Stop the CO2 producing enzymes in the fat cells and don't be surprised if you get fat!

Today's post loosely follows on from the previous one, as it will again be about the mitochondrial glutathione antioxidant system, which is an integral part of the oxidative phosphorylation system, i.e. obtaining energy through combustion. The antioxidant system of the mitochondria converts the resulting hydrogen peroxide into exhaled CO2 and thus enables the cell to obtain and breathe oxygen. Fat cannot be burned without the antioxidant system that mediates this. It is also no coincidence that lack of oxygen is signaled by the increased production of hydrogen peroxide H2O2 in the mitochondria, it is part of the regulation of breathing.

It's that simple, either you exhale carbon in the form of CO2, or you build it into your own body. There is no other possibility. Well, except for the ketogenic diet, where you exhale it as acetone and pee it out as ketones, but that's not what this post will be about. It's just that if you don't breathe out the carbon, it takes up residence in your fat cells.

Let's follow this trail, looking for processes and enzymes that produce CO2. We already know about one, it is the PDH complex, the main enzyme for the processing of carbohydrates. If it does not work, the carbohydrates will not be burned by oxygen but will be processed by the cell by fermentation into lactate. It will be burned in another tissue that can still do it. Importantly, tissue that does not produce CO2 does not receive oxygen, does not need it. The change from oxidation to fermentation acts like a switch at the cellular level. It is not easily flipped back. We can thus find both methods side by side, e.g. fast muscle fibers use fermentation and neighboring slow muscle fibers use oxidation, while they can also process lactate produced by fast fibers.

Other enzymes that produce CO2 are part of the TCA cycle, which processes the intermediate fuel acetyl-CoA mainly into NADH and CO2. So if we burn carbohydrates via a functional PDH complex, enough CO2 is always produced. This can be stopped by an excess of NADH or an excess of acetyl-CoA, but if the NNT enzyme is working, the resting heat production will ensure enough CO2, which will also ensure the transfer of enough oxygen from the red blood cells to the tissues.

How does fat burning work? Fatty acids are first broken down into acetyl-CoA to form intermediate fuels NADH and FADH2 (beta oxidation). But not a single molecule of CO2 is created during this process. Where is the necessary CO2 created? If the TCA cycle is running fine, then in it. This applies to the simultaneous burning of carbohydrates and a small amount of fat in the mitochondria. But we already know that a certain part of fats is processed in peroxisomes. We also already know that the more unsaturated fats there are, the more the breaking down of fatty acids will be carried out in peroxisomes. There is also no CO2 production. So how is it ensured that enough CO2 is produced to exchange for oxygen?

The mystery of the missing CO2 will be clarified only after the involvement of the antioxidant system in the fat burning process. This is because hydrogen peroxide is produced both in the mitochondria (during the processing of FADH2) and in peroxisomes (mainly during the production of succinate and its processing in the mitochondria). The antioxidant system converts the stream of H2O2 molecules into a stream of NADP+ molecules. These can be used either to produce heat and NAD+ (via NNT) or to produce CO2 via isocitrate dehydrogenase 2 (IDH2). Whether heat or CO2 wins is likely determined by the NADP+/NAD+ intermediate fuel level, the two CO2 producing enzymes compete there, IDH3 uses NAD+ and IDH2 uses NADP+. With enough NAD+, there is no reason to use IDH2, so heat will instead be produced. When burning unsaturated fats in peroxisomes, however, there will not be enough NAD+, they work until NAD+ is completely exhausted, so CO2 production will be dependent on IDH2 and the antioxidant system.

Let's take a look at the mice model in which they specifically suppressed the enzyme IDH2. We have already clarified that this enzyme is part of the mitochondria's antioxidant system, without which fat cannot be burned. What are the consequences of deactivating it? See for yourself.

The fat mouse on the right (IDH2KO) shows exactly what happens when there is insufficient recycling of glutathione, i.e. disruption of the mitochondrial antioxidant system. If the food is low in fat (LFD), nothing happens. Even when IDH2 is turned off, the antioxidant system recycles glutathione with another enzyme (G6PD?). However, this does not apply to a high-fat diet (HFD). G6PD is probably not enough for this. The production of CO2 must be ensured by IDH2, i.e. an enzyme dependent on the production of H2O2 and the activity of the antioxidant chain. Hydrogen peroxide production is just as vital as an intact antioxidant system.

In the aforementioned study, they suppressed the activity of an important enzyme genetically. In the body, this enzyme can be stopped, for example, by a lack of NADP+ molecules. These are created during the recycling of oxidized glutathione, which reduces H2O2 to water. Without the resulting H2O2, IDH2 activity is not ensured during a high-fat diet. Without H2O2 processed by the antioxidant chain, not enough CO2 is produced to process fats, the TCA cycle stops, enzyme acetylation occurs, fat burning stops, the chopped fatty acids will be reassembled and stored in adipose tissue.

There is one more important thing, the functional antioxidat chain is also used for thermogenesis. As this study tells us, tissues release succinate (succinic acid) into the blood when exposed to cold. This succinate is processed by mitochondria in the so-called brown adipose tissue by the enzyme succinate dehydrogenase (SDH). This enzyme produces superoxide and hydrogen peroxide. For proper heat production to occur, the mitochondrial antioxidant system must be fully functional. Any malfunction or lack of cofactors in the antioxidant chain will cause dysfunction, insufficient heat energy output, and obesity. However, intervention in these processes may not always be beneficial, e.g. antioxidants can reduce the oxidative load when the antioxidant system is dysfunctional, but they also can promote obesity because they prevent the production of CO2. 

But it can be improved by recycling CO2 by breathing properly with the mouth closed and by training to increase the control pause (BOLT score). You can  cover one nostril several times for five minutes, for example. You'll see, maybe your hands and feet will warm up afterwards. Maybe even your vision will improve for a while due to better oxygenation of the brain.

Addendum:

The mechanism of fat formation is beautifully described in the fifth chapter of the book Transformer by Nick Layne. The point is that you need citrate and NADPH to make fat. So if they damaged IDH2 in this study, then the high-fat diet turned IDH3 running in opposite direction and NADPH in the cytosol has been  produced by IDH1 enzyme. This can easily explain the low levels of NADH in HFD-KO mice. NADH is simply used for fat formation, it is not oxidized in the electron transport chain. This can only be rescued by stopping fat production by activating AMPK and phosphorylating ACC1. Only then can excess citrate provide feedback to stop glucose uptake and slow down glycolysis, avoiding overloading the metabolism and prevent inducing pseudohypoxia (by activating HIF1).

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References:

Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

Accumulation of succinate controls activation of adipose tissue thermogenesis