Welcome to the Metabolic Classroom. I'm Dr. Ben Bickman, a biomedical scientist and professor of cell biology. Before we get started in the lecture, I want to remind you about the launch of my new site, benbickman.com.
At benbickman.com, you can subscribe to become an insider or a pro-insider. And of course, as a subscriber, you'll gain access to the show notes for the podcast. which also gets you access to the references or the scientific citations.
And there's some bonus podcast content, early access to upcoming lectures that I'll be releasing, hangouts, and additional perks to help deepen your understanding of metabolic health. If you're curious and you want to learn more, please visit benbickman.com. Now, in today's lecture, we're diving deep into a fascinating and probably unexpected topic.
Namely, the connection between salt-regulating hormones and blood pressure-regulating hormones and metabolic health. Now, when you think about salt and body water regulation in the body, you should think about blood pressure. That's the main focus for those kinds of topics.
And while salt consumption certainly can influence blood pressure, And I invite you to see the previous metabolic classroom where we spoke about blood pressure medications and their metabolic effects. But the hormones that regulate salt and body water balance, namely, and we'll get to these and each of them in more detail, angiotensin II, aldosterone, and antidiuretic hormone, or ADH, these do much more than just regulating body water and salt. In fact, There is a substantial body of evidence that shows they play a critical role in insulin resistance and even directly influencing the growing and shrinking of fat cells.
This means that they have a role when it comes to these problems that we typically think are just metabolic, like obesity, diabetes, insulin resistance, and all of the consequences that follow those things. So today in the lecture, we're going to start by discussing the primary roles of these hormones. how they regulate salt, water, and thus affect blood pressure. And then we'll shift to how they influence insulin resistance and fat cell biology. So the dynamics, the growing and the shrinking of the fat cell.
By the end, my hope is that you'll have a deeper appreciation for how tightly connected these systems are. It is unexpected. When you think about the hormones that regulate blood pressure, you now need to think about how they also regulate metabolic effects.
All right, let's get started with the lecture. So in this first bit, as I mentioned, I wanted to go through a bit of a primer to help you understand a couple of these hormones. Now, I do again invite you to watch the lecture that I recorded earlier, looking at the blood pressure medications and their metabolic effects.
In that lecture, I talk in more detail about the renin-angiotensin-aldosterone system, or sometimes just abbreviated as RAAS. It is within that system we come to two of the hormones we're talking about today, namely angiotensin 2 and aldosterone. Now let's explain the physiology. When your blood pressure drops, for example, if you are dehydrated, that, of course, becomes problematic, and your kidneys will sense the reduced blood flow.
And when they sense this reduction in blood flow, which happens with the drop in blood pressure, everything's getting a little less blood because the blood is slowed down. It's not moving as rapidly. The kidneys will respond to this and release an enzyme called renin or renin. R-E-N-I-N.
I say renin. Renin's job is to convert angiotensinogen. That's a liver protein.
Angiotensinogen. into angiotensin 1. So we now have the first enzymatic step in this process. Remember, what started it was a drop in blood pressure.
So the drop in blood pressure causes the kidneys to release renin. Renin will take angiotensinogen, a protein from the liver, and snip it apart. In so doing, we get angiotensin 1. Now, angiotensin 1 isn't really relevant to this story. It doesn't really do much on its own.
But there is, in fact, an enzyme in the liver sorry, the lungs now, a different tissue in the lungs of all places that will convert angiotensin 1 into its much more active version, namely angiotensin 2. So now we've come to the most, the first of the very relevant parts or the first of the action. parts components of this system angiotensin 2 is a powerful signal and it has its own effect as i'll get to in a moment but let's just finish this system or pathway when angiotensin 2 goes up it will bind receptors on the adrenal glands these little glands tucked above the on top of the kidneys or just above the kidneys and it will stimulate the adrenal glands to release aldosterone what's called a mineralo corticoid. Anytime you hear a hormone class that ends with the term corticoid, you think that it is built, it is a steroid.
It is built on cholesterol. So it takes a cholesterol molecule and rearranges it and turns it into the hormone that we're talking about. Again, in this case, aldosterone, a mineralocorticoid. So a cortisol, a cholesterol-derived hormone that influences minerals like salt, for example.
