The Science of Everything Podcast - Episode 152: Obesity, Diabetes, and Hypertension

Episode Date: March 29, 2025

A review of the science between the metabolic syndrome, including discussion of obesity, diabetes, hypertension, and hyperlipidemia. We discuss the pathophysiology of how enlargement of adipocytes disrupts metabolic signalling pathways and leads to buildup of lipid intermediates. We then consider how these effects impair health, examining the causes of insulin resistance, atherosclerosis, and dysregulation of blood pressure. We conclude by looking at how such symptoms lead to pathology and increased mortality in overweight and obese individuals. Recommended prelistening is Episode 151: Diet and Nutrition, and Episode 18: Biochemistry Basics. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything

Hello, you're listening to The Science of Everything podcast, episode 152, Obesity, Diabetes, and Hypertension. I'm your host, James Fodor. So today we are going to continue from the previous episode, Diet and Nutrition, and talk about some of the consequences of malnutrition, specifically overnutrition, and look at what's sometimes called metabolic syndrome. This is a clustering of multiple different medical conditions, including obesity, high blood pressure, high blood sugar, and high blood lipids.

this is going to be a bit of a bulky, intense episode, because there's a lot to get through, and the biology here is a bit complicated, and it's still not fully understood. But we'll do our best, and in particular, the way I'll talk about this is, I'll first outline the basic biological processes that are relevant to metabolic syndrome, particularly talking about the role of blood lipids, blood glucose, and blood pressure, and some of the systems that regulate those. And then I'll talk about how those systems go wrong, or some of the things that happen in metabolic syndrome, in obesity, in high blood pressure, and diabetes, including the

effects of abdominal obesity and how that affects other body systems, how lipid, metabolism, insulin, and blood pressure become dysregulated. And then finally, we'll talk about the health effects of these underlying dysregulations. So the idea is to sort of gradually build up from basic mechanisms and core biological systems to the actual health effects that those have. And this is always a tricky topic to discuss because these different systems are so interconnected with each other. And it's really hard to separate the effects of high blood pressure from high blood sugar from adobinol obesity, how they interact with each other because they're also closely interconnected and associated. And that's why we're talking about them together. So recommended pre-listing

would be the previous episode, diet and nutrition. And some background in cellular biology and biochemistry would also be useful to understand some of the concepts. we're talking about, such as episode 18 biochemistry basics. So, that being said, let's get started, and we'll begin with a short introduction to this concept of metabolic syndrome and why it's important. So metabolic syndrome is a clustering of at least three of five different medical conditions, particularly these are abdominal obesity, so this refers to essentially like central obesity, so a big belly, essentially. Fat in that location around the belly region is particularly,

associated with negative outcomes even more than overall body fat. Then there's high blood pressure or hypertension, high blood sugar or high blood glycemia, insulin resistance, we'll talk about what that is in a moment, and abnormal serum lipid levels or dyslipidemia. So these are the different conditions that are clustered together to refer to and refer to as metabolic syndrome. And it's interesting that the interplay and relationship between these different factors has only been understood fairly recently since roughly the 1960s, 1970s,

and formal diagnostic criteria are only established in the 1990s. So this is relatively recent science that we're talking about here, which is partly why many aspects of it are only incompletely understood. And one of the reasons, as I said, that it's difficult to study is because all of these symptoms typically take a long time to develop decades, and there's a complex interplay between in many different components of metabolism, the immune system, cardiovascular function, as well as genetics. So very difficult to study and understand. So I'll do my best to articulate what is known about the core processes that are ongoing here, but just do bear in mind that there's still a lot that we

don't know or is only incompletely understood. The general risk factors for metabolic syndrome should be familiar. So sedentary lifestyle, lack of exercise. Poor diets are particularly excess intake of fats and sugars and just too many calories in general. Aging also contributes significantly and chronic stress has been shown to be associated with poorer outcomes due to poorer immune function. Now as to the epidemiology of metabolic syndrome in terms of how common it is, it varies obviously by country. In the previous episode we talked about the distribution of obesity in different countries and metabolic syndrome is tightly correlated with obesity.

