This content explains the physiological pathway of cortisol production, its molecular mechanisms of action, and its diverse effects on the body, particularly in response to stress and low blood glucose.
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All right, ninja nerds. In this video,
we're going to continue our discussion
about the adrenal gland. If you guys
haven't already, go and watch the video
on the adrenal gland where we talk about
the zona glomemeillosa. Okay, in this
video, we're going to focus on the
zonaficulata. Okay, so zonapiculata is
again this middle layer of the adrenal
cortex because there's three layers of
the adrenal cortex, right? This orange
layer was the zona glomemeilosa. We
talked about that one. This green one is
the zona faciciculata. Okay. So what's
this layer here called? This green
layer. It's called the zona
faciciculata. Okay. Zona faciciculata.
It's this middle layer here and it's
responsible for secretreting a specific
hormone that we put in a category of
glucocorticoid. So cortisol is the
specific one. And then the other part of
the adrenal cortex is this uh purple
layer which is the zona reticularis. And
we'll talk about that one next. Okay. So
zonop faciciculata where does all of
this response for this guy to make this
hormone start? It starts in the
hypothalamus. So in the hypothalamus you
have these specific nuclei. You see
these these red nuclei up here in the
hypothalamus. These red nuclei are
called the parah
ventricular nucleus.
And these nuclei are responsible in the
hypothalamus for secretreting a specific
type of hormone. This hormone that they
release is called corticotropen
releasing hormone. So CR again it's
called corticotropen releasing hormone.
That corticotropen releasing hormone
comes down through the hypothesial
portal system and stimulates the
corticotropes that are present within
the anterior pituitary gland. When these
corticotropes are stimulated by
corticotropen releasing hormone, they
secrete into the blood
blood
adrenal corticoot tropic hormone. Okay.
So again, what is this hormone here
called? It's called
adreno corticotropic hormone. Once this
adreninocorticotropic hormone is
released from the anterior pituitary by
the stimulus of corticotropen releasing
hormone, act then moves and goes to
stimulate the
zonopiculata. So what we're doing here
is we're blowing up a cell of the
zonopiculata. We're taking a very deep
look at the molecular mechanisms
involved. So let's follow this
adreninocorticotropic hormone over here.
So look what the adrenal corticotropic
hormone does. It comes over here and it
binds onto this G-proin coupled
receptor. See this orange protein here?
That's a G-proin coupled receptor. It's
a part of the cell membrane. So when
adrenal corticotropic hormone binds onto
this receptor, it activates you guys
should already know this by heart.
Now a G stimulatory protein. Normally
Gstimulatory proteins is bound to GDP
which keeps it off. But whenever ACT
binds, it takes and binds GTP to the G
stimulatory protein and then GTP turns
the G- protein on. Once this G- protein
is on, it's activated and it's moves
along the actual cell membrane. When it
moves along the cell membrane, you guys
know that there's an aector enzyme
that's a part of the cell membrane. Look
at this guy. This guy right here is called
called
adenolate cylace, right? And what does
this guy do once it receives the
stimulus from this G stimulatory
protein? He then takes
ATP and converts it into cyclic AM. And
then look what cyclic AMP does. It
activates a special enzyme. And this
enzyme is called protein kynise A. And
you know that kynases are responsible
for phosphorolating different types of
proteins. Proteins and what? Okay. So
you guys have already known that we've
already gone through transcription and
translation where we take DNA to make
mRNA mRNA to make proteins. But those
are for protein hormones. You know in
this cell we're making steroid hormones.
Steroid hormones don't come from DNA or
from mRNA. They come from a basic unit
called cholesterol. So what is that
molecule called? It's called
cholesterol. So cholesterol is the basic
unit for this synthesis of steroid
hormone. Not DNA, not mRNA, not
proteins. We're making steroid hormones.