All right, now, Why is all of this connection important? Let's just stick with the blood pressure aspect before we move on to the metabolic aspects. Firstly, angiotensin 2 is a hormone of action. It does something that influences blood pressure, namely, it stimulates vasoconstriction.
So when angiotensin goes up, one of the ways this system, remember, it was activated because blood pressure goes down. Now, as we've gone through renin to angiotensin 1, with now angiotensin 2, it will take these blood vessels and tell them to narrow. As you narrow the blood vessel, blood pressure goes up.
So you're starting to correct the problem that turned the whole thing on. At the same time, angiotensin 2, as I discussed a moment ago, has activated the release of aldosterone. Now aldosterone is going to act on the kidneys, telling the kidneys to reabsorb sodium, that critical electrolyte. And as it reabsorbs sodium, water is going to be more retained.
And then with the water retention, of course, we have more water in the blood. And that means blood pressure goes up. Now, this partnership works very, very well. It's very efficient.
It is activated when blood pressure drops. And they both work in concert to help blood pressure go back up. Now, with all that having been said, let's transition away from the canonical.
effects of these two hormones, angiotensin 2 and aldosterone, and shift into the less well-known aspects, namely their effects on metabolic function, like insulin resistance and fat cells. Okay, so with angiotensin 2, because that one comes before aldosterone, angiotensin 2 does play a direct role in insulin resistance. It actually at least interferes with the insulin signaling pathway by blocking the movement of GLUT4.
With GLUT4, that is the critical mediator that opens up the channels to allow glucose to come in. So there are a handful of glucose transporters on every cell. And these are often just open doors. If glucose levels go up in the blood, the glucose levels will come in but GLUT4 is going to stay closed unless insulin comes and knocks on the door and now the channel will open or the transporter will open and glucose will come in but again that's an insulin dependent phenomenon so GLUT4 is opened when insulin is working and comes knocking and it is thereby helping control blood glucose levels And GLUT4 is expressed on some of the biggest tissues in the body, like muscle and adipose.
So you need insulin to be working well at muscle and fat. Now, how does angiotensin 2 come into play here? It does so by at least, among possibly other effects, by activating the biosynthesis of a molecule called ceramide. Now, any of you that have listened to some of my lectures before, you know what ceramides are. Ceramides are a class of sphingolipid.
There are lots of different types of lipids. The sphingolipid family, its effects were so poorly understood for so long that they were named after the mysterious Sphinx. We now know much better about what they do.
But a paper was published in the very good Journal of Biological Chemistry, JBC, in 1999. And they documented how angiotensin II, when it comes and binds a specific receptor called the angiotensin II type 1 receptor, AT1 receptor, it actually stimulates ceramide biosynthesis. And as you have, again, angiotensin II binding and activating the AT1. receptor.
It is activating the rate-limiting enzyme of ceramide production called serine palmitoyltransferase, or SPT. And so we have ceramides getting produced much, much faster when angiotensin II comes to a cell. And once the ceramides accumulate, they act like a molecular roadblock when it comes to the insulin signal. Ceramides specifically target a process called AKT phosphorylation. So AKT is one of the critical steps in the insulin signal.
Definitely, certainly critical in order to activate GLUT4, which again, we need to do if we want to try to control blood glucose. So ceramides are blocking AKT phosphorylation, which means it's preventing AKT from becoming active. And without AKT activity, the insulin signal stops, GLUT4 stays trapped inside the cell, glucose uptake stops. And insulin resistance is in full force. And so with all of this in mind, it won't surprise you to learn that angiotensin 2 has been implicated in the development of type 2 diabetes, especially in individuals with high blood pressure where the hormone tends to be overactive.
So this is a fascinating series of events where if you have a person who... It has blood pressure for high blood pressure for whatever reason. Perhaps it's something as simple as ongoing stress or sleep deprivation.
That can be partly mediated through elevated angiotensin II, and that could be then driving insulin resistance. As much as we typically embrace the view justifiably that insulin resistance is driving high blood pressure, again, that's not wrong. We can actually flip it around. because we see some of these components.
