53: Salt and Cardiometabolic Health with Dr. Ben Bikman

Hello and welcome to this week's episode of the Metabolic Classroom. I am Professor Ben Bickman. I'm a biomedical scientist and professor of cell biology. Thank you for joining me today as today's lecture or classroom episode is all about salt and its cardiometabolic consequences. Today's episode is actually sponsored by a local company. This is not only a US based company, but even a Utah based company, which is where I am coming at you from Redmond Real Salt. Redmond Real Salt is again a local company. They find their salt here from actually these massive salt caves and they have worked this high quality ancient salt into a number of products. Let me just tell you guys, one of the reasons I'm so delighted is because I literally use their products every single day. I like the Boost product. Once they have their pre workout back in stock, I can highly recommend the pineapple mango flavor. It is one of the most delicious flavored powdered drinks I've ever, I've ever had and I use it as a pre workout every day. But check it out. Go to Redmond Real Salt and you can use the code BEN15 for 15 off. It's a pretty generous coupon code. So if you're looking for some salt and after this I suspect you're going to want some, check out Redmond Real Salt. They're the ones I go to for not only just salt for general use around the house and in the kitchen, but also for a number of salt based or electrolyte based supplements. I know of none better. Remember, use Ben 15 at checkout. All right, now as we get started, I just want to put a question in your mind to keep in mind as we discuss this topic. Are you eating sufficient salt to burn fat? Isn't that a weird question? It's not going to seem so strange once we go through it and we start talking about how some of the salt regulating pathways, these, these biochemical processes and, well, biochemical and endocrine based so these hormones that are eliciting various signals within cells across the body, some of these, some of this is, has classically been considered only in the context of salt and water regulation. But more recent research has found that these pathways also have an effect on metabolic processes, most especially in the fat cell. Now, before we get started and explore the cardiometabolic consequences of salt regulation, I just wanted to go through a brief primer of how the body handles salt and. Well, why even maybe first and foremost, why should we even care about salt? Well, and mind you, salt is as a chemical term just going to be the union of a positively charged mineral and a negatively charged mineral. But usually when we say salt, we mean sodium and chloride. And usually the part of that that's most especially focused on is the sodium. So why does salt matter? But why does sodium matter as a component of it? It is totally essential in the body. And if blood sodium levels get too low, the body dies. So, I mean, there's no better proof of its necessity than that. So firstly, salt is of course, very relevant in electrolyte balance and fluid regulation, which we're going to talk a lot about. You're going to be an expert on that aspect, the fluid regulation aspect. But where salt goes, water follows. And so if we don't have sufficient salt in our body, we're not going to have sufficient water. The kidneys will have a harder time holding on to that water. Also, we need sodium in these electrolytes for nerve function, the transmission of these electrical signals through the nervous system, sending nerve impulses or action potentials that we need for not only just sensation, but also muscle contractions and reflexes and various functions over which we have no control. Like for example, the contraction of the intestine to move food. I mentioned muscle function. Similar to its role in nerve signaling. Sodium is vital for proper nerve function. We have to have enough sodium to be rapidly moving across the membrane of the, of the muscle cell, similarly with sending a signal down a nerve. But also we need sodium for acid base balance, keeping the body in its very narrow range of ph. We can't get too acidic, we can't get too basic. We have this kind of Goldilocks range where we need to stay when it comes to ph. Well, sodium helps regulate that tremendously. Sodium also helps the body absorb nutrients. So there are certain transporters or channels that will open to allow nutrients to come in when signaled to the blood vessels to constrict. And that is to try to increase blood pressure. Because remember, the main stimulus for this whole pathway is when blood pressure goes down. So angiotensin2 wants to immediately try to address this by constricting the blood vessels vessels. And if we have a relatively lower volume in the blood, well, then if we start to constrict the vessels, we can restore blood pressure by narrowing the overall volume or the overall space of the blood vessels. So angiotensin II will immediately do that. It'll also have an effect on antidiuretic hormone production from the pituitary gland. But we won't get into antidiuretic hormone today. That's its own topic, with its own fascinating effects on even metabolism. Another effect of angiotensin 2, well, that it will stimulate is that it will stimulate thirst centers in the brain. We will start to feel like we want to drink, which is, of course, a helpful stimulus, assuming the water is round, because if we drink, we can start to correct the blood volume and restore blood pressure. But lastly, Angiotensin 2's most famous effect is that it will flow through the blood and get to the adrenal glands, specifically the adrenal cortex, or the orange peel part of what we call the adrenal glands. The peel, not the fleshy, fruity part, that's