So what happens is cholesterol actually
pregnnolone. And then pregnnenolone
actually gets converted into what's called
progesterone. And then progesterone
actually gets converted into what's
hydroxy
progesterone and then into 11
11
deoxy cortisol and then look into
into
cortisol. This is the one that we care
about. We care about cortisol. The whole
point of me going through this pathway
was to show you that before we were
taking DNA, converting it into mRNA, and
then translating it to make proteins at
the ribosomes. Now, we're starting with
a different thing. We're starting with
cholesterol and using all these
different types of uh intermediates to
get to cortisol. Cholesterol is the
starting point. Now, now, out of all the
enzymes that control all of these steps,
one of the more important enzymes is
right here. And I'm just going to put it
down because we're going to talk about
it later. And this one's called 21
21
hydroxilase, okay? Called 21 hydroxilase
enzyme. And he catalyzes this step, the
conversion of 17 hydroxy progesterone
into 11
deoxycortisol. Now, where is this
protein kynise A going to be involved in
here? He's actually helping to stimulate
a lot of these enzymes. So, you know how
21 hydroxilates is acting in this step?
Well, there's multiple enzymes. There's
enzymes working in this reaction,
enzymes working in this reaction,
enzymes working in this reaction, and
even enzymes working in this
reaction. Protein kynise A is
phosphorolating different types of
enzymes involved within this enzyatic
reaction to produce cortisol. Okay. So
now if protein kynas is phosphorolating
a lot of these enzymes involved in this
pathway, it's going to help to lead to
the synthesis or the formation of
cortisol. So that's why
adreninocorticotropic hormone is one of
the strong stimuli for cortisol
synthesis. Why? Because it stimulates
this intracellular pathway to make pKa
protein kynise A which phospholates
enzymes for the synthesis of cortisol.
So now we've made cortisol. What is
cortisol going to do? He's going to get
pushed out into the blood. But you know
cortisol, he's special. Cortisol is
special because he can't be in the blood
in free form. He's a lipid soluble
hormone or a steroid hormone, right? So,
he's not water soluble. He has to be
bound to certain types of transport
proteins. So, there's two transport
proteins. Let's say I bifurcate it here
and I bifurcate it here. And here's our
cortisol. This little purple dot here.
He's going to bind on to two different
types of transport proteins. Let's say
that we use one as an orange. One's an
orange transport protein, right? Look at
this guy. about
25% of the
actual steroid on this cortisol is
actually bound to this one. So about
25%. This one is called that orange
protein is called
albumin. Okay. The other 75% of it is
bound onto this nice little blue transport
protein. about 75% of
it. And this protein right here is
called cortico
steroid binding globbulin. Okay. Another
name for it is actually called
called
transcortin. Okay. So that transcortin
or corticosteroid binding globulin is
actually carrying and transporting most
of the cortisol. Okay. Now cortisol gets
transported to multiple different target
organs through the blood. What are some
of these target organs? Let's start with
the muscles. So let's say cortisol comes out
out
here. When cortisol comes over to the
muscles, so let's say cortisol comes out
here and he acts on the muscles. You
know inside of our muscles we have
proteins, a lot of proteins that make up
a lot of different types of myofilaments
or other different components. So let's
say here I I
represent these proteins here as like
this squiggly like structure, right? And
these little red dots that I have on it
are amino acids because amino acids are
the building blocks of proteins, right?
And how do you identify proteins? One
has a aminois and the other one has a
caroxy terminus, right? So there's our
protein. Look what cortisol does. Now
cortisol is a steroid hormone. So the
only way he can work is he has to come
into this cell and let's say here's your
DNA. He has to activate specific types
of intracellular receptors, right? So
what he'll do is he'll stimulate, right?
because he can actually move through the
cell. He can move to the cell, bind onto
an intracellular receptor and activate a
specific gene. That gene will make mRNA.
It'll get transcribed, right? And then
it'll get translated to make proteins.
Look what these proteins are going to
this. Look as this little scissor
enzymes. These enzymes are going to
start cutting up the proteins. They're
proteases. Proteases break the peptide
bonds. And look what you release out of
this reaction. out of this reaction.
Look what look what gets released into
the bloodstream as a result. All these
different amino acids. So all these
amino acids, those little
circles are released into the
bloodstream. So what are these things
here called? These are called amino
acids. Okay? So these amino acids are
the building blocks of this whole thing
which is called proteins. Right? So we
have proteins here that are getting
broken down, catabolized into amino
acids. So what's it doing in this area
right here? What's it stimulating? It's stimulating
stimulating protein
protein
catabolism. Why? We'll see. Okay, these
amino acids, they're going to get used
for something. They're going to get
taken up by the liver. And we'll explain
why in just a
second. Okay, next thing. Let's look at
what it does on the fat tissue. So, we
already know what it does on the
muscles. Let's see what And also, not
only does it do it on the muscles, guess
what else is doing it, too? It can even
come over here and stimulate the protein
catabolism in the bone. So, not only is
there going to be protein catabolism in
the muscles, but there's also going to
be protein catabolism within the bone.
So, then look what comes out of this.
Look what comes out of
this amino acids, right? And that's also
going to occur in some of the connective
tissues as well. So, not only is there
going to be protein catabolism in the
muscles, but there's going to be protein
catabolism within the bone in certain
types of connective tissues. So we
release amino acids into the
bloodstream. So the amino acid
levels in the blood are going to go up
because of protein catabolism and
they'll be taken up by the liver for a
specific uh function and we'll see that
in a second. Let's look at the atapose.
How is it affecting the atapose? So same
thing. Let's say that the cortisol comes
up here and it comes in and it acts on
a adiposite, right? Because that's what
you call them collectively. It's called
atapost tissue. But each one of these
cells are called
adipocytes. These adyposytes, remember
cortisol is a steroid hormone. So it
moves through the cell, activates an
intracellular receptor, stimulate
specific genes to make mRNA and then
proteins. Look what these proteins are
going to be. You've already seen these
proteins. You see these little scissors
again? Look what these scissors are
doing. They're
cutting these triglycerides.
Why are they cutting the
triglycerides? They're going to cut the
triglycerides right here at this point
there. There's two components of a
triglyceride, right? What are the two
components? When this guy starts
breaking this triglycerides out, it's
going to break it down into two different
different
components. One component is actually
going to be
be
glycerol. Okay, that's that like we'll
represent it by the head, right? That
little circle there. That's the
glycerol. The other components are going
to be the fatty acid chains. So these
are your
fatty acids and these fatty acids can
either be utilized over the muscles or
they can be redeposited or redeposited
or redistributed to different parts of
the body. Okay? So fatty acids can be
utilized by the muscles or they can be
redistributed and relocated to different
parts of the body. But now this glycerol
gets taken up by the liver for a
specific reason and we'll talk about
that. Okay. Cortisol also loves to act
on the liver itself too. So let's say
that we have cortisol here. He's also
not just going to So here was our
cortisol. We'll represent him by that
little purple dot there. Here's and
again cortisol look what he's going to
do. He's going to come out here and he's
going to act on the liver. So you know
how inside of the liver we have these
liver is actually made up of apatocytes.
So inside of this you'll actually have
specific DNA. So here's a nucleus. Let's
say it stimulates the nucleus here.
Activate specific genes. And look what
these genes are going to do. Well, first
off, here's what you need to remember.
You're taking these amino acids and
you're taking this glycerol in. We can
take this glycerol and these amino
acids. Now, look what happens here. I'm
going to take the glycerol and I'm going
to funnel into a specific pathway. I'm
going to take the amino acids and I'm
going to funnel these amino acids. I'm
going to denote it with aa into a
specific pathway. Look what it's going
to form as a result. The result of this
is actually going to be the formation
of glucose.
When I take glycerol converted into
amino um into gluc I'm sorry when I take
glycerol convert it into glucose or I
take amino acids and convert it into
glucose. What is that reaction called?
What is this whole step right here
called? This right here is called
called gluco
neoenesis. Not only can it use uh amino
acids, but you know your muscles are
also producing what's called lactic
acid. So your muscles can also produce
what's called lactic acid. It can also
take that lactic acid and use that as
well to make glucose too. So that's not
the only stimulus is just amino acids
and lactic acid and glycerol. You could
even use oddch chain fatty acids too if
you want to. But in general we're just
going to be talking about glycerol and
amino acids here. But it can use lactic
acid also.
Okay. Now very very weird mechanism that
can happen here with cortisol because
generally cortisol wants to increase our
blood glucose levels because usually
this glucose what's happening to it?
you're actually going to get this
glucose out of the liver and it's going
to go into the bloodstream because its
desire is to increase blood glucose
levels, cause hypoglycemia. Cortisol
normally wants to increase our blood
glucose levels. That's his goal and I'll
explain why at the end. What's his
stimulus? Now, what happens is is
something really weird. This is one of
the weird mechanisms of
cortisol. It can actually take glucose
and convert it into glycogen. Okay, so
now let's actually show you glycogen
here. Let's say this is our glycogen
molecule. And glycogen is just basically a
a
long polymer
of glucose. Okay. So, let's move our
lactic acid arrow out of the way here.
Let's put him over here. Let's take our
lactic acid and show it actually
funneling in here. Right there. Okay.
Because these guys can actually come
together here and be involved in this
pathway. Okay. So,
again, you have glycogen. Glycogen is
basically the storage form of glucose.
just a polymer of glucose
molecules. But look what happens. Let's
say I represent glucose over here by
just like a little dot here. Actually,
I'll just put glucose here. Let's say I take
take
glucose. Cortisol direct effect on this
pathway. It's very odd. It can take
glucose and convert it into this polymer
of glucose. What is this polymer of
glucose called? This polymer of glucose
glycogen. Okay. So this polymer of
glucose here is called glycogen. Now he
can directly stimulate this pathway,
right? He'll activate specific enzymes
in the DNA and produce certain types of
proteins and these proteins as a result
will stimulate the conversion of glucose
into glycogen. What is that called when
you take glucose and convert it into
glycogen? That is called
glycogenesis. So this right here is called
glycogenesis. So it is directly involved
in glycogenesis which is converting
glucose into glycogen directly. Now
watch what else happens. This is the weird
weird
part. Okay. So you know cortisol loves
to be able to enhance the sympathetic
nervous system. You know how it does it?
Look what cortisols can do. he can act
on a lot of different types of uh
tissues that are dependent or sensitive
to norepinephrine. So let's say that
cortisol comes over here and it acts on
a smooth muscle cell because you know
smooth muscle cells within our blood
vessels are very sensitive to the
norepinephrine. So he can actually
stimulate specific genes and these
specific genes look what they can do.
They can come over here and they can
increase the sensitivity of these
adronurgic receptors. You see this
little groin coupled receptor? Look what
cortisol does. He acts on this smooth
muscle cells in our blood vessels. So
the to tunic media and he can increase
the sensitivity of these adinuric
receptors because look here's a neuron,
right? This neuron is an adinuric neuron
meaning that it releases what chemicals
it releases. Let's actually do this in
blue. It releases
norepinephrine. So this actually releases
releases
norepinephrine. Look what the
norepinephrine does. It binds onto this
receptor and usually what's the result
of norepinephrine binding on to the
smooth muscle cells within the tunica
media? The overall result is called
vasoc constriction. So what's the
overall result here? It's called vaso
vaso
constriction. Who's enhancing this
process? Cortisol. Cortisol is
increasing the sensitivity to
norepinephrine. How? By increasing the
sensitivity of these aduric receptors.
So that when norepinephrine acts on it,
the effect is amplified. So it causes an
increase in vasoc constriction. What's
the result of vasoc constriction? What
does that do to the actual resistance on
our blood vessels? It amps it up. So as
a result, what's going to happen to the
blood pressure here? It's going to
increase our blood
pressure. Okay? So that's one effect of
cortisol. One effect of cortisol is he's
causing excessive vasoc constriction by
increasing the sensitivity of these
adinuric receptors and increasing the
BP. Look what else he can do. Cortisol
can act on the
liver. And look what happens here. Super
interesting. It comes over
here and stimulates these receptors.
What are these receptors? These are
adinuric receptors. So you know
norepinephrine is also secreted onto the
liver and look what it does to the liver.
liver.
So here's a norepinephrine. It acts onto
the liver cells. When it acts onto the
liver cells, guess what this liver is
responsible for doing? He breaks the
glycogen down into glucose. So he does
the opposite reaction. So let's show
that with this arrow. So look at this
one. This is going to be the the
specifically the pathway for
norepinephrine. So what is
norepinephrine doing? He's stimulating
the conversion of glycogen into glucose.
That's called glycogenolysis.
But cortisol is helping that process
indirectly. You see how that's a little
interesting here is that cortisol's
direct effect on this glycogen
metabolism is what? He directly
stimulates glycogenesis. But at the same
time, cortisol is also increasing the
sensitivity of these adinuric receptors
for who? Norepinephrine. So that when
norepinephrine binds onto these
receptors on the liver, guess what? The
glycogenolysis pathway is enhanced. And
so you're breaking down glycogen into
glucose. And as a result, what's
happening to the glucose levels in the
blood? It's going up. So as a result,
here. You're increasing your blood
glucose levels. Okay? But remember, only
time that you're increasing the blood
glucose levels is due to the indirect
activity of cortisol acting on these
adronurgic receptors. So that when
norepinephrine binds onto it, the effect
is more amplified. All right. So now
it's also going to affect our immune
system. It's going to affect our immune
system. Okay. So how is it affecting the
immune system? Let's say cortisol comes
out here. So here's our cortisol, right?
So this this purple dot is representing
cortisol. Look what cortisol can do. It
can inhibit specific processes with
inside of
these immune cells. Right? So this would
be like a monocy, a lymphosy, and a
basophil. Right? What are basophils
responsible for secretreting? It's
really really responsible for
secretreting a lot of different types of
histamines, right? So it releases a lot
of different types of
histamines and
lucotrines and prostaglandins, a lot of
different types of chemicals.
Lymphosytes are responsible for
secretreting a lot of different types of
interlucans. So a lot of different types of
cytoines and even monocytes are
responsible for secretreting different
types of interlucans and cytoines.
Right? So these are responsible for be
basically being able to promote the
inflammatory immune response. Look what
cortisol does. He inhibits these immune
system cells from producing different
types of inflammatory cytoines like
interlucans like interlucan one,
interlucan 4, interlucan 2, all those
different types of chemicals. And it's
inhibiting the release of histamines and
lucatrines and prostaglandins, a whole
bunch of different types of chemicals
that are basically alerting our immune
system that there is microorganisms that
are pathogenic and causing tissue damage.
damage.
But cortisol is inhibiting this. You
know how this makes sense? Here's why.
Okay, let's actually come over here
because now I'm going to explain why
this is actually significant. Okay, so
you know, we need to understand now that
we've looked at all the effects of
cortisol. Guess what the stimulus of
cortisol is? It's going to make so much
sense now, guys. Look, his main stimulus
is hypo. It's not the main stimulus. I'm
sorry. It's one of the very strong
stimuli, but one of them is hypoglycemia.
hypoglycemia.
What's hypoglycemia? It's low blood
glucose levels. What was his effect? It
was to increase the blood glucose
levels. How? What was the way that it
treated hypoglycemia? So if we look at
hypoglycemia here, what did it do? It caused
caused
glyco genolysis. But let's put this in
specific parenthesis here. We have to understand
understand this.
Indirectly, this is so important.
indirectly. How it does this? By increasing
sensitivity to
to
norepinephrine. So norepinephrine is
really the one who's doing
glycogenolysis, but cortisol is
increasing the sensitivity of those
adinuric receptors. So that when
norepinephrine binds onto the liver's
adinuric receptors, guess what happens?
Glycogenolysis is amplified and that
increases blood glucose levels. What's
the prime metabolic effect though here
with the uh the glucose levels with
cortisol? It's gluco
gluco
neoenesis which is taking amino acids
and glycerol and lactic acid and oddch
chain fatty acids and turning it into
glucose. And what was the result of
that? It was increasing blood glucose
levels. What's the result of
glycogenolysis? It's increasing blood
glucose levels. And now that odd
function of cortisol directly is
glyco genesis and we need to remember
that this is what again this is the direct
direct
effect. Okay. So that should make sense
now why these mechanisms have happened.
What's another stimulus? You know
another stimulus is actually going to
be stress. So let's put here but more like
like
longterm stress or chronic
stress. This should make sense by all
means. Why?