but as you see, obesity is only a component of the overall syndrome. Globally, the metabolic syndrome is something like three times more common than diabetes, and that gives an estimate of about 20, 25% of the global population, so that's, you know, one and a half to two billion people affected with metabolic syndrome, which is obviously a very large amount, so this is a major health problem. In most countries these days, even developing countries, this is a significant issue. In wealthy Western countries, you know, North America, Western Europe, obesity rates have increased from 5 to 10% in the 1970s to 30 to 40% in the

2020s. So the last 50 years have seen a massive increase, five to 10-fold increase in the prevalence of obesity in adults and increasingly children as well. Prior to the 1970s, you know, going back into the 1960s or before, obesity was not a significant health problem really in any country and indeed obesity traditionally was often associated with with abundance and prosperity, which obviously is not the case anymore, certainly in the West. Metabolic syndrome is a major health problem, and I mentioned more in the previous episode about some of the health effects of obesity, and we'll talk at the end of the episode about some of the health consequences of various symptoms within metabolic syndrome. But what we want to first

explain is how and why obesity and things like high blood sugar, diabetes, how, how how these things develop, why they're connected to each other, what are the underlying biological processes, and then how the negative health consequences are brought about, like what specifically about being obese leads to negative health outcomes. So that's sort of the primary focus here. And to understand that we first need to understand some basic biological processes relating to regulation of and function of blood lipids, blood glucose, and blood pressure. So in this section here, we're going to talk about these processes just in general, not in a pathological context, and then after that we'll talk about how things go wrong in the case of metabolic syndrome.

So let's start with blood lipids, and by blood lipids, I just mean like lipids in the blood, so you can see what I mean in a moment. So lipids are molecules that are insoluble in water, and that means that in order to be transported around the body, they have to be carried in the bloodstream in special, essentially packages. And these packages that they're transported are called lipoproteins, which are water soluble because they essentially consist of a big central mass of lipids, including like triglycerides. So that's the glycerol molecule with the three fatty acid tails on the end, as well as cholesterol molecules, just a different type of lipids. You see the biochemistry basics if you're a bit confused about this. So there's a big central glob of

lipids, which are then surrounded by a phosphory lipid layer, which is kind of like cell membrane, but except in this case it's just a single layer of phospholipids, and then that phospholipid layer is studded with lipoproteins, which are proteins that are associated with lipids. So this complex allows the lipids to be soluble in water and therefore to be carried around the body. This is incredibly important because these different packages or particles they're sometimes called, or just lipoproteins,

are a critical component of the overall sort of metabolic syndrome and regulatory processes, and play a vital role in things like atherosclerosis, so hardening of the arteries, which we'll talk about later. But here let's just understand their function a bit better. Scientists have classified these packages or particles of lipoproteins based on essentially their size. It's a little bit confusing because the way they're described is in terms of their density.

So they're sort of ranked from high density down to very low density. I think it's just a bit easier conceptually to think about them in terms of of size rather than density because density in terms of like the weight relative to their volume is relevant. It does affect their behaviors and it's something you can measure. But generally, I think it's easier to just think about the most. The highest density are the smallest ones. And then as the density decreases, they get bigger and bigger.

And that's why their density is low because there's more fats relative to proteins and other components. And fats are less dense. So let's just talk about the sort of lineup of different types. types of these lipid packages. So the very largest ones, the real big ones, are called chylomicrons. It's a bit confusing, again, because they are given a different name to all of the others, but they're essentially the same thing. So I might sometimes just call chylomicrons like very low density lipoproteins, but technically they are actually distinct. So chylomichrons

are the very big ones, and then the next one down are VLDL or very low density lipoproteins, and then there's intermediate density lipoproteins, I-D-L, and then there's low-density lipoproteins, L-D-L. Really, all of these can be lumped together as just sort of, broadly speaking, low-density lipoproteins. And so I'll generally do this in explanations just because they share a lot of relevant functions.

