Who will tell us that we have eaten enough food?

How is food consumption controlled? You may think that our will decides this. Perhaps, sometimes. But animals probably have no such will and yet know when they have had enough and how much to eat. They know better than we do! That's a surprise. So how do they know when they've had enough to eat or not yet?

I haven't delved too much into this issue yet, so it might not be as well thought out as it should be. But it doesn't matter, it has to start somehow. What led me to this problem is this picture from a study on laboratory rats and also an excellent blog written by Peter.

We are seeing several step changes in their diet. First, at the very beginning, a change from a standard rat diet to a high-fat, human-like western diet. We first see an interesting transitional event there, when fats are not a food for rats, which would relieve them of hunger. They cannot oxidize them for energy. Only over time will they learn to process them and can therefore gradually reduce excesses in their food intake. But there will never be a balance between income and expenditure, by a tiny bit. Interesting. It takes them about 8 weeks, long enough. So all this time they overeat and get fat. Why? I will try to answer that. Furthermore, we see other step changes in the diet, when instead of soybean oil, the fat is mixed in part as MCT oil (C8:0+C10:0 1:1) or as triacetin (a special type of fat with short chains, like vinegar). And again there will be a change in food intake, first immediate and after some time adaptation to this diet. We also see that the weight of the rats changes upwards and downwards, often in the opposite direction than the caloric food intake suggests. Puzzle? Let's explore it, we'll have to go into the details again. Let's denote the energy of intake and output

Ein = Eout

Energy expenditure should equal energy intake. So is the energy consumed equal to the energy released? It's not, we can see it on the graph. So better.

Ein = Eoxidized + Estored - Ereleased

That looks better now. This could already explain the jump in food intake when switching to a fatty diet. Energy must be stored, probably as fat. So what to write

ECPin = ECPoxidized + ECPstored - ECPreleased

for carbohydrates plus proteins

EFin = EFoxidized + EFstored - EFreleased

for fats

Carbohydrates and proteins cannot be stored well in the long term, but they can be converted into fat. So when it comes to daily in- and outcome, it will be better to separate carbohydrates from fats and simplify to

ECPin = ECPoxidized + ECPtoF

EFin = EFoxidized + EFstored - EFreleased - ECPtoF

So, back to the chart. At the time of transition to a fatty diet, the oxidation of fuels must be maintained before and after the change

ECPoxidized before = ECPoxidized after

EFoxidized before = EFoxidized after

EFreleased before = EFreleased after

ECPtoF before = ECPtoF after

i.e. if we suddenly change the input ratios of macronutrients

carbohydrates+proteins 83 % before to 54 % after

fats 17 % before to 46 % after

ECPin ~ ECPoxidized

EFin ~ EFstored

After the change, there must be no discontinuity in the intake of usable energy. Excess fats cannot be burned, energy intake must be covered by carbohydrates and proteins, i.e. the original 83% = new 54%, this requires more food, the increase in energy intake will be 83/54 = 1.54, i.e. + 54% kilocalories! Does it follow the chart? Yes, 1400 x 1.54 = 2156 kcal value even before the first point.

If fat burning cannot be increased, and this is not immediately possible with long fatty chains, almost all the extra fat is stored. The animal maintains the same carbohydrate intake as before and therefore takes in more calories. A small part of the excess fat is burned and provides a little extra energy, this leads to a gradual increase in satiety and a reduction in the amount of carbohydrates eaten. As we will see in the next graph, carbohydrates directly control the process of de novo lipogenesis (DNL). A decrease in carbohydrate intake will cause a decrease in DNL and thus a decrease in the ECPtoF component. If DNL can be reduced, the activity of the ACC enzyme and the level of malonyl-CoA molecules will also decrease, which slightly unblock the entrance of long-chain fats into the mitochondria. Thus, more fat can be oxidized for energy.

De novo lipogenesis (DNL), which among other things blocks fat burning, is activated in humans by dietary carbohydrates (CH). Short-term fat excess has no effect (+50% fat).

At the end of the transitional period, however, a higher energy intake remains, and more carbohydrates are burned. Why? Or rather the opposite, a certain amount of energy is stored as fat through DNL and the intake of carbohydrates must be higher than would correspond to a balance. This will also cause a higher intake of fats that cannot be burned.

