction nor it is the obvious proximate cause of the weight reduction. In theory, the energy imbalance can be just a necessary consequence, for example in a situation where the energy expenditure adapts to a tissue’s drive to grow (i.e. to accumulate energy).

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