The “Peatosphere” and the general fitness blogosphere speak
of increasing metabolism quite frequently. Peat speaks of it to include mostly
ATP production with some uncoupling as beneficial, where as the fitness
blogosphere speaks of it as a tool to increase the rate of fat loss, which
usually entails a great degree of uncoupling. All of the pathways that have
been characterized describe ATP formation from the reassembly of the
dephosphorylated ADP molecule with an corresponding inorganic phosphate
(Pi). Thus, speaking of increasing ATP by
this process does not increase the cells ATP reserved but rather increases the
relative number of ATPs in comparison to the already existing adenine
nucleotides. But what if your cells are actually deficient in the raw number of
ATP as well ? A true increase in cells ATP reserves would require the uptake of
one part adenosine (Ad) molecule for three parts Pi molecules which are the
constituents of ATP. Furthermore, it would also require the Pis to attach to
adenosinediphosphate (ADP) somewhere along the way. I will try to identify
certain mechanism that would enable the transport of Ad and Pi into cells and
ones that would facilitate their conversion to ATP. The real world relevance of
this to fitness is that the current methods of metabolic enhancement for weight
loss rely on uncoupling. This poses significant health risks due to
overheating. However, if there were enough ADPs and Pi to generate a high
metabolic demand for ATP synthesis (coupled oxidative respiration), then
coupled metabolic enhancement could burn enough calories to make a substantial
difference. Furthermore, increased ATP reserves might mitigate some of the
negative effects of uncouplers, which presumably stem from their ATP depletion,
like lethargy and water retention.
Before
really delving into the technical details (that I myself have a tentative
understanding of), I want to explicate some assumptions and give a basic primer
on ATP. ATP is used to “give” energy to intracellular enzymes by donating them
a Pi. Once it does this, it turns into ADP. Most of this happens outside of the
mitochondria. Later, both the ADP and the Pi (which is recovered from the
enzyme that it is attached to, by other enzymes) return to the mitochondria to
make ATP again. The formation of ATP from Pi and ADP is what requires energy
from food. I think that people can vary on the amount of ATP that they have in
their body. Throughout this text, I will refer to this as ATP reserves. Another
assumption is that ATP reserves can be increased. Thirdly, increased ATP
reserves, up to the point where they would lead to the fastest intracellular
ADP and Pi formation rate, would be a metabolism increasing factor. This is
because intramitochondrial ADP stimulates the oxidative respiration, by
increasing the activity of the Isocitrate dehydrogenase enzyme13. Essentially,
ADP signals the mitochondria to generate ATP, which is equivalent to the
mitochondria “burning” calories from food.
The first
constituent factor that I will address is adenosine. Ad, uptake seems to be
triggered by activity of the adenosine receptor and the relationship between
the two seems to be mediated by potassium channels1, at least in rat
liver cells. In their experiment, Duflot
et al. saw that an adenosine receptor agonist increased the rate at which the
adenosine transporter transferred adenosine to the interior of the cell1.
This suggest that there is a signaling mechanism between the receptor and the
transporter which enables the cell to “know” that there is “adenosine to be
gathered” from the surroundings. Interestingly, they also found that the
signaling between the receptor and the transporter was mediated by ATP
dependent potassium channels. Chemicals that increased the potassium channel
activity increased the activity of the transporter even when the receptor was
not activated by adenosine, and furthermore, further activating the receptor
did not increase the activity of the transporter when an independent chemical
already opened the potassium channel.
This implies that the direct regulator of adenosine transport is the
potassium channel. But the channel is conveniently linked to the adenosine
receptor so that the transporter can be activated when adenosine is around. Another
interesting part of the experiments was that excess glucose inhibited adenosine
transport. This is a very important point that I will come back to later. So
based on the above, if the adenosine uptake mechanisms of most human tissues is
similar to that of rat liver cells (which I know is a big assumption) than
consuming foods that have the raw materials to synthesize adenosine and making
sure that our potassium channels are not blocked would increase our likelihood
of increasing intracellular adenosine. Adenosine receptor agonists would help
as well. Lestan and collogues did a study supporting the underlying rationale
that increasing Ad would improve ATP reserves.
He and his colleagues noted that the introduction of betahyroxybutrate (BHOB,
a type of ketone body) diminished the amount of ATP degradation products
measured from plasma under the effect of ATP degradation agents. They
interpreted this as BHOB increasing the rate of ATP resynthesis.
Adenosine
is a purine and the liver is the primary site of purine synthesis2. The cofactors necessary for purine synthesis
are, glutamine, cysteine, CO2 aspartate and formyltetrahydrofolate3.
Glutamine, cysteine and aspartate are amino acids that can be obtained from
animal protein consumption and CO2 is a byproduct of mitochondrial
respiration, which can be obtained from uncoupled mitochondrial activity as
well. Formyltetrahydorfolate is a dihydrofolic acid (vitamin B9) derivative
from what I understand is itself a folic acid derivative.
Given all
of this, a tentative course of action presents itself regarding how to increase
adenosine production. Eat protein and
supplement with protein sources that would supply the necessary amino acids,
get adequate folate and find a way of increasing CO2.
The last
bit is a little less straightforward. Respiration itself increases CO2
but any factor preventing ATP formation as a result of respiration has an
inhibitory effect on the whole (coupled respiration) process4. Therefore,
as long as respiration is coupled to ATP synthesis, the creation of CO2
depends on the existence of the very substrates we are tying to increase. A way
around this might be using respiratory uncouplers in order to free CO2
formation from the restraints of ATP formation. Ray Peat claims that CO2
production increases when respiration is uncoupled4. Carbonic
anhydrase inhibitors, bicarbonate supplementation and regular bag breathing and
breath holding exercises may help as well. Here, the point is not to use
uncouplers to the point where one is feeling a discomfort from the increased
heat production but is rather comfortably warm.
