Does losing all your money stress you
out? If so you probably feel like your
liver does when it's engaging in
gluconeogenesis because it's flooded in
cortisol. If that sounds like something you
can relate to this video is for you.
A ketogenic diet has neurological benefits.
Why do we have to eat such an enormous
amount of food?
Complex science.
Clear explanations.
Class is starting now.
Hi. I'm Dr. Chris Masterjohn of
chrismasterjohnphd.com. And you're
watching Masterclass with Masterjohn.
We are now in our 31st, I think, but who
can count, lesson on the system
of energy metabolism.
And today we're talking about how
gluconeogenesis is regulated by cortisol.
As you can see on the screen
gluconeogenesis is kind of like saving
all your money so that you can pay your
kids' college tuition and they get a
degree in English. Gluconeogenesis
consumes 6 ATP to get glucose so that
cells will do the reverse reaction,
glycolysis, to generate only 2ATP.
You spend 6 and the return on your
investment is 2. Gluconeogenesis is
a very expensive investment with a
negative ROI. As we talked about in the
previous lesson the day-to-day
regulation of gluconeogenesis is
primarily by the insulin-to-glucagon
ratio and the energy status of the liver cells.
Insulin inhibits gluconeogenesis
because it's the signal that you have
plenty of glucose. Glucagon stimulates
gluconeogenesis because it's
the signal that you don't have enough
glucose. High energy status stimulates
gluconeogenesis because gluconeogenesis
is expensive and the liver can only
afford to engage in it when it has
enough energy reserves that it can meet
its own needs, its needs for biosynthesis,
and enough left over to make glucose.
For the same exact reason low energy status
inhibits gluconeogenesis.
But if gluconeogenesis is something that
can be extremely essential because all
of the physiologically essential roles of
glucose and yet is extremely expensive,
that sounds like something stressful; and
in fact stress hormones also regulate
gluconeogenesis. Glucocorticoids, as their
name implies, are powerful regulators of
blood glucose. Glucocorticoids are
steroid hormones and -oid, kind of like
humanoid for example from a
science-fiction film, means resembling,
like, or taking the form of. And a steroid
is something that resembles cholesterol
because all the steroids are made from
cholesterol. A corticoid is a steroid
that's produced by the adrenal cortex,
which is the outside layer of the
adrenal glands. It's a glucocorticoid
because its primary purpose is to
increase blood glucose. In humans the
predominant and most powerful
glucocorticoid is cortisol. Cortisol has
a number of actions on blood glucose
concentrations that are all geared
towards increasing the availability of
glucose to the brain. For example
cortisol acts on the liver to increase
gluconeogenesis and to increase glycogen
storage. So remember that the liver is storing
glycogen for the purpose of increasing
blood glucose at a future time.
So the liver is both, under the influence
of cortisol, increasing the production of
glucose for output into the blood and
taking the excess of what is newly
produced to store it as glycogen so that
after these effects wane the liver is
still very well primed to further
increase blood glucose with its extra glycogen.
In the muscle, cortisol
decreases glucose uptake, decreases
glucose utilization, and increases
protein degradation. That means that the
muscle will conserve its use of glucose
for the blood so that the increased
blood glucose can reach the brain.
Meanwhile the increased protein
degradation in the muscle frees amino
acids from those proteins to go to the
liver and to become substrates for
gluconeogenesis. At adipose tissue, cortisol
decreases glucose uptake and utilization
and increases lipolysis; that releases
free fatty acids. Those free fatty acids
can now be used by other tissues such as
the muscle in place of glucose so that
the glucose can increase in the blood
and become available to the brain.
That even includes the liver because, if free
fatty acids go to the liver and amino
acids go to the liver, the free fatty
acids can focus on providing the liver
with the extra energy it needs to make
glucose, meanwhile the amino
acids become the building blocks for
that glucose. It also acts acutely on the
pancreas to decrease insulin and to
increase glucagon, although chronic
exposure of the pancreas to cortisol can
actually, in the future, increase insulin output.
Altogether this serves,
whether by hormonal reasons, or because
of the release of substrates from muscle
and adipose tissue for gluconeogenesis,
or by conserving glucose utilization in
all the tissues except
liver and allowing the liver to ramp up
its glycogen storage and its glucose
output; all of these converge on
increasing blood glucose and making it
more available to the brain. Because the
brain is primarily sucking out glucose
using glucose transporters that are
simply extracting whatever happens to be
floating in the blood in proportion to
the concentration that's floating in the
blood, so the only way to drive extra
glucose into the brain is to increase
blood sugar levels. In order to
understand how cortisol operates we
should review gene expression from
biology, something we actually haven't
covered here yet. I should note now that
insulin and glucagon and many of the
other things that we've been talking
about do regulate gene expression and we
haven't talked about that yet. We'll talk
more about that in the long-term
adaptations to diet once we are able to
tie everything together in this course.
