Phillipa says, "There's a lot
of talk in the low carb world about how stearic acid is the best fatty acid due to promoting
mitochondrial reactive oxygen species leading to cellular insulin resistance and hence satiety
signaling downstream from that effect. However, I understand that stearic acid beta oxidation
also produces more ATP, so would it be true to say that the reactive oxygen species created are
just proportionate to the amount of ATP created? Do you think we can categorize fatty acids as
better or worse in any way respect in regards to mitochondrial reactive oxygen species generation?"
I'm not sure I entirely understood this. So there's talk about
how stearic acid is the best fatty acid because
it promotes mitochondrial reactive oxygen species and cellular insulin resistance,
and hence satiety. I'm not exposed to these arguments, but I don't think that mitochondrial
reactive oxygen species and insulin resistance is the proper way that you want to induce satiety.
Now granted, I'm very much on board with the idea that reactive oxygen species play
important roles in cell signaling. That's undoubtedly true, but that doesn't change
the fact that they are a liability to cause a damage, and in fact I personally believe
that one of the main reasons that reactive oxygen species play a role in cell signaling is because
the signaling is designed to limit that liability. And actually I have the antioxidant course
for free at chrismasterjohnphd.com/antioxidant, and in the Masterpass you all have
special features including transcripts with slides embedded and stuff like that.
If you go under 'my products,' you have to click forward one or two pages but the antioxidant
system course is there. And I go through my working model of how this stuff works,
but basically if you generate more reactive oxygen... So basically
all metabolism generates some reactive oxygen species in the mitochondria. All of it.
And there are two... It's sort of a double-edged sword. On the one hand, more reactive oxygen
species could very quickly cause very bad damage to the mitochondrial membrane and to all the
leaks out of the mitochondria, all the other cellular membranes. So that's why you have
a whole antioxidant system designed for that damage control. We have vitamin E,
we were just talking about ferritin. Even ferritin is really part of that system to sequester iron,
because if the mitochondria generates superoxide, it gets converted to hydrogen peroxide.
If there's free iron there it reacts with iron to produce the hydroxyl radical.
But both hydrogen peroxixe and just more so the hydroxyl radical, if they reach a PUFA in the cell
membrane, will oxidize it. And if vitamin E is not there, that will lead to a lipid peroxidation
chain reaction that basically destroys the whole membrane. In fact, in vitamin E deficiency,
one of the things in a severe deficiency, you have hemolytic anemia, because if the
lipids oxidize the membrane, the membrane falls apart, red blood cells just fall apart because
of lipid peroxidation chain reactions in the cell membrane. So any level of reactive oxygen species
is very much a threat of oxidative damage. It doesn't necessarily cause a lot of oxidative
damage because we have an antioxidant defense system. And part of that system is damage control,
like vitamin E. The other part of that system is a whole cell signaling
infrastructure designed to create feedback loops to minimize oxidative damage.
So one of the feedback loops is that if you have more input to the mitochondria
or you have a decreased ability for the mitochondria to handle that energy input load,
you will have more reactive oxygen species. So in general, what we could say, there's a tone of
reactive oxygen species at the mitochondrial level where there's always a certain small percentage
of oxygen that is turned into superoxide, which is then converted into hydrogen peroxide
instead of being converted to water for full production of ATP. And
then that tone adjusts, right? If you have some deficit
in the electron transport chain that prevents you from fully handling the incoming energy,
reactive oxygen species go up. Similarly, if you have a greater input, beyond what it's able to
handle, reactive oxygen species goes up. And so what is the effect of that? Well,
more reactive oxygen species then shuts down the input of energy. Doesn't matter
if it's because there's too much energy or if it's because we can't handle it,
either way if there's some deficit between the incoming energy and what you can handle burning,
reactive oxygen species will shut down fatty acids. I know they act on the porous and the
outer mitochondrial membrane and shut down fatty acid input into the membrane.
And they act on glucose transporters to shut down glucose input into the cell.