If angiotensin 2 is elevated, again, perhaps due to stress and other factors we'll talk about like salt restriction or water restriction, that is then potentially driving insulin resistance. Now, angiotensin 2 is relevant metabolically speaking beyond just insulin resistance. It has some fascinating and complex effects on fat cells directly.
The primary role in fat tissue is actually to promote... adipocyte or fat cell hypertrophy, meaning it increases the size of the fat cells rather than their number. Once again, this happens through the angiotensin 2 type 1 receptor, the AT1 receptors. As this is active by stimulating more lipogenesis, that's the specific process, it's making the fat cell grow, but it is at the same time inhibiting hyperplasia, so it's not allowing the fat cells to multiply.
And if you'll recall from previous lectures, having more fat cells is this paradoxical way of both being able to get fatter, but still being able to store the fat in those fat cells. And thus, you maintain insulin sensitivity and metabolic health. And so that is, again, it's an effect because of angiotensin inhibiting adipocyte differentiation.
And so it's preventing hyperplasia. in that specifically it's by inhibiting some of these adipose transcription factors like PPAR-gamma. But at the same time, amplifying angiotensin 2's ability to stimulate adipocyte hypertrophy, it can do so further by inhibiting lipolysis. So not only is angiotensin 2 stimulating the growth, the production of fat in the fat cell, but it's inhibiting the ability of the fat cell to break that fat down. It's inhibiting lipolysis.
So the cumulative effect here, of course, is going to be a strong stimulus to promote growth of the fat cells. Again, hypertrophy, which is, as you know, problematic for reasons that I've discussed abundantly before. Now, to add to all of this complexity, the canonical view, again, here is that and we have a lot of unorthodox discussion here.
with regards to these blood pressure regulating hormones, you're thinking of angiotensin II as a product of cleaving angiotensinogen, which itself was a hormone or a protein that came from the liver. However, this is where it gets a little more complex. Fat tissue itself produces angiotensinogen, the precursor to angiotensin II.
So in a way, it kind of has its own local... Renin-angiotensin system right within the fat tissue. This of course can amplify angiotensin 2's effects, particularly in conditions like obesity, where more fat cells would mean more of these precursors being produced, which is feeding back on itself. That's something called an autocrine. effect, where a cell is releasing a hormone that can then come back and stimulate itself.
All right, so that is some of the discussion, or all of the discussion, on angiotensin 2, the first action hormone in the renin-angiotensin-aldosterone system. But there's still one more, which is aldosterone. So let's transition to talking about aldosterone. As I mentioned, aldosterone is a steroid hormone that is generally just produced by the adrenal glands, which sits on top of the kidneys. The primary job is to help the body maintain blood pressure by controlling salt.
Now, that's how it controls salt, but the same, or that's how it controls blood pressure, by regulating salt handling in the body, or specifically at the kidneys. But again, the primary stimulus for this is, in fact, low blood pressure. Just keep that in mind.
So if blood pressure is dropping, this is one way where the body is saying, hey, I need to... This is another redundant way. I need to increase blood pressure.
And in this case, when aldosterone comes on the scene, it does so by telling the kidneys, hey, you're about to let some of those minerals go, the sodium. I need you to keep it because if you hold on to that sodium, I can make the body hold on to its water. If we hold on to water, we can help blood pressure be up, you know, increase it to try to correct the drop.
Now, once aldosterone is in the body. or in the blood, it's going up in the blood, yes, it will have all of those effects at regulating minerals and thus regulating water and thus regulating blood pressure. But it's also going to have this off-target effect of influencing metabolic function. That's where, once again, things get kind of interesting. Chronically elevated aldosterone has been shown to impair insulin signaling.
So once again, in addition to other possible effects, you'd think, well, how does it? do so. And just as a tangent, I want you as your guest professor, I want you to appreciate some of the biochemistry and the signaling.
When I kind of put these outlines, never really totally scripted together, I sometimes have an internal debate of where I think, oh, that's too much detail. My guest student won't care about that. And then I always sort of go back and bring it back in.