And really the only important thing for our purposes is to distinguish them from the very smallest lipoproteins or lipid particles, which are HDL. Now, you may have heard a distinction between LDL and HDL cholesterol. I'll talk about that in a moment, but that's the distinction we're getting out here. Just bear in mind that technically speaking, it's not just a distinction between LDL and HDL, it's a distinction between all of the really big packages of lipoprotein and lipids that are transported in the blood, which is chylomicrons, VLDL, IDL, and LDL, on the one

hand, and I'm just going to call those LDL for short. And on the other hand, the very smallest package of lipids that are carried around in the bloodstream, which is, HDL, high-density lipoprotein. And they're the very smallest ones. So that's the distinction we'll work with hitherto, LDL and HDL, but just bear in mind I'm using the terms a little bit loosely there just for simplicity. Now, these packages of lipids are often referred to as cholesterol, and this is very confusing. I think it's a real shame that this has happened because it causes an awful lot of confusion. Cholesterol, recall, is a particular type of lipid molecule, but it's not a fatty acid.

it's not like a triglycerol, it's a number of carbon rings connected together, so it's a very different structure to other lipids, and it plays an important part in various aspects of metabolism. But the important point here is that when we're talking about LDL versus HDL cholesterol, cholesterol itself is really not very important in the function of these LDL and HDL. I mean, it is important, but it's just, it's not critical. We're not actually primarily talking about a bunch of cholesterol. What we're actually talking about is this lipoprotein structure that I mentioned, which has fatty acids and some cholesterol's in the center, surrounded by a phosphorylipid layer, and then these lipoproteins studded throughout. So it's a complex structure, and it's not just cholesterol.

So then why do people talk about it as cholesterol? Why is it often talked about in terms of like your blood cholesterol or good cholesterol versus bad cholesterol? So when people talk about good cholesterol, what they mean is HDL lipoproteins, right? And when they talk about bad cholesterol, they mean LDL lipoproteins. I mean, these really big packages of lipids compared to the small ones, which are the HDL. The reason for this is essentially because of how the test is performed. What really matters, or what's most important, is whether the lipid package we're talking about is the low-density version or the high-density version and how much of each there is.

But it's very expensive to measure blood lipids directly. So instead of that, what we do, or what's typically done in blood tests, is you measure a surrogate value, you measure a proxy. So you don't measure the lipids itself. What you measure is the amount of cholesterol that's associated with either HDL or one of the LDL proteins, lipoproteins. And that gives you a proxy for how much of the LDL versus the HDL you have in total. So by measuring the amount of cholesterol in each of them, you get a measurement for how much of each of them there is in total, right? But really what's important is the amount of HDL versus LDL, not the cholesterol itself. The cholesterol is in the a proxy that tells you how much of the rest of the thing there is. Hopefully that makes sense,

right? And so, but just sort of by shorthand or laziness or whatever it is, by convention, people often talk about it, even doctors talk about it in terms of the cholesterol itself. But it's not really the cholesterol, it's the lipids that are associated with that cholesterol that's important. Okay, so that's a really important conceptual clarification to understand much of what's going on here, because people talk about cholesterol, but it's not really the cholesterol that's important. It's these H-DL versus LDL particles that are transporting lipids around in the bloodstream. Now, what do these lipoproteins do? I've been talking about them, but I haven't really explained what they're for, other than transporting lipids around the bloodstream. Well,

in a sense, that's it. Like, they transport lipids, right? The lipids don't live in the bloodstream. Their bloodstream is essentially a highway that they use to get around or be transported from place to place. So these lipoproteins are the structures that are used to transport lipids, mostly to and from the liver. So the liver is the organ that performs most of the biosynthesis of fats I mean, something's happened in other places, but a lot of it occurs in the liver. So essentially what happens is when fats are consumed in the diet, they may be transported to the liver for processing, or if they're not needed immediately, they may be transported to adipocyte, so fat cells, we'll talk more about those later, for storage. If those are then needed later, they may be transported back to the liver for processing,