Is that going to cause satiety in the brain? Maybe. I haven't studied that. I think Stephan
Guyenet would be a great person to talk to about that, he knows much more about satiety
mechanisms in the brain than I do. It wouldn't surprise me in the sense that if you want to
shut down energy coming into the cell, why wouldn't you also want, at some bigger level,
to shut down energy input into the body? I guess that makes sense. But I've mostly studied this
in the case of outside the brain, peripherally, what is it doing? And what it's doing in adipose
tissue or in skeletal muscle is it's shutting down glucose uptake, leading to hyperglycemia,
and it's shutting down fatty acid uptake into the mitochondria leading to elevated free fatty acid
levels, all of which are generally harmful to the body. Now this is an adaptively desirable thing
because, let's say you have a trillion cells. If it's only 50,000 of them that can't handle
the energy load, and they stop taking up glucose and they stop taking up fatty acids, that doesn't
necessarily cause hyperglycemia or elevated free fatty acids because those energy levels, if they
couldn't get into 50,000 of the cells, they have the other rest of the trillion. So it's really
only when the preponderance of the cells are all signaling in that way that we have hyperglycemia
or elevated free fatty acids. But, the thing is, yes you can look at that and you can say,
"Well, this is about balancing energy metabolism." And I think it works out that way,
but I doubt that it evolved because of selective pressure to prevent body fatness. In particular,
I'm pretty sure that... Why did Robb Wolf name his book Wired to Eat?
Or look at Stephen's The Hungry Brain or look at... I believe everyone
who has thought about this has pined that human beings evolved to seek energy in a world where
famine was a much greater risk than being fat. And so I think the risk of obesity is very much
a modern context that most people, and I think this is correct, most people thinking about it,
thinking about it from the perspective of, we did not evolve to be able to handle
constant access to the most delicious food. And so if we're constantly surrounded by
the most delicious food and must sacrifice nothing to get it, then due to the wiring
that we had evolutionarily we will be biased towards eating too much and getting fat. So
I don't think that reactive oxygen species evolved as signaling molecules to regulate energy balance
because if they weren't there we'd get fat. I don't think that jives at all with the general
theme that we actually did evolve to seek out energy-dense foods to counter the risk of famine.
So why did it evolve? Well, what happens when you remove antioxidant protection? If you don't
shut down energy input into the mitochondria in response to reactive oxygen species, then what
happens? You get more reactive oxygen species. And what happens when you get more reactive oxygen
species? Same thing that happens when you remove oxidants, they will oxidize the lipid membranes.
The lipid membranes will fall apart and you will completely lose functionality itself.
So I think that it's an interesting hypothesis, that you want satiety via reactive oxygen species,
but, and I'd have to confirm this with Stephan or someone else who's really in this area, I believe
that reactive oxygen species is probably... I believe they're thought to play a role actually
in leptin resistance and central leptin resistance, which probably plays a role in
adiposity more so than satiety. But putting that aside,
it's an interesting hypothesis that you want more reactive oxygen species to get more satiety. I
overwhelmingly do not believe that it's correct.
And so I'm not familiar with this argument, but if stearic acid promotes
more mitochondrial ROS, then I don't think that that's an argument for getting more stearic acid.
Now Philippa continues that question, "However, I understand that stearic acid beta oxidation
also produces more ATP. So would it be true to say that the ROS created are just proportionate
to the amount of ATP created?" So I haven't dug into stearic acid in the mitochondria recently,
so I'm not sure what mechanism that they're referring to, but generally ROS is not...
Although it might loosely be correlated with the amount of ATP produced in the sense
of when the primary variation is coming from variation in energy input. For example,
over the course of the fasting feeding cycle you probably have ROS correlating with ATP
because when energy inputs go down ROS goes down and ATP goes down.
However, in the context of varying the different types of energy inputs
or different other contextual factors all the course of isocaloric fed-state metabolism,
you generally are going to have a negative correlation between ATP produced and ROS
produced because generally the ROS is produced exactly as a result of incomplete metabolism. So
the more completely you harness the energy from NADH and FADH2, the more ATP you will produce
and less ROS you'll produce because oxygen will be fully converted to water instead of being
converted to superoxide. But the less completely you harness the energy from NADH and FADH2
the less ATP you will produce because you've extracted less energy, and then because the oxygen
was not fully converted to water, it was converted to superoxide.
And so I don't think that it would just be from producing more ATP.
I think you would produce either more ATP and less ROS or less ATP and more ROS
when you're specifically talking about varying things in isocaloric fed-state metabolism.
And then the final question is, do I think we can categorize fatty acids as better or worse
in any respect in regards to mitochondrial ROS generation? That, I'm going to decline
to answer because I haven't kept up with the literature on which fatty acids generate
more ROS in the mitochondria, but I will say that having excess PUFA in the cell membranes
from consuming PUFA over and above the nutritional requirement is a liability where the more ROS you
produce the damage relates to the membrane. So that would be my one comment on that as
an indirect question. Okay. Thank you, Philippa for your question.