I believe the culprit here is omega-6 linoleic acid, its ability to reduce insulin resistance. The burning of this fatty acid does not prevent the entry of glucose and there is competition for fuels and increased production of H2O2, this increases the activity and consumption of materials in the GPx/GSH antioxidant system, and in some fat cells the threshold for triggering pseudohypoxia, i.e. activation of HIF-1α, will be exceeded. This activates fat formation via DNL from carbohydrates and proteins, it also activates the enzyme NADPH oxidase (NOX2) in the immune system, and it manifests outwardly as inflammation. In our picture, this will be reflected in increased food intake.

But let's continue. Here we have more step changes in diet. First, 30% of the fat was replaced with C8:0/C10:0 MCT oils. Food intake normalized almost immediately. MCT oils pass into the mitochondria and are not blocked by malonyl-CoA molecules. The energy is therefore usable and the intake of carbohydrates can be reduced. But after a short time there will be a gradual increase in intake, why? Because we're trying to get on the fast track that's already in motion. MCT oils only work as a prevention before the change induced by the activation of pseudohypoxia occurs, i.e. before the activation of HIF-1α.

It's actually simple, in the first week we see a huge peak in food intake, caused by the impossibility of burning long-chain fats. It is prevented by malonyl-CoA as a product of DNL after a long period of a standard low-fat diet full of carbohydrates (DNL does not harm on a low-fat diet). If we had added medium chains to the long-chain fats at that time, they would have gone into the mitochondria, replenished the missing energy, and there would not have been such an increase in food intake at all. This would sharply reduce the intake of carbohydrates and therefore reduce DNL much faster and allow long-chain fats to be burned after a short time. There would be no activation of pseudohypoxia. We know of such studies that MCT oils work as prevention, but they do not work as therapy. It cannot suppress pseudohypoxia, abolish HIF-1α activation. After some time, they activate omega oxidation of fats, activate peroxisomes, but in this environment they only increase fat formation. It is not possible without suppression of pseudohypoxia.

Here we go! We have one more try! If you have read the older posts, you already know the solution. Yes, pseudohypoxia is turned off by acetate, i.e. triacetin here. It is clearly visible on the graph, in the ninth week it completely cleared the DNL, food intake was suppressed to such an extent that the DNL then had to be restored to the correct amount. Suppression of pseudohypoxia activates another mechanism to prevent overloading the cell with excess fuel, UCP2. We know this from another study, see an older post. In order to maintain this state even with a relatively high content of linoleic acid in the diet, we would have to supply triacetin or at least MCT oil permanently. So there is only one solution, to reduce the content of omega-6 linoleic acid in the diet to about 2%, i.e. real butter, beef fat, beef meat. Butter contains up to 13% of short- and medium-chain fats, so it allows our body to respond quickly to changes in food composition. See older posts.

It appears that sudden changes in meal composition can lead to a significant increase in calories consumed to satisfy hunger. A long-term stable ratio between macronutrients helps to optimize processes in the body and enables the best use of energy from food without unnecessary fattening.

Supplement

I think the main parameter that determines whether we ate enough food during the day is the level of liver glycogen before going to bed. If there is the right amount for the whole night and rest, we will not be hungry in the morning either. But if it is not enough, in the morning we will have a great need to eat and replenish our glycogen reserves.

So how is the production of glycogen, our carbohydrate store, controlled. Let's show it in a picture from a study of the kinetics of glycogen production. Sufficient supply of quick carbohydrate energy is controlled by measuring and stabilizing the level of fructose-1,6-bisphosphate (Fru1,6BP), further by controlling the level of citrate, and directly at the entry of glucose into the cell by the level of glucose-6-phosphate (Glc6P). If Glc6P is in excess, the PGM enzyme flips the phosphate at position 1 and Glc1P is the input for glycogen formation. If there is a shortage of Glc6P molecules, Glc1P is released from glycogen and converted to Glc6P for further use.

Importantly, Glc6P is pumped away by the PPP pathway (to the left), which restores the level of NADPH in the cytosol. Therefore, if there is a large consumption of NADPH, for example in the formation of new fats by the DNL process or with high activity of NADPH oxidase (inflammation), the reduced level of Glc6P will slow down the production of glycogen and we will eat more and longer until the necessary reserves are replenished.

DNL regulation via AMPK and the glucose sensor Fru1,6BP together with the enzyme ALDO is also indicated here as my notes (red). This process also simultaneously determines the dominant fuel, whether it will be carbohydrates (with high GAPDH activity, i.e. low sensitivity of Fru1,6BP levels to changes in glucose intake) or fats (with low GAPDH activity and therefore high sensitivity of Fru1,6BP level to changes in glucose intake).