called the adrenal medulla, but the adrenal cortex, the outside of the adrenal gland. So angiotensin II comes to the adrenal cortex of the adrenal glands and now stimulates the production of aldosterone, which is the hero of this particular part of the story. Aldosterone has a powerful effect acting at the kidneys. Isn't it funny? The whole journey started at the kidneys with the production of renin, and now we're back, albeit with many, many characters that have been introduced along the way. So, first and foremost, aldosterone will stimulate the kidneys to reabsorb any sodium. Any sodium that had been filtered out of the blood and would have been moving its way through the kidneys to urine will get pulled out of the kidney tubes, the tubules of the kidney, and moved back into the blood. It's basically aldosterone's way of telling the kidneys, hey, kidneys, you're trying to filter out that sodium, but we really need it, because if I can pull that sodium back in, then I can have water follow it. That sounds a little strange, but it's a principle called osmosis, where if you have these molecules that are moving into one direction, moving into a particular compartment or, well, let's just go with direction. Water wants to get pulled with it. So the movement of the sodium is going to pull water with it. And thereby we've addressed the two primary problems that are originally kicking this whole process off that are triggering it as the sodium's coming back, that's restoring sodium levels, which is the secondary signal, but it's bringing with it a substantial amount of water, which, of course, is addressing the primary signal, namely the low blood volume and low blood pressure that results from it. And then I, of course, will turn it back off. That's the part of the negative feedback. One of the most fundamental principles in cell biology, the system gets turned off once aldosterone has done its job. And again, that job being primarily focused on pulling the sodium from what would become urine and moving it back into the blood and having the water that had also been filtered in the kidneys that would have gone to turn into urine, follow that sodium and go back into the blood. Now, throughout this description, you might have heard some words that are familiar. If there are some of you who are on what's called antihypertensive medications, like, for example, you might have heard of ACE inhibitors. ACE inhibitors inhibit the angiotensin converting enzyme. That enzyme from the lungs that are converted, that converts angiotensin 1 into the much more active and essential in this process, angiotensin 2. And angiotensin II again has specific effects. And so even it is a target of some antihypertensive medications. And there are such thing, such drug class known as angiotensin receptor blockers. So trying to block the effect of the angiotensin, all of its effects, including activating aldosterone production. Okay, now this has all been just basic physiology. And you're wondering, Ben, why on earth did you even invoke the term metabolic in this. In the title of this episode? I'm getting bored because I'm not hearing anything. Metabolism. All right, well, your patience is now about to be rewarded. So insulin, which is the mother of all metabolically related hormones, having an influence that is extraordinarily powerful in every cell throughout the body. It also has an effect on salt handling. Now, just as a interesting thought experiment, why on earth would insulin, who wants to tell tissues to grow, have an effect on electrolytes at all? Well, if you're telling cells to grow, which again, is insulin's kind of thematic effect, it wants cells, it wants to grow things, it wants to promote anabolism or anabolic reactions. If you're telling the body to grow, you need more electrolytes, you need more minerals to support that growth. So that could be some of the reasoning for this. But first and foremost, insulin has a direct effect. Insulin directly stimulates sodium reabsorption in the kidney tubes, or tubules, particularly in the more distal part. You know, the tubules are really long, winding things. And this is mediated because of insulin's activity or action of these pumps, these sodium potassium pumps. And it will overall effect will be driving the sodium back into the body. But also, we come back to the renin angiotensin aldosterone system. Insulin has a heavy interaction with that raa system or the raas. Insulin can increase the activity of the sympathetic nervous system, which can turn on renin production, which will then of course initiate this whole cascade, ultimately resulting in higher aldosterone. So that's the sort of meandering path. If insulin going up, it'll have a direct effect at sodium reabsorption, but it will also recruit aldosterone's help. And then aldosterone will really, of course, kick that up a notch and aggressively start pulling in the sodium back into the blood. Also, insulin Inc. Can enhance vascular sensitivity to angiotensin too. So insulin can help the blood vessels have a better response to angiotensin 2, which of course has a vasoconstriction effect, which can help restore blood pressure. Now, unfortunately, this knowledge is generally wildly unappreciated, if it's even known at all. And thus you have. We have had, and I would say even perhaps suffered from policies in the past that have really vilified salt, that have told us to reduce salt at all costs. Whatever we do, we must reduce our salt restriction. And that has resulted in extraordinarily underwhelming results. By the way, I'm not getting into that. That is a topic I really discussed in a previous metabolic classroom. So please go and find my earlier episode about salt and blood pressure. I wanted this one to focus, to