The reason it's important to talk about
with respect to cortisol is that unlike
glucagon and insulin, which have acute
effects on phosphorylation cascades and
such immediate pathways, cortisol has all
of its known effects through mechanisms
that require protein synthesis. So if we
want to take the information in DNA and
turn it into a protein this in general
is what has to happen. In the nucleus is
where the DNA is, we have a process
called transcription that makes an RNA
template from that information in the
DNA. The RNA leaves the nucleus and in a
process called translation it feeds into
a ribosome, which is made of a different
type of RNA that plays structural roles
to make the ribosome, and it feeds into
the ribosome, the ribosome takes that
information and makes a protein with it.
The ribosomes are in the membrane of the
endoplasmic reticulum, the RNA is on the
outside, the protein comes out on the
inside, if it needs modification that
happens in the endoplasmic reticulum,
maybe it goes onto another organelle
called the Golgi apparatus, but in any
case the protein can be made and simply
exported from the ER -- the endoplasmic
reticulum, not the emergency room -- once
it's gone through the process of translation.
Some people may point out to help
remember these things that transcription
means to simply copy something,
translation means to go from one
language to another; so an analogy that
people often use to remember this is
that DNA and RNA are both made of
nucleic acids. So they're like different
variants of the same nucleic acid
language, whereas protein is something
fundamentally different. So you're taking
whatever information is in the DNA
and the RNA and you're translating it in
to this fundamentally different
language of protein.
Genes need to respond to signals in the
environment. So every gene can be roughly
broken down into its coding region, shown
on the right, and it's promoter region,
shown on the left. The coding region is
what contains the information needed to
assemble the proper amino acid sequence
to make the protein.The promoter region
consists of structures called response
elements, abbreviated here RE, and
these response elements respond to
signals in the environment. This is
actually a continuous strand of DNA and
as far as the gene is concerned there's
no difference between one region and the
other. We humans look at what happens and
we say, "hey everything from here on is
coding for amino acids, everything before
here contains sequences that respond to
the environment." But actually this is
just one nucleic acid after another, one
nucleic acid after another perfectly
continuous down this line.
One of the many response elements that
are in the promoter regions of genes is the
glucocorticoid response element
abbreviated here as GRE. If the GRE is in
the promoter region of a specific gene
then that gene is a glucocorticoid-
responsive gene
because the GRE in its promoter region
allows that gene to respond to
glucocorticoids. Unlike insulin, which
binds to a cell surface receptor and
carries out a cascade of reactions that
occur inside the cell,
all the while insulin remains outside
the cell binding to the receptor, unlike
that situation, cortisol has to enter the
cell and even get into the nucleus.
The glucocorticoid receptor is normally
present in the cytosol and it's bound to
a chaperone protein called Hsp90,
which stands for heat shock protein 90.
This is part of a class of proteins that
are known to respond to heat stress, but
this particularly well characterized
binding is primarily a way to allow the
glucocorticoid receptor to respond to
cortisol. In the absence of cortisol the
glucocorticoid receptor stays bound to
Hsp90 and it stays in the cytosol. And a
gene with a glucocorticoid response
element in its promoter region inside
the nucleus will not be expressed.
By contrast, if the cortisol enters the cell
and it binds to the glucocorticoid receptor,
that causes the dissociation of the
cortisol receptor complex from Hsp90.
That allows cortisol in the
glucocorticoid receptor to enter into
the cell and to bind to the promoter
region of genes that are responsive to
glucocorticoids. That will allow the
information in the DNA to be turned into RNA. Now it should be noted I've
simplified this here by showing the DNA
getting expressed upon binding to the
receptor, but it's not true that the
response elements always bind to
something in order to express the gene.
Sometimes the gene is expressed in
the absence of something binding to it,
and when that binding occurs it
actually suppresses it.
What we'll say here in general is that the
presence of a GRE in the promoter region
of specific genes makes those genes
glucocorticoid-responsive genes.
The binding of cortisol to the
glucocorticoid receptor releases the
receptor from Hsp90, allows it to go into
the nucleus, bind to the GRE within the
promoter region of glucocorticoid-responsive
genes and thereby regulate
the transcription of those genes.