So appreciate that while it seems like it's getting complicated, I'm trying to, I really want you to be able to leave the lecture with a deeper understanding than when you came into it. And so that's what I'm doing here again, that you'd think, well, how is aldosterone causing insulin resistance? Once again, it is at least partly through the accumulation of ceramides, those highly active sphingolipids that directly block the insulin signal. So in this case, not only does aldosterone stimulate the de novo ceramide biosynthesis, so making it from scratch, similar to what angiotensin 2 does. But it also activates the breakdown of a lipid called sphingomyelin, which can become ceramides.
Now, sphingomyelin, all the sphingolipids are primarily components of membranes, like many lipids are throughout the cell. When you get to ceramides, ceramides can become sphingomyelin, which really gets enriched in cell membranes. But that That process can reverse itself, and this is something aldosterone is doing. Not only is aldosterone stimulating the de novo growth or production of ceramides from scratch, but then as ceramides may turn into sphingomyelin, it's activating an enzyme called sphingomyelinase, which is kind of reversing that process, taking the freshly made sphingomyelin and turning it back into ceramides. So the collective effect here is to once again… substantially increase ceramide accumulation within the cell.
And as the cell's accumulating ceramides, it's once again blocking or compromising the insulin signal. Thus, we have insulin resistance in response to aldosterone. Now, let's move to the next subtopic of that metabolic effect, namely the fat cells.
Because once again, aldosterone has a direct impact on fat cells. Its effects are primarily mediated through a receptor called the mineralocorticoid receptor. Now remember, I told you that aldosterone is kind of the poster child for mineralocorticoids, just as a fun another tangent.
So the corticoid, you know what that means now. It's a hormone based on cholesterol. Mineralo, at the beginning, of course, evokes the idea that it controls minerals. No surprise to you, cortisol...
which is also made from the adrenal gland, specifically the adrenal cortex, although a different layer of it, just like aldosterone is. It's called, cortisol is the most famous of the glucocorticoids. So you can start to see a pattern here, right? You hear the corticoid again, which means that it is based on a cholesterol molecule.
But in this case, cortisol is affecting glucose. which it does, of course, very, very well. And we've discussed that abundantly in the past.
All right, so aldosterone activates the mineralocorticoid receptors, which adipocytes have a lot of. So adipocytes have these mineralocorticoid receptors, which means they do respond to aldosterone. Now, firstly, aldosterone will influence adipogenesis.
Now, I haven't used that term yet. Earlier in the lecture, I used the term. lipogenesis, which refers to a fat cell making new fat, making it get bigger.
Adipogenesis is a term that is used to describe the production of new fat cells, taking these pre-adipocytes, these kind of precursor stem cells that have the potential of becoming fat cells, and telling them, your job is to become a fat cell. So they then become a mature fat cell. Studies suggest that aldosterone through the mineralocorticoid receptor activation can promote the differentiation of pre-adipocytes, leading to the not surprising effect of having more fat cells.
Now, of course, if you have more fat cells, that means the potential for fat gain goes up a lot. But interestingly, aldosterone goes further because it also affects fat cell size. High levels of aldosterone enhance lipid accumulation. or fat accrual within the cells, which again increases the size.
Now you have this hypertrophic effect alongside aldosterone's hyperplastic inducing effect or hyperplasia inducing effect. So in short, aldosterone doesn't just regulate electrolytes and thus water, but it directly influences fat cell growth and development by increasing both the hyperplasia through adipogenesis and the hypertrophy through lipogenesis. Findings, of course, highlight another way in which some of these unexpected hormones, like aldosterone, can contribute to metabolic dysfunction.
Now, once again, we have a final note here, is just the unexpected microcosm of the fat cell itself. Like with angiotensin II, the fat cell can make its own aldosterone. Angiotensin II, which is, as I mentioned earlier, produced in substantial amounts from fat tissue can stimulate aldosterone secretion by the adipocytes.
