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

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.

The last paragraph is from a blog post I made in 2017. The rest is a modified version of that post. Unfortunately, the observation still rings true. There is still controversy. Coincidentally, several recent posts in social media raise the question.

My own take is simply that

1. The comparative benefits of low-carbohydrate or ketogenic diets for weight loss are often observed. Not all the time, or even most of the time, but it is an experimental observation.

2. There are two types of folks: those who say it can’t happen because of the laws of thermodynamics and those who are curious or even surprised and want to know how it could happen given the laws of thermodynamics.

3. It turns out that the majority of both kinds of people don’t understand much about thermodynamics. That might even be true of those of us who have studied or teach the subject.

4. A little bit of expertise, however, tells you that the question is experimental and can’t be solved theoretically by thermodynamics. Metabolic efficiency or “metabolic advantage” can only be explained by mechanism. That’s what’s in this post.

---

Substrate-cycles

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) from fatty acids and lipolysis (break-down) backs to fatty acids 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).

The lipolysis (breakdown) step goes by itself (does not require energy). To re-synthesize TAG , however, constitutes an uphill reaction (requires energy) — it’s easy to break stuff but it costs you if you want to make things, So, to put the fat molecule back together, you have to transform the fatty acid and glycerol molecules so as to make them more reactive. The actual substrates for fat synthesis are glycerol-3-phosphate and fatty acyl-CoA which are more chemically reactive. You have to get the energy from someplace, so the synthesis of these compounds requires ATP. This is how fat is synthesized and how it is stored using 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 process is glyceroneogenesis, the truncated form of gluconeogenesis, although some may come from glycolysis. The reactions:

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

fatty acid + CoA-SH +  ATP → fatty acyl-CoA  + AMP + 2 phosphate +  H₂O.

The grayed out part represents the reactions from the previous figure. There is thus a steady-state cycle that continuously readjusts levels of fat and fatty acid. The process will drift in the direction of oxidation when stored fat provides energy for other cells and will tend in the opposite direction — toward synthesis — when fat is stored. The important point is that this cyclic 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 — each of the synthesis of TAG steps requires ATP while the lipolysis step is spontaneous and no ATP is re-synthesized. 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?

It turns out that the energy in the TAG-fatty acid cycle is not really wasted even though it looks that way on paper. What you get is an overall increase in efficiency. The cycle regulates the availability of energy to the body. As such it must be able to respond rapidly to differing conditions. 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 starting and stopping in response to different conditions. The TAG-FA cycle :

Diesel 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 is 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 technical and 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.  By analogy it is more efficient to run a cycle of metabolic reactions in the forward and reverse directions and then to readjust which direction to go in than it is 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 more cycles you run before cashing in your lipid oxidation chip, the lower the efficiency (of 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 acids and glycerol (the two products) 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, that fatty acid is re-processed, that is, put back into a fat molecule, then ratio of fatty acid to glycerol that will appear in the blood will be less than 3. 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 (keep the fat in the fat cell).

Whether, and to what extent this figures into metabolic efficiency and CICO seems like a good question. It is an illustration how you can use thermodynamics to your advantage. Anyway, here’s picture of the main inputs and outputs: