- [Instructor] In this video, I want to explore
the question of how does our body adapt
to periods of prolonged starvation.
So in order to answer this question,
I actually think it's helpful to remind ourselves first of a
golden rule of homeostasis inside of our bodies.
In order to survive, remember that our body
must be able to maintain proper blood glucose levels.
I'm gonna go ahead and write, "We must be able
"to maintain glucose levels in our blood."
And this is important even in periods of
prolonged starvation because it turns out that
we need to maintain glucose levels above a certain
concentration in order to survive, even if
that concentration is lower than normal.
And this of course brings up the question
well, how does our body maintain blood glucose levels?
Let's go ahead and answer this question
by starting off small.
Let's say we have a mini case of starvation,
let's say three or four hours after a meal.
Your blood glucose levels begin to drop.
And so what does your body do to resolve that?
Well, at point it has a quick and easy solution.
It turns to its glycogen stores in the liver.
Remember that our body stores up these
strings of glucose inside of our body
so that we can easily pump it
back into the blood when we're not eating.
But unfortunately, humans only have enough
glycogen stores to last us about a day.
So after a day of starvation, our body is pretty much
reliant exclusively on the metabolic pathways
involved in gluconeogenesis, which if you remember is
the pathway by which we produce new or neoglucose.
And we produce this glucose from
non-carbohydrate precursor molecules.
So let's think about what else we have in our body.
Remember that our other two major storage fuels are
fats, and we usually think about fatty acids
containing most of that kind of energy.
And we also have amino acids.
So I want to talk about both of these fuels in turn and
how and if they can contribute to gluconeogenesis.
Now, even if you forget most of what I say in this video,
try and remember just this one next key point,
which is that the breakdown products of fatty acids
cannot be converted for the most part into glucose.
They can't contribute to gluconeogenesis.
On the other hand, the breakdown products of
the catabolism of amino acids can.
So to talk about why this is the case, I want to
remind you of the Krebs cycle and gluconeogenesis and
how these two cycles are connected.
Remember that the major breakdown product of the
oxidization of fatty acids is
a molecule called acetyl coA.
And this is a very special molecule because
it represents the entry point into the Krebs cycle.
Remember that it combines with a
four carbon molecule called oxaloacetate,
which we usually abbreviate here as OAA.
And it is turned into this molecule called citrate.
And of course, there are many, many other
conversions that I'm not going to write, but
the gist of the Krebs cycle is that we end up
cycling back to oxaloacetate.
Which means that we lose those two carbons that we
added in the form of acetyl coA into carbon dioxide.
All right, so fairly simple enough, right?
We end up producing these acetyl coA molecules
from the oxidation of fatty acids which cycle through
this Krebs cycle, allowing us to produce all of those
electron carrier molecules like NADH and FADH2
which end up contributing to the production of
ATP in the electron transport chain.
But how does this all connect up with and
implicated with this gluconeogenesis process?
So let me remind you that generally remember
we think about gluconeogenesis as essentially being
the reverse of glycolysis, minus a couple of steps
that we have to change around a little bit because
some steps in glycolysis are irreversible.
But largely we can think about it as a
reverse of glycolysis and remember that the end product of
glycolysis was this molecule called pyruvate, right?
And so somehow, we can funnel things into pyruvate and
if we end up getting this molecule pyruvate through
the process of gluconeogenesis, we can actually
convert it to a molecule called oxaloacetate,
which should ring a bell because
remember it's also in this Krebs cycle here.
And then we can also then eventually turn it back into
phosphoenolpyruvate, another molecule
also found in glycolysis.
And then we can essentially run this entire
sequence of glycolysis pretty much backward
with changing around a couple of enzymes of course.
And eventually we get back to producing glucose.
All right, so now here's the reason why amino acids
can contribute to this pathway of
gluconeogenesis but fatty acids can't.
It turns out that the catabolism, the breakdown of
amino acids allows these breakdown products to be
turned into some of the intermediates along the Krebs cycle.
So I'm just kind of drawing arrows loosely because
I know I haven't written out the
specific names of the molecules but suffice to say
the big picture is that we're able to get these
amino acids converted to these intermediates.
And what's really cool is that we know that this
molecule oxaloacetate is eventually what
these intermediates are going to become.
And we also know that oxaloacetate is a
compound in gluconeogenesis.
And in fact, we can even shuttle this even more directly
to be converted right into phosphoenolpyruvate right here.
And so that's how these amino acids eventually
get into this gluconeogenesis pathway.
Likewise, amino acids can also when they're broken down
also be converted into pyruvate as well, which from this
diagram I've shown you also allows them to
contribute to this production of glucose.
Now, even though all the ATP that's produced by this
acetyl coA molecule from the oxidation of fatty acids
might be fueling this anabolic reaction of gluconeogenesis
because remember, anabolic reactions require ATP.
This acetyl coA model in itself
has no place to enter this gluconeogenesis pathway.
Remember that pyruvate can be converted to acetyl coA
using the enzyme pyruvate dehydrogenase
but the thermodynamics of this chemical reaction,
the Delta G value for this reaction is very negative.
And so this forward reaction is irreversible.
In other words just to make this super clear
we cannot go the opposite direction.
We cannot go from acetyl coA to pyruvate.
And so acetyl coA cannot enter the gluconeogenesis pathway.
Now, I remember when I was first learning about this
that part made sense but what didn't make sense to me was
how acetyl coA, it looked like acetyl coA could eventually
be converted into oxaloacetate and then from here
it seemed to me that we could enter
the gluconeogenesis pathway right here.
But I want to remind you that remember the two carbons
that were in acetyl coA molecule here.
We end up losing those two carbons
in these molecules of carbon dioxide.
