- [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 body.
So 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?
So 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 this 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's pretty much reliant exclusively
on the metabolic pathways involved in gluconeogenesis,
which if you remember is the pathway
by which we produce new or neo glucose.
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.
So 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 oxidation of fatty acids
in 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 gonna 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 that 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 the 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 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 molecule 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 to 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 through 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 performing
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 energy,
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 in 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, you know,
about, you know, 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 oxidation,
but this does not occur.
There is no 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'll essentially feed back
onto the electron transport chain
to say hey, slow down.
And if the flux through the
electron transport chain is slower,
than 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 or three days of starvation
into the production of ketones,
and this occurs mainly inside of the liver.
Now of course just to bring this story full circle,
the big idea here is that these ketones
can then 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.