The profile of proteins that are produced
under the influence of cortisol have two
major impacts on gluconeogenesis.
The first is that some of these proteins
antagonize insulin's phosphorylation
cascade. That means in the presence of
insulin more cortisol will stop the
activity of that insulin. So it induces a
state of relative insulin resistance.
Since insulin suppresses
gluconeogenesis the insulin resistance caused by
cortisol promotes gluconeogenesis.
Meanwhile cortisol also directly
regulates gluconeogenic enzymes.
Among those increased are PEPCK,
fructose 1,6-bisphosphatase, which catalyzes one of
the final steps in gluconeogenesis, the
conversion of fructose 1,6-bisphosphate
to fructose 6-phosphate. It stimulates
fructose 2,6-bisphosphatase, which
catalyzes the degradation of fructose
2,6-bisphosphate, the regulatory molecule
that stimulates glycolysis and inhibits
gluconeogenesis. It stimulates
glucose 6-phosphatase and the glucose
6-phosphate transporter that allows
glucose 6-phosphate to get in the
endoplasmic reticulum where it has
access to glucose 6-phosphatase, which
catalyzes the conversion of glucose
6-phosphate to free glucose. That's the
truly final step in gluconeogenesis in
the liver and its role is to allow that
glucose to become free and enable it to
leave the liver and go into the blood.
So from the beginning through the end
cortisol is increasing the expression of
the gluconeogenic enzymes. And in doing that
it increases the total capacity for
gluconeogenesis and it amplifies any
other pro-gluconeogenic signaling.
In other words, if insulin and glucagon
interact to suppress or stimulate
gluconeogenic enzymes that are already
produced, and cortisol increases the
amount of those enzymes, then whatever
insulin or glucagon does to gluconeogenisis
is amplified by the fact
that your total capacity for
gluconeogenesis is increased. For example
if you increase the total capacity for
gluconeogenesis two-fold and if you have
a low insulin-to-glucagon ratio, you could
potentially get double the impact than
you could without cortisol increasing
the expression of those genes. In sum
cortisol is a molecule that represents
the stress response, the need for more
glucose, unlike insulin and glucagon,
which are primarily responding to the
normal level of blood glucose. If you
have high cortisol in a fight-or-flight
response it may be because you need
higher blood glucose than normal in
order to meet the demands of that stress
response. That would be a
glucose-demanding stress.
However, hypoglycemia is
also a stress in itself.
Hypoglycemia could be caused, for example,
on the one hand, by poor blood sugar
regulation. In some cases if you eat a
carbohydrate load that you can't handle
because your regulation of that load is
messed up and that provokes you into
hypoglycemia, then that hypoglycemia
could provoke a cortisol response.
It shouldn't, because when the regulation
is happening naturally insulin and glucagon
are fully capable of doing what they
need to do to regulate blood sugar.
But if you go into hypoglycemic stress, that
means there's something wrong with that
first layer of regulation and you need
to tap into the second layer of the
stress response. But it could also simply
be glucose deprivation. At least in
theory if there's some level of glucose
deprivation that goes beyond the ability
of insulin dropping and glucagon rising
to normalize your blood sugar then that
itself could potentially lead to the
hypoglycemic stress that elicits the
cortisol response. The end result is that
cortisol is there as a backup mechanism
to acutely promote and also amplify all
the other signaling, to stimulate
gluconeogenesis out of necessity.
Because remember this is an energetically
expensive process that only makes sense
to do when you have to. So let's look at
a handful of studies about whether
carbohydrate restriction could provoke a
cortisol response. I want to emphasize
that I'm just going to show you three
studies and this is not an exhaustive
review of the literature. But the
literature in general is inadequate and
to my knowledge we're not skipping over
anything that would offer any kind of
definitive conclusions about any of this,
certainly no conclusions that are
contrary to the ones that I'm going to
make in this presentation.
Here's data from rheumatoid arthritis
patients who were given a
weight-appropriate ketogenic
diet, meaning not designed for any kind
of fat loss, and they didn't report the
exact percentage calories or exact
nutrients in the diet, but we can
approximate that it was about 80%
calories as fat. They were given this for
seven days and then they were re-fed for
two weeks on a lacto-ovo-vegetarian diet.
The authors said that the purpose of the
lacto-ovo-vegetarian diet was to act as
a kind-of-sort-of placebo in the sense
that the patients were told that both of
these were experimental diets and that
allowed them to essentially trick the
patients into thinking that either of
them had potential to treat their disease.