So even though our diagram looks a bit misleading
in that we can kind of follow acetyl coA's journey
to oxaloacetate, you just have to remember that you know
that these two carbons we end up not having a net production
of carbons anywhere along this cycle because these two
carbons end up exiting as carbon dioxide molecules.
Now a couple minor points that I do want to mention are
that it turns out that there are some fatty acids
specifically odd chain fatty acids that can contribute in
some way to the Krebs cycle like these amino acids so
some portion of these odd chain fatty acids
can be converted to intermediates
in the Krebs cycle and be used for gluconeogenesis.
But on the whole, we generally consider fatty acids
not to contribute to gluconeogenesis because
we think about acetyl coA being
the primary product of fatty acid synthesis.
And the next point that I actually want to make as well is
it turns out that there are some amino acids that can also
be converted directly into acetyl coA.
And so I'd ask you the question, would these amino acids
be able to contribute to gluconeogenesis?
So think about that for a moment.
Now of course the answer to that question is
as long as those amino acids don't have
any way to contribute to any of these intermediates
in the Krebs cycle, it's just like the situation
for fatty acids because we're ultimately
turning into acetyl coA there's no way for acetyl coA
to contribute to this pathway of gluconeogenesis.
So these amino acids if they're exclusively
being turned into acetyl coA
cannot contribute to gluconeogenesis.
All right so this seems all fine and good.
We have a solution, right?
We're able to use amino acids to eventually produce glucose
though gluconeogenesis but what might be a potential
pitfall of using amino acids?
Because remember that proteins are
vital molecules inside of our cell.
Many of these proteins have functions inside of our cells.
Many of these are enzymes that carry out important processes
and proteins often comprise the bulk of our muscles.
So you can imagine that using all of these amino acids
and breaking them down would be bad for our survival
as a species because of course we need our muscle mass to
be able to move around and we need our enzymes to be
preforming their activities inside of our cell.
So that's why in states of prolonged starvation,
our body comes up with another golden rule
which is to save our protein.
We don't want to waste our protein
in the production of glucose.
And luckily for us, many of the tissues in our body that
rely exclusively on glucose for the production of energies
such as the brain, because remember fatty acids
can't cross the blood brain barrier.
Many of these tissues tend to be a little bit more
flexible for us in times of starvation and they start using
a different fuel that our body switches to making several
days after starvation called ketones.
And for the brain in particular, these ketones
are effective unlike fatty acids because these ketones are
water soluble enough to cross the blood brain barrier and
allow us to produce ATP in times of starvation.
All right, so what's the big picture idea behind ketones
and how does ketone synthesis save our proteins?
So to describe this, I want to go ahead and make some
more room here to draw out a flow chart to remind you
what happens when our body is subjected to starvation.
Remember that our hormones are
the orchestrators of all metabolic pathways.
And so let's remind ourselves what happens
to our hormones in times of fasting.
Remember glucagon levels begin to rise because they're
sensing we have low blood glucose in our blood.
And insulin levels, which only respond of course to
high blood glucose levels begin to drop.
And this stimulates our body
to start breaking down fatty acids.
And fatty acid oxidation which occurs
primarily in the liver, and as we talked about above
this ultimately leads to having
a lot of acetyl coA molecules.
And in the beginning about maybe three to four hours
after our last meal and up to a day, our body is working
on building up these acetyl coA stores
so that they can enter the Krebs cycle
to eventually produce the electron carrier molecules
that will allow us to produce ATP
in the electron transport chain.
So that's kind of our main goal in these first kind of
one or two days of fasting.
However, about two to three days after fasting,
the levels of acetyl coA inside of your body begin to rise
above the amount that you need to maintain ATP levels.
And the reason why this is able to happen
is for several reasons.
One thing to recognize is that most metabolic pathways
we've talked about have some form of regulation,
some form of product inhibition,
but it turns out that there is no
type of product inhibition
when it comes to fatty acid oxidation.
So normally we might think that rising levels of acetyl coA
would signal somehow the body to decrease fatty acid
oxidization, but this does not occur.
There is not type of product inhibition.
So acetyl coA levels can continue to rise essentially.
In addition, remember that one of the biggest regulators
of metabolic pathways in our body is ATP.
And if we have enough fatty acid oxidation to produce
enough ATP in our cells and ATP levels are plenty,
it will essentially feed back onto the
electron transport chain to say, hey, slow down.
And if the flux thought the electron transport chain
is slower, then that will lead to an increase in the amount
of our reduced electron carrier molecules like NADH
for example, because these won't be donating electrons
into the electron transport chain as fast.
And remember that NADH is one of the biggest regulators
of the Krebs cycle, and so if we have a lot of NADH
it will slow flow through the Krebs cycle.
And so the acetyl coA molecule will no longer
want to enter the Krebs cycle as much.
And that is what allows our body to shunt this extra
acetyl coA that develops after about two to three days
of starvation into the production of ketones.
And this occurs mainly inside of the liver.
Now of course we just to bring this story full circle
the big idea here is that these ketones can now leave
the liver, go into the bloodstream, and other tissues
like the brain can take out these ketones and convert them
back to acetyl coA, and of course we know then that
acetyl coA can enter the Krebs cycle like this and
contribute to the production of ATP.
Moreover, as the body shifts several days after starvation
to this new fuel of using ketones, it puts less pressure
on the body to undergo gluconeogenesis.
And if there's less pressure to undergo
gluconeogenesis there will be less pressure
for our body to break down protein.
And so actually it turns out that the majority of protein
breakdown occurs in the first couple, first two to three
days of starvation but after that protein degradation,
the rate of protein degradation
will decrease because our body is shifting
to use more of these ketones as an energy fuel.