go a little beyond that, but please, we'll put a link to that episode in the show, notes to this one, but go scroll through the previous episodes and find it. Or if you're watching this on the YouTube Insulin IQ channel, you'll find it just by. Yeah, scrolling through previous shows, but here we have this effect where given, and it shouldn't be surprising given that insulin, part of its action is to increase blood, increase salt or sodium. If you begin to restrict sodium in your diet, if you go on a deliberate salt restricted diet, what do you think is going to happen to these systems that I've been elaborating? So firstly, what would you think would happen to the renin angiotensin aldosterone system in its normal, if compared to normal, a normal sort of normal salt intake in a normal person, if you just immediately start restricting salt, you're going to turn on that system. That's the primary trigger, right? So no surprise that the renin angiotensin aldosterone system would turn on. That's going to become relevant again later when we come back to the fat cells in just a moment, or when we start talking about the fat cells in just a moment. But also insulin, given that it has a sodium retaining effect, it also goes up. So if you restrict your salt, a normal physiological resp response to that salt restriction is an increase in, in insulin levels. So reducing salt intake will absolutely result in these compensatory pathways or mechanisms turning on aldosterone will go up. Angiotensin 2, it's, it's earlier signal will go up, but also insulin will. And thus remember in a previous, you've learned this by now that chronically elevated insulin is a cause, indeed a primary cause of insulin resistance. So increased reduction in salt consumption will increase aldosterone in order to try to restore salt, but it will als CRE also increase insulin, thereby, no surprise, promoting insulin resistance. So yes, salt restriction has been shown to cause insulin resistance. You can look up the study Lastra L A S T R A et al in 2010, another one, Sharma et al in 1999, they found that once again, salt restriction leads to increased insulin levels, reduced insulin sensitivity, which they found complicates overall metabolic syndrome. Isn't it ironic that we've been told to restrict salt in order to reduce the, you know, health consequence risk or disease risk, particularly in things like diabetes and heart disease. And yet by restricting salt, we're increasing insulin resistance, which is arguably the leading contributor certainly to type 2 diabetes, but even to heart disease. So that is it for hypertension and the cardio part of the cardiometabolic in the title of this metabolic classroom and the focus of the classroom. But now I want to go to the metabolic part and focus much more heavily on the fat cells. And just think of this question. How does the salt, how do the salt regulating pathways affect fat cells? Well, aldosterone in. In, which is of course the end result of the renin angiotensin aldosterone system. It has direct effects on fat cells, but so too does its stimulator, angiotensin 2. So firstly, aldosterone. There are receptors for both aldosterone and angiotensin 2 at or in the fat cell. All right, that's of course critical. That allows the fat cell to respond. It senses those signals without. Let's start with aldosterone, then we'll talk about Angiotensin 2 as we wrap up. So firstly, there are aldosterone receptors in the fat cells, and these are called mineralocorticoid receptors. Aldosterone is the poster child for that little family of hormones. Mineralocorticoid. When you hear the corticoid, it means it's coming from the cortex of the Adrenal gland. The orange peel part of the adrenal gland and the mineralo of course, evokes this idea of minerals or salt in this case. So fat cells contain mineralocorticoid receptors which allows them to bind aldosterone and binds to the fat cells. You'll never guess what it does. Unfortunately, the binding of aldosterone to its receptors in the fat tissue can change and stimulate, change its behavior and stimulate growth. So it can not only promote fat cell differentiation, helping pre adipocytes or early fat cells actually become mature fat cells, but also promote the growth or hypertrophy of those fat cells. So that is a direct effect of aldosterone stimulating the growth of new fat cells in the and the expansion of existing fat cells. Now, as interesting as that is, it actually gets even more relevant this effect of the renin angiotensin aldosterone system when on fat cells, when we talk about angiotensin 2. So angiotensin 2 has, there are receptors for angiotensin 2 on the surface of fat cells. In fact a lot of receptors for angiotensin ii. Angiotensin II can stimulate the expression of multiple lipogenic enzymes. Now lipogenic is the term to explain the synthesis of fat. So it turns on an enzyme called fatty acid synthase which is responsible for building the fat and other complementary enzymes like acetyl Coa carboxylase, that's another enzyme that's taking little innocent carbons and starting to link them together. So the combination of these two enzymes will take little carbons and turn it into a fatty acid chain, so it can make fat from scratch. Also, angiotensin 2 can promote fibrosis of the fat cells. And that becomes a particular problem, not only relevant to lipedema, which we talked about in the previous episode, but as fat cells undergo substantial hypertrophy and become pro inflammatory and fibrotic, that key development in the evolution of a fat cell going from an insulin sensitive anti inflammatory state to of course an insulin resistant pro inflammatory state. So angiotensin 2 promotes inflammation in the fat cell by increasing the production