So you have an adipocyte making angiotensin 2, and then that angiotensin 2 can come back and stimulate the production of aldosterone, which can be released from the fat cell, which again, in turn, can come back and activate the very same fat cell or any of its neighboring fat cells. Of course, Just to help you be familiar with some more of these terms of endocrinology, when one individual fat cell is making a signal that comes right back to it, that's autocrine. But as it is activating its neighbors, that would be called paracrine. So it's spilling over to its neighboring cells, all of them activating each other. So you, again, have this kind of microenvironment that as much as I introduced the whole body view coming from renin coming from the kidneys, angiotensinogen coming from the liver, The conversion with the enzyme at the lungs of the angiotensin converting enzyme giving us angiotensin 1 to 2, and then that going to the adrenal gland giving us aldosterone, all of this can be sort of scrunched down to the level of the fat cell.
It's pretty fascinating. All right, now, there's one more hormone that I want to mention, which is maybe one you were actually more familiar with coming into this lecture, which is antidiuretic hormone. Just so that you're aware, it also has another name, which is actually used more in science teaching than ADH is, which is arginine vasopressin.
Vasopressin. That name actually comes from the fact that ADH does also have this stimulating effect on the blood vessels to induce constriction. It's pressing in the vessels, the vasopressin.
which is actually it's one single amino acid different from oxytocin that hormone of pregnancy that you may be familiar with but i'll call it adh because that's kind of the lay term for anti-diuretic hormone anti-diuretic hormone is produced in the hypothalamus and then released from the posterior pituitary gland you've heard of the pituitary gland and not surprising the main stimulus once again is low blood pressure so if someone's dehydrated blood pressure goes down It stimulates the hypothalamus, basically saying, hey, we're running out of water in our blood. We need to bring that back up. And so then the main effect of ADH is to go to the kidneys, telling the kidneys to reabsorb water.
So water that might have been filtered at the kidney that would have been making its way down to the bladder to be excreted as urine doesn't get that far. ADH basically opens up these little pores and pulls the water back in, saying, hey, I— Actually, sorry, change that note. I need you to stay and work a little longer.
So the water comes back in. It helps restore blood pressure by increasing water volume. All right, that's the primer on ADHs. typical or classic function.
But of course, we're going beyond that and looking at the metabolic effects. Now, let's talk about insulin resistance first. The evidence with insulin resistance and ADH is a little murky. It's not totally clear. Animal studies suggest that vasopressin or ADH's effects on insulin sensitivity could depend on which particular receptors.
And these are arginine vasopressin receptors so they're not even called adh receptors generally and so that it kind of complicates things where some receptors appear to if they're activated in response to adh they improve insulin sensitivity others appear to compromise insulin sensitivity so we'll just say that it's a little vague what is less vague is the effect of adh on fat cells like aldosterone and angiotensin 2 Although this is a totally separate pathway. The renin-angiotensin-aldosterone system is separate from ADH. They have complementary or even redundant effects, but they are not part of the same pathway.
You don't need one to activate the other, in other words. But nevertheless, despite them orbiting in different areas, like aldosterone and angiotensin II, ADH also affects fat cells. In fact, it has been shown to directly stimulate fat cell growth.
by most especially decreasing fat breakdown. So ADH has an anti-lipolytic effect on adipocytes by inhibiting the breakdown of fats. This is primarily mediated through what's called the V1A receptors. And in particular, there's some pretty good animal evidence involving V1A receptor deficient mice or these knockout mice. They don't have this particular V1A receptor.
And what they see is that there's a significantly greater level of lipolysis and greater levels of glycerol, which is a sign of lipolysis, and even ketogenesis. So a lot more fat mobilization and even a lot more fat breakdown when you get rid of these V1A receptors. All right, so this suggests that when ADH goes up, it's blocking those effects.
So it's going to force the fat cell to hold on to it all. Now, with all of this kind of basic biochemistry and endocrinology in mind, I wanted to make sure that we actually zoomed out at the end of the lecture and talk about the whole body phenomenon. Because there's a bit of a surprising twist that has been kind of underlying all of this, which is that salt restriction can actually worsen insulin resistance. And there's a particular irony here, because while low-sodium or low-salt diets are often prescribed for blood pressure control, They can lead to an overactivation of the renin-angiotensin-aldosterone system in particular. Because if salt is going down, that particular pathway gets turned on.