And what you see here is that after
seven days on a ketogenic diet there's a
statistically significant increase in
blood cortisol. It was about a relative
increase of 15% or 14%. After they were
re-fed on two weeks of the lacto-ovo-
vegetarian diet it went back down to
baseline. This was not randomized, it was a
before-and-after study, but it supports
the idea that carbohydrate restriction
at least across seven days is going to
increase cortisol levels because insulin
and glucagon modulation isn't enough to
maintain blood glucose at what they need to be.
Here's data from nine children with
epilepsy who were put on the traditional
four-to-one ketogenic diet, which refers
to the amount of fat versus non-fat mass
in that diet, and this provides
approximately 90% of calories as fat.
Again they didn't report those details in
the paper, but these diets typically
provide about that much. This was for
the purpose of seizure control; this is
the well-established method of seizure
control in children with epilepsy that
doesn't respond to drugs. They were on
the diet for three to four weeks and you
can see there was again a statistically
significant increase in cortisol levels.
In this case the increase was almost
4 times larger than it was in the
previous study. Let's come back to why
there might have been differences in the
cortisol response to the ketogenic diets
after we look at a third study.
This data is from a radically different population.
These people are not only not sick but
they're competitive off-road cyclists.
Eight of them underwent a randomized
crossover study involving four weeks of
a ketogenic or a mixed diet. That means
that everyone got both diets, but some
got the ketogenic diet first others got
the mixed diet first. After they were on
each diet for four weeks continuing on
that diet they cycled on an ergometer
with progressively increasing intensity
until they reached maximal effort.
In other words, as you see rest, 45 minutes,
90 minutes, max effort, what they're doing
is they measure the data that's shown on
the screen before they start the trial,
then they cycle for 45 minutes. Through
that 45 minutes they're progressively
increasing the intensity, they keep going
for 90 minutes, at 90 minutes they've not
only gone twice as long, but they're also
going at a much higher intensity, and
eventually they get to max effort, which
is when they reach, what it sounds like,
the absolute maximum that they're able
to tolerate. And these diets were, on the
ketogenic diet, 70% fat by calories and
on the mixed diet 30% fat.
If you look at what happened
to cortisol... I should note among the
things that I don't like about the
reporting of the data in this study, they
did not look at statistical significance
between each of the groups at each of
the time points; instead they looked at
the significance overall to say that
through this data there are differences.
That's not statistically rigorous, but it
is what it is. So the cortisol was either
not different or slightly higher on the
mixed diet than the ketogenic diet at rest.
That flips around when they start
exercising. You can see that during
exercise the cortisol levels are lower,
but on the ketogenic diet they have higher
cortisol levels than the mixed diet.
That's also true as you get to 90
minutes. Then as you get to maximum
effort that difference pretty much
disappears. So it seems like at rest
these extremely healthy competitive
athletes, who, by the way, as we covered in
lesson 17 and 18 are doing exercise that
should be largely fat adaptable. These
athletes seem to be meeting their needs
for carbohydrate
on the ketogenic diet at rest,
which suggests at least from the
cortisol response that they are meeting
those needs to maintain their blood
glucose at normal because of the natural
regulation you'd expect of insulin and glucagon.
They didn't measure glucagon in the study,
but you can see that at rest
insulin levels are 19 on the mixed diet
and 10 on the ketogenic diet.
So insulin basically drops in half to
maintain the same level of blood glucose.
That could be partly mediated by
glycogen release or partly mediated by
gluconeogenesis, probably a little bit
of both. When they start exercising the
muscles need more glucose. And you can
see that the blood glucose starts to
rise in each of these cases, insulin
levels drop in both of them to the point
where the mixed diet has hardly any more
insulin than the ketogenic diet does.
The changes in insulin and the glucagon
that we don't see don't seem to be
enough to sustain the increased need of
the muscles for glucose during the
exercise because upon exercising is when
we see this ratio flip around and the
cyclists on the
ketogenic diet having higher cortisol
than they did on the mixed diet.
This continues at 90 minutes. The glucose
in the blood drops back down to about basal
levels, perhaps because the output of
glucose isn't quite keeping up with the
uptake of glucose to keep it any higher
than basal levels as it was at 45
minutes. But presumably you have a lot
more glucose utilization in the muscle, a
lot more glucose output, but they're
balanced and so the blood sugar is
staying pretty even. Insulin is maybe a
little bit lower, about the same in both
groups, about the same as it was at 45
minutes. Cortisol is a little higher in
each group and it's again higher on the
ketogenic diet. At maximum effort
that difference seems
to even out, cortisol is the highest as
it was across the entire thing,
perhaps because at that point needs for
blood glucose are maximal and no one on
any diet can't exert maximal effort with
no spike in cortisol. And you can see
that the spike in cortisol is driving
blood glucose up to 120 and that is
maintained partly by these relatively
high levels of cortisol compared to the
earlier time points at 45 and 90 minutes.