of cytokines like TNF Alpha and some of the interleukins. So directly triggering the inflammation inflammatory pathways within the fat cell. And then similarly not to get into the nitty gritty biochemistry of it, but when insulin binds to its receptor on a, on a cell, there are a series of events which we commonly call a signaling cascade. So one thing telling something else to do something, then that thing tell relaying the signal and the signal just Keeps getting relayed from protein to protein, from mediator to mediator. Well, when I'll. When Angiotensin 2 comes knocking, it starts to disrupt that signal directly antagonizing the insulin signal. Also, I'd mentioned fat cell differentiation before, but let's just. With aldosterone. But the same thing happens with angiotensin 2. Independent of its ability to promote the growth of the fat cell by activating lipogenesis, angiotensin II also affects the fat cell differentiation by activating this kind of master fat cell regulator called PPAR gamma. PPAR gamma, when angiotensin 2 turns it on, will tell early fat cells, immature fat cells that actually have a few different fates that will say, hey, I need you to turn into a fat cell. Don't turn into anything else. Turn into a fat cell. Which of course can just continue to promote fat gain. Now, how does all of this apply to at least the front question that I posed to you, which are you eating enough fat to kind of be lean? You know, I was deliberately being a little cheeky and provocative and asking it, but start to see the relevance. If you are salt restricted or you have low sodium levels in your body, you're going to have higher levels of the renin, angiotensin, aldosterone mediators, more angiotensin 2 and more aldosterone. And we just got done exploring how those are able to induce a direct signal at the fat cells, promoting not only the hyperplasia or an increase in the number of fat cells, but also the growth or the hypertrophy of fat cells. Now, with that in mind, and considering the antihypertensive medications I mentioned earlier, what is the effect then of these medications that deliberately reduce aldosterone production and angiotensin II production actually and angiotensin receptor blocking? Well, there is evidence that angiotensin 2 receptor blockers in particular have the potential to actually have an anti obesity effect. So there are some studies that have shown that angiotensin receptor blocking can influence adipose tissue metabolism and reduce adiposity. So actually shrinking and reducing over time, reducing the number of fat cells. So that's kind of an off target effect here where it's been, it's, it had been observed for years and now it, it's the focus of explicit study. Just noting that angiotensin receptor blockers, while overtly being used or mo primarily being used to address the hypertension, one of the consequences is that the patient we're tending to lose weight likely because of the direct effect at blocking angiotensin 2's effects in particular at promoting fat cell growth. Now, one final note as we wrap up, you may, you've heard me state before that no signal in the body can really promote fat cell growth except insulin. I've just planted a seed of doubt in your mind where you're thinking, well, Professor Bickman just taught me that there are these other hormones like angiotensin 2 and aldosterone and IND. There are others even that we've not really explored that are also capable of promoting fat cell growth. But let me just put things in perspective. Imagine, if you will, a type 1 diabetic. Now, you may roll your eyes because I use them. I use that disease state often because it's such a powerful example. In an untreated type 1 diabetic, their insulin levels are essentially zero. And they have, they are urinating a lot because of the high glucose and so their blood volume. They're almost constantly dehydrated because they are almost constantly dehydrated. Low blood volume, very low blood pressure. What do you think the levels of angiotensin II and aldosterone are in this untreated type 1 diabetic? If you're thinking through the roof, you're right. The levels, the activity of the renin, angiotensin, aldosterone system is exceptionally high and yet they are wasting away. They literally cannot keep fat on their bodies. So let's just keep things in perspective. As much as I have explained to you, and rightly so, that angiotensin II and aldosterone have the ability to contribute to fat cell growth, it still pales in comparison to the fat cell stimulus that comes from elevated insulin. Now, if you imagine someone who's eating lots of refined starches and sugars has high insulin levels, promoting energy storage and fat cell growth while also restricting salt because they've been told to eat a high carb diet and been told to avoid salt, you can see how we are just really adding fuel to the fire here to promote fat cell growth. Or adding salt to the starchy chips, if you will, to make it a more apt analogy. So anyway, it's, it's, you can't help but be a little empathetic to people and to those of us who struggle with, with, with excess body fat. Because following the advice, low fat, high carb diets, low salt, you are potentially amplifying the potential, of course, for weight gain. That's it, guys. Thanks again as ever, for joining me in this week's episode of the metabolic classroom. As always, I hope that you find this helpful and educational. Nothing thrills a professor more than the idea of teaching good ideas to sharp minded students. Please make sure you share this with a friend or family member. And if you're listening to this on YouTube, please subscribe to the Insulin IQ channel and always give it a like. All right, thank you guys. I will see you next time.