[Rhonda]: I think there's a lot of parallels between ketone bodies and ketone supplements
and how they're not only being used as a preferential source of energy in the brain.
Do you know anything about this, about, like, how frees up glucose then to be used for other...
[Dom]: Glucose sparing.
[Rhonda]: ...metabolic pathways?
Yeah, glucose sparing.
[Dom]: Yeah, it's thought that some of the work by Stephen Cunnane, I think, is shedding
light on this, too.
[Rhonda]: Where is he at?
[Dom]: He's in Canada.
I forget the institute that he's at.
Joe LaManna has done some similar work and he's at Case Western and looked at the, kind
of, the interaction of what does the brain prefer...what's the preferred fuel source
for the brain.
I get this question a lot.
I think it depends on, you know...I don't know if it's right to say that the brain always
prefers ketones.
[Rhonda]: The brain cell we're talking about, for one.
The neuron, astrocytes.
[Dom]: Neurons and astrocytes.
But, yeah, I guess, I mean, maybe we're definitely biased towards understanding neurons relative
to astrocytes.
[Rhonda]: I think most people that ask me that question are....
[Dom]: Astrocytes are fascinating.
I think we need to study that more.
But I think in the context of, like, aging and a context of traumatic brain injury or
pathology, I think the brain will really prefer to use ketones because...or in the context
of some kind of stress hypoglycemia or something like that, I think the brain will also prefer
to use ketones.
[Rhonda]: Yeah, so why do you think that is?
[Dom]: Well, I think...
[Rhonda]: I might have my own reasons why.
[Dom]: There's a whole host of reasons or things that can cause impaired brain energy,
brain glucose metabolism and that could be internalization of the GLUT3 transporter,
which occurs...it's kind of linked to Alzheimer's pathology.
[Rhonda]: GLUT...
[Dom]: GLUT3, yeah.
And there's a couple of key enzymes that are either deficient or not active like they should
be, pyruvate dehydrogenase complex is deficient.
[Rhonda]: So wait, are these in...are the GLUT3 changes in astrocytes or in neurons?
[Dom]: Primarily in neurons.
[Rhonda]: Neurons, okay.
[Dom]: So the glucose transporter in neurons.
[Rhonda]: So if neurons are using lactate primarily...the astrocytes are actually what's...
[Dom]: Shuttling a lot.
[Rhonda]: The astrocytes are using glucose and that's why the brain needs glucose and
they're producing the lactate.
The neurons are using the lactate because it's getting shunted and converted into pyruvate.
[Dom]: And the contribution of that is not completely known, but it's pretty significant
contribution during hypoxia, I would think.
[Rhonda]: There's been studies out there showing that not just during hypoxia, but actually
just under normal physiology that...
[Dom]: It's a key player.
[Rhonda]: It is, yeah, the neurons are getting lactate continually from astrocytes which
are generating it, but that the astrocytes become aberrant during...for whatever reason,
it's not known, Alzheimer's leaves traumatic brain injury, so they can't make that lactate
and neurons have to start using the glucose, which then is, but I mean, that's just one.
[Dom]: Yeah, I've heard about that, I haven't looked into that.
Yeah, so there's some key enzymes then that people look at not only just the lactate levels...
[Rhonda]: I think that...I have no idea what they're looking at, but for the pyruvate dehydrogenase
complex, you're saying that's also aberrant in some of these disease states because then,
you wouldn't be able to use the lactate because you couldn't convert it into pyruvate.
So anyways, it's all kind of, I totally interrupted you, though, but you were talking about...
What were you talking about, the aberrant enzymes, like GLUT3 and pyruvate dehydrogenase,
and how these are aberrant in different neurological disorders.
[Dom]: Yeah.
So I think, I think, well, maybe the question we're trying to get at is the contribution
of ketones as a brain energy source and especially in, sort of, in academia and circles where
I teach, it's not even, still not really known, it's not really accepted or understood that
much.
But I think the capacity, the metabolic flexibility of the brain to be able to use ketones, we
can exploit that and we do that with nutritional ketosis, and it's altering brain energy metabolism
and the neuropharmacology of the brain in ways we don't completely understand now, meaning
the neurotransmitters in the brain.
So I could draw off GABA.
So you have more GABA, the GABA-to-glutamate ratio is shifted in favor of higher GABA.
So there's a higher GABA-to-glutamate ratio when one is on the ketogenic diet.
[Rhonda]: In people that are not having...in normal people, as well?
Just, like, in general?
[Dom]: Yeah.
[Rhonda]: Interesting.
[Dom]: It's thought that, and there's different reasons for that.
There's glutamic acid decarboxylase is an enzyme.
[Rhonda]: Is that how it helps with epilepsy?
[Dom]: That's part of it.
I think there's about 20 or more things going on if you look at all the signaling pathways
[crosstalk 00:39:37] actually what happens, yeah, with metabolism, but I think a key player
in that is an elevation of GABA to glutamate.
And we need glutamate to make GABA, right, but the enzyme is elevated and the pathways
are shift in favor of more glutamate to GABA, which has a stabilizing effect on your cell
membrane and neural interactivity, in general.
[Rhonda]: How readily do ketones cross the blood-brain barrier?
[Dom]: It's thought up to five millimolar, maybe six, seven millimolar, they can readily
cross the blood-brain barrier.
[Rhonda]: You have to get that high before they start crossing?
[Dom]: No they start impeding once you get levels up that high.
It hasn't really been studied in-depth.
We did brain metabolomics to show that when we looked at the ketone levels in brain tissue
and ketone levels in the blood, and there's a high correlation there.
Interestingly, we had a diet, too, that was high in medium-chain fatty acids.
And although I heard the medium-chain fatty acids could readily cross the blood-brain
barrier long-chain fatty acids typically don't, short-chain fatty acids sort of do.
But we found very high levels of medium-chain fatty acids indicative of them and these were
normal, healthy animals.
So when you take medium-chain fatty acids, they are readily from the looks of our metabolomic
data, just readily crossing the blood-brain barrier and capable of being used as fuel...
[Rhonda]: That's fascinating, I had no idea.
[Dom]: ...which is very, yeah, it's really interesting.
I heard about that, but when you see the data it's at really high levels.
[Rhonda]: So when they're in the brain, then how are they...so then what happens?
So they're used...
[Dom]: Yeah, their medium-chain fatty acids can be oxidized just like fatty acids for
fuel, yeah...
[Rhonda]: Wow, interesting.