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How does the body adapt to starvation?

Video transcript
- [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.