At maximal effort that seems to be the
place where the high demand for glucose,
because of the exercise, is becoming the
dominant factor in cortisol beyond
anything about the insulin-to-glucagon
ratios and the glycogen levels in the
ketogenic diet versus the mixed diet.
So if you look at this study it seems like
in healthy people who are very well
trained you may not see a spike in
cortisol on a ketogenic diet except in
the cases where the exercise drives up
the need for glucose. Now we have to be
really careful with interpreting these
studies. So, for example, let's look at the
carbohydrate and fat contents of the
diet. The first study we looked at
derived 80% of calories as fat and it
showed a moderate increase in cortisol.
The second study that we looked at
derived 90% of the calories as fat and
it showed a much larger, almost four
times larger, spike in cortisol. The last
study that we looked at showed that
cortisol didn't spike except when
exercise was increasing the demand for
glucose, but it derived only 70% of its
calories as fat, the least out of any of
these studies. On the other hand the
first study involved rheumatoid
arthritis patients. These people are sick
with an inflammatory disorder. The second
study involved children with epilepsy
that was resistant to drugs. These
children have severely disturbed
physiology that puts them into such an
energetic crisis that without this
treatment they have seizures. The third
study involved healthy competitive
off-road cyclists. These people don't
just not have diseases; they engage in
physical performance that puts them in
top shape, especially with respect to
energy metabolism. So are these studies
coming to conflicting results because of
the health of the people involved?
Do significant health problems raise the
need for blood sugar or the need for
cortisol in some way that precipitates,
or allows, enables the ketogenic diet to
provoke that increase in cortisol? Or is
this all about the degree of
carbohydrate restriction? Do the
ketogenic dieters with epilepsy
have the strongest increase in cortisol
because their situation demands the most
intense ketogenic diet out of any of
these and the greatest degree of
carbohydrate restriction? Do the patients
with rheumatoid arthritis have a less
pronounced cortisol spike because their
glucose restriction was less pronounced?
Do the off-road cyclists have the least
evident spike in cortisol out of
anything that only becomes clear during
exercise because they're healthy or
because they had the most moderate
ketogenic diet that was the least
intense in its glucose restriction out
of all three? These are questions that we
can't answer because we just don't have
a lot of data on the cortisol response to glucose
restriction. It makes sense to me that if
the glucose restriction gets intense
enough it's likely to induce an obligate
increase in cortisol if the insulin and
glucagon modulations just aren't enough
to handle the degree of restriction that
you're imposing on your system. I can't
support that because there's too many
studies with different methodologies
that don't clearly control those
variables. I also believe that if you're
less healthy and you have other taxes on
your energy supply or other things going
on in your body that are contributing to
inflammation or obesity or other
derangements of normal physiology; other
things that are totally normal but are
stressors like pregnancy, like work
stress, like family stress, anything that
goes into your stress bucket; then maybe
the addition of all the things into your
stress bucket makes glucose restriction
going on top of it, if that's the thing
that makes it overflow, then maybe that's
what would also put you into the
cortisol response. In any case we can see
from these studies that glucose
restriction in and of itself does not
always regardless of context increase
cortisol. However, there may be a degree
of glucose restriction, particularly as
you get down to 10 to 20% of
calories, where you cross a threshold
that does require an obligate increase
in cortisol. And it's at least true that
in the context of other stressors on the
system many people will experience a
rise in cortisol, indicating a stress
response, in response to carbohydrate
restriction. Cortisol is called
a glucocorticoid because it is a powerful
regulator of gluconeogenesis.
And it makes sense that the stress
response is a powerful regulator of
gluconeogenesis because
gluconeogenesis
is an energetically expensive investment
with a negative ROI that it only makes
sense to engage in if there's a real
need for it.
The audio of this lesson was generously
enhanced and post-processed by
Bob Davodian of Taurean Mixing, giving
you strong sound and dependable quality.
You can find more of his work at
taureanonlinemixing com.
If you want to keep watching these
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youtube.com/chrismasterjohn.
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All right, I hope you enjoyed this lesson.
Signing off, this is Chris Masterjohn
of chrismasterjohnphd.com. You've been
watching Masterclass with Masterjohn.
And I will see you in the next lesson.
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