So angiotensin 2 and aldosterone would go up. And of course, as I've presented, these hormones can impair insulin signaling and promote fat storage. So the irony, of course, is that while reducing salt may lower blood pressure a little, because the evidence suggests that it is a very modest effect, if any at all. It may inadvertently harm metabolic health in the long term, especially in people who have a bit of an increased risk of insulin resistance.
So I wanted to highlight just a few studies among dozens that have been published. And in the show notes, you can find a review article that I link where you can find dozens of other studies. So the first study examined the effects of moderate salt restriction on insulin resistance.
This was a crossover study, so patients, the study subjects did one and the other with a washout period in between. There were eight participants that included people with normal blood pressure and high blood pressure. And they followed a low salt diet of around 1,700 milligrams per day compared to a normal intake of about 5,400. So they took people with normal salt consumption and then had them go on to a lower salt consumption.
After just one week, Fasting insulin levels more than doubled on the low-salt diet, jumping from 4.4 milliunits to 9.9. So more than doubled. This indicates, of course, a significant increase in insulin resistance with just one single change, namely restricting salt. Another study looked at patients with hypertension, and they had either a low salt diet, very low, which 782 milligrams a day, or a high salt diet, over 8 grams, about 8 grams a day.
So about 10 times higher. And once again, it was a crossover. After just one week, the results showed that glucose and insulin levels with this was powerful because they used an oral glucose tolerance test.
And they actually... all of it was significantly better on the high salt diet. The low salt diet, on the other hand, impaired glucose metabolism. So it took them much longer and required more insulin in order to clear the same amount of glucose as salt was restricted. Now I'll just share one more, although I could share more.
A third study had 34 patients with hypertension and they looked at them for 12 weeks with moderate salt restriction and the results were striking. Salt restriction led to a 40% increase in C-peptide. Now, C-peptide is a co-release hormone, if you will, released with insulin.
So it's not a perfect indicator of insulin levels, but it's a very good indicator of insulin secretion. So again, that went up by 40%. Over the same time, glucose went up about 6%. But interestingly, HDL dropped by 11%. Now, HDL is embraced as the so-called good cholesterol.
Well, salt restriction doesn't do it any favors. So these findings certainly suggest that reducing salt worsens insulin resistance and even exacerbates this lipidemia. All of this in people with hypertension. So taken together, these studies and many, many others reveal that there is a surprising metabolic consequence to salt restriction.
It can exacerbate insulin resistance, especially in people with hypertension or metabolic vulnerabilities. This challenges the assumption that less salt is better, and it highlights the importance of people just really being smart about what they're doing based on their own family history and proclivities to metabolic problems. Remember, insulin resistance is one of the leading causes, if not the main cause, of hypertension. So what irony.
Here in this situation, the intervention that is most readily embraced globally to reverse blood pressure, namely salt restriction, happens also to be a primary and potent cause of insulin resistance, which is probably the main driver of insulin resistance in general. So now one final thought here before I actually conclude is also dehydration, that the last few studies that I've mentioned focused on salt restriction. But also just water restriction will do this too.
So if a person is under hydrated or dehydrated, it's going to turn all of these things on, not only the renin-angiotensin-aldosterone system, but also ADH. And now you see a pretty large combined potential effect where if a person is dehydrated due to being, well, not drinking enough water in particular. You're turning all of this on. And so that might be a hidden variable in some people's struggles to improve their metabolic health. So let's wrap it up.
What have you learned today? You've learned that the hormones that regulate salt and water in the body, like angiotensin 2, aldosterone, and ADH, they are deeply interconnected with metabolic health. They don't just control blood pressure.
They influence how the body responds to insulin, and they directly impact the dynamics of the fat cells. So when these hormones are chronically elevated, whether it's due to poor hydration or salt restriction, given with the best intentions, the result can be metabolic catastrophe, insulin resistance, and greater fat storage. So things to keep in mind.
All right. Thank you for joining me today on The Metabolic Classroom. And thanks, as usual, for letting me be your professor for the last half hour or so.
If you found this lecture helpful, of course, please share it with someone who might benefit from understanding the unexpected metabolic connection between blood pressure hormones and metabolism. And as always, until next time, more knowledge, better health.