To make
sure that the adenosine enters cells, consuming MCT oil might be particularly
effective on the account that it gets metabolized to ketone bodies more
efficiently than any other food substance, and there is evidence to suggest
that ketone bodies stimulate adenosine receptors6.
But adenine
nucleotides consist of phosphate as well so in order to increase the total
adenine nucleotide and particularly ATP reserves, we have to increase the amount
of intracellular Pi alongside adenosine as well. There is evidence to suggest
that Pi transport into cells is at least partially dependent on insulin7.
Poglreen et al. showed that insulin stimulated Na dependent Pi influx into rat
muscle cells and myoblasts in vitro. Petersen and colleagues’ finding that the
children of insulin resistant parents had lower insulin stimulated ATP
synthesis and a concomitant lower phosphate transport into cells8
supports Polgreen’s findings. The study
done by Nishi et al. impaired the phosphate transport capacity of rat
insulinoma mitochondria and found that doing so reduced their glucose induced
ATP production8. Thus, it seems that insulin promotes phosphate
transport into cells and phosphate is one of the regulatory factors in the
formation of ATP. A stronger support to this notion comes from Johnson et al.
who has found that ATP degradation agents increase ATP degradation products in
the blood of Pi depleted people but not in Pi repleted people14. This
suggests that the higher blood Pi stimulated the reformation of ATP from the
breakdown products of the degradation agent.
The most
significant practical implication of this is that having some form of
insulinogenic food would aid in the formation of ATP by driving phosphate into
cells. Thus, despite the adenosine
promoting effects of ketones, reaching ketosis through carb and protein
starvation could oppose the effects of increased adenosine into cells. This is another support for producing ketone
bodies through MTC oil instead of severe carb restriction. Furthermore, either
MCTs, ketone bodies or both are insulinogenic so carbs can still be restricted
if it is desired. It seems that phosphate is ubiquitous in food so getting
enough of it does not seem to be a problem but just as a note, animal foods
seem to be particularly rich in it. Supplementation might be beneficial for
some as well.
I want to
come back to MCT oil and ketone bodies for a minute. First of all burning
ketones and burning fats are not the same thing. Ketones are produced when fats
are incompletely oxidized by the liver and ketone burning by peripheral tissues
occurs when the said ketones are used by peripheral tissues as fuel. Since
insulin drives blood lipids into fat or muscle cells (depending on the rate of
muscular activity) and prevents the liberation of fatty acids from fat cells,
carbohydrates tend to counteract ketone production. What is useful about MCT
oil in this case is that it gets shuttled directly to the liver through the
portal vein instead of going into the blood stream through chylomicrons first10,12.
This means that they reach the liver before they enter general circulation. So
insulin is bound to have less of an effect on them, if any. The fact that MCTs
hit the liver first might allow for more carbohydrates while still producing
ketones at a beneficial amount. According to Peter Attia MD. , ketone bodies
also produce more ATP per carbon in their backbone and per oxygen consumed11.
He does not give an explicit reference for this claim but he seems to be very
knowledgeable about ketones so I trust his claim. This maybe another reason why
they might be particularly useful fuel sources for people who are metabolically
compromised. People who have low metabolisms most likely have low tissue CO2
concentrations. Since CO2 is a potent oxygen releaser, people
with low metabolisms might be hypoxic as well. The use of ketone bodies for
fuel might side step the hypoxia induced barrier to ATP production. An
additional reason that this is useful is that once adenosine is inside the
cell, it gets phosphorylated by ATP into AMP to be added to the adenine
nucleotide pool. Also, the ADP and Pi that is outside the mitochondria is
transferred into the mitochondria by being exchanged with intramitochondrial ATP,
so having as much ATP at hand as you can is conducive to increasing total ATP
reserves.
Before giving a complete practical
summary, I want to draw attention to a few things. Firstly, I don’t believe
that Pi transport into cells can be entirely dependent on insulin. This would
not make sense since fat ultimately ends up becoming ATP as well, which means
that it would have to correlate with plasma to cell Pi transport as well since
it creates a demand for intramitochondrial Pi.
If Pi transport were entirely insulin dependent extremely low carb diets
would not be feasible. Another thing to note is that the excess sugar seemed to
prevent adenosine transport in Duflot’s experiment. This suggests that
carbohydrate limitation may be conducive to increasing intracellular adenosine
reserves. Another point to consider is that the cells in this experiment were
isolated and in vitro. Therefore the effects of glucose were not mediated by
insulin. Thus the experiment does not make the suggestion that insulin is an inhibitor
of adenosine uptake. This means that the insulinogenic foods that would help
with Pi transport would not necessarily limit adenosine transport.
With all
that has been said, application is relatively straightforward. Get some urine
ketone measurement sticks and consume enough MCT to give you a reading of
moderate to large. Up your carb and protein intake to the greatest amount that
will still allow you to stay in ketosis. Eat or supplement with proteins that
give you the Ad forming amino acids, get some folate and try to increase CO2. Try to eat phosphate rich food sources or experiment with
supplementation and aim to consume them at the same time with insulinogenic foods. At
this point some of the more avid Peat followers might have noticed that I am suggesting
limiting carb intake, which is sacrilege for some. Yet given how differently
people can respond to carbohydrates, the fact that a lot tend to gain weight on
Peat, and some actually get worse and that ketone bodies have such a wide variety
of benefits, some of which seems to be washed away by excess blood glucose,
makes that (tentative) suggestion sensible. And keep in mind, the point is not
to induce ketosis through carb starving but to lower carbs to the point where
they don’t prevent MCT’s converting to ketone bodies.
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