Okay, stress is not the kind of stress
that you're technically thinking about.
It's it's talking about more like trauma
or like you know basically like
starvation if you haven't eaten in a
long time. a lot of different things
that are causing long-term stress in the
body, not just necessarily the stress
you think about whenever you know you're
talking about your job or something like
that. It's just long-term aectors of
stress. Now, long-term stress can cause
direct release of corticotropen
releasing hormone and can cause the
excessive release of ACT and that
produces lots of cortisol. How did
cortisol deal with
stress? Come back over here. Let's look
what did it do to your nervous system?
Cause vasoc constriction. What happens
when you have vasoc constriction? It
increases your blood pressure. That's
one way of dealing with stress is we're
increasing our blood pressure so we can
get more nutrients, more glucose, more
amino acids to the tissue cells. What
else was it doing? It was catabolizing
different proteins. That's not something
that you want. So whenever you're
starving yourself for a long period of
time, you have protein catabolism. And
what else? It depresses your immune
system. That's so important. So again,
it depresses your immune system. So
let's write that down now.
So what is it doing with long-term
stress? With the long-term stress
aspect, it's actually causing what? Protein
Protein
catabolism of the muscles
mainly catabolism. It's also causing
what? Increased blood
pressure by how? increasing the
sensitivity to our actual uh blood
vessels to norepinephrine which causes
vasoc constriction
and it
depresses immune system. And last
example here to like give it let you
understand how this is effective. If you
guys are taking finals, which you guys
probably are, or you're taking a test,
and you start having a lot of long-term
stress on the body, because when I talk
about stress, it could mean not just
like I said, trauma or certain types of
situations where you're not being able
to uh get enough nutrients like
starvation, but it could be long-term
stressors like preparing for your final.
If you're preparing for your final, a
lot of stress is coming on your body.
When there's a lot of stress on your
body, what happens to your immune
system? Your immune system gets
depressed. If your immune system is
depressed and it's not able to release
certain types of inflammatory mediators
and let your immune system know that
there's bacteria in the area, what
happens? Your immune system lets its
guard down and microorganisms start
actually causing damage to the tissue
cells and causing infections. And what
happens to these people? They get sick.
You ever notice how a lot of people get
sick before their finals? That's the
reason why because it's depressing your
immune system. It's bringing down that
guard and exposing ourselves to more
different types of bacterial infections.
That's why they use cortisol in certain
types of uh leukemias to treat it by
depressing the bone marrow from
producing white blood cells or from
actually decreasing the actual
inflammatory cytoines. All right guys,
last thing here uh with cortisol,
cortisol is different from aldoststerone
and from other different types of
hormones. He's interesting because let's
say that I take over here two different
scenarios. Let's say I put over here on
the left side high
cortisol levels, right? So, high
cortisol and then let's p say I put right
right
here. Let's say I put low
cortisol. So, two different situations.
Whenever there's really high cortisol,
look what cortisol does to the
hypothalamus. It comes up to the
hypothalamus and exerts a negative
feedback on the hypothalamus which
decreases the release of corticotropen
releasing hormone. Look what else it
does. It inhibits the anterior pituitary
from releasing ACT. What's the function
of ACT? To stimulate the synthesis of
cortisol. If you don't release ACT, what
happens to the cortisol production? Then
it goes down. That's the way that our
body deals with that. What if it's low
though? If there's low cortisol, then
not as much of this cortisol is going up
to the actual hypothalamus. And if not
as much of it is going up to the
hypothalamus, it's not going to be
causing a lot of inhibitory effect on
the parventricular nucleus in the
hypothalamus. So therefore, these nuclei
are stimulated. And guess what happens?
They release a lot of CR. It also
doesn't put as much inhibitory stimuli
on the anterior pituitary. And if
there's not a lot of inhibitory stimuli
here, it's going to release more act.
What happens when you release more ACT?
It helps to stimulate the synthesis of
cortisol. That's the way that our body
deals with elevated
elevated
and decreased levels of cortisol. All
right, engine nerds. I hope all of this
made sense. I really hope you guys
enjoyed it. In the next video, we're
going to talk about the actual zona
reticularis and the hormones that it
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