and then the components are then sent to peripheral tissues like muscles and organs for actually using the energy. So the liver sort of serves as a sorting and processing function for many of the fats in the body, mediating between the intestine where they're initially absorbed, the fat deposits where they're stored long term, and then the peripheral tissues like muscles and so forth, where the energy is actually used. So the liver serves as the processing center and packaging and dispatch a depot, if you like, for lipids. and it uses different types of these lipoprotein structures, the lipid packages, for different purposes. It's rather complicated in the detail, but we're going to simplify it a little bit and just talk about it in terms of basically the low-density lipoprotein, so that's the quote-unquote bad cholesterol. The low-density lipoproteins are used for transporting lipids away from the liver or from fat cells to the liver.

So most of the transport is performed by low-density lipoprotein. high density lipoproteins, the quote-unquote good cholesterol, those are primarily used for cleaning up residue lipids that are found around the body or unneeded residues and taking them back to the liver. So it sort of picks up bits and pieces that have been left behind and takes them back to the liver. That is a crude characterization, but it will serve our purposes here. And that highlights why it's important to have, like HDL is often thought of as good cholesterol, because HDL particles serve an important role of sort of cleaning up and removing excess lipids from, say, artery walls or from peripheral tissues.

So they're taking up the leftover bits or unneeded lipids and taking the back to the liver for processing. So they reduce and help to prevent the buildup of fats around the body in places they're not supposed to be. Whereas the other lipoproteins are involved in transporting those lipids around the body and sort of they're responsible for them being, the liver's being there in the first place. So that's why they're kind of the quote-unquote bad cholesterol because low-density lipoproteins essentially deposit fats around the body, either kind of deliberately like intentionally or just kind of leaving bits behind. We'll talk about that later.

Whereas the HDL are responsible for removing them and taking them back to the liver. And so they reduce the amount of fats distributed around the body. Now, one final thing is that LDL and HDL are both important for regular metabolic function. There's nothing inherently bad about LDL. It's just that too much of it is associated with negative outcomes, as we'll see later. But they're both playing an important role. And really what happens in metabolic syndrome is that there's a dysregulation and the system, which normally works fine, goes out of whack. And we'll talk about how that works in a moment. So that's the discussion of blood lipids and what's supposed to be happening normally. The liver is involved in mediating and

regulating the flow of lipids around from the intestine to the fatty tissue for storage and the peripheral tissues for usage and it packages them up and sends them around and they're transported by LDL proteins and the residues sort of build up around organs and arteries is picked up and then transport it back to the liver for processing by HDL, kind of like the garbage man if you like for lipids. So that's what happens normally. Now let's shift gears a bit and talk about blood glucose. glucose is also important. Now we're looking at the carbohydrate side of things rather than the lipid side of things and carbohydrates are essentially all eventually broken down into glucose. Normally after a meal that's rich in carbohydrates, blood glucose levels increase up to about

30 minutes after the meal of subjected. So glucose can be transported directly in the bloodstream because it's a carbohydrate, so it's not a lipid, it's soluble in water. So glucose is normally found in the bloodstream, but the levels vary. And after a carbohydrate rich meal, meal, the blood glucose levels increase up to about 30 minutes. And that occurs, obviously, the food is digested. It's converted into glucose, which then is released into the bloodstream and circulates around and is taken up by tissues as needed. After one to two hours, blood glucose levels then decline back to normal levels. So if you have a carbohydrate rich meal, your glucose levels will spike. They increase up to about like 50% or so, maybe a bit more, 50 to 100% of normal

levels and then they gradually go back down after the next couple of hours. So that's what normally happens. Hyperglycemia, which is such that just means high blood sugar, occurs when blood glucose levels are too high both during the fasting and during the fed period. So that is just after eating. So one way to measure blood glucose is to use milligrams per deciliter, and normal levels of blood sugar in the fasting state will be around like 80 to 100 milligrams per deciliter, and levels of blood glucose in the fasting state of something like 150 milligrams per deciliter are often used as a diagnostic criteria for diabetes. I couldn't find a single number here. It seems that there's variation across jurisdictions,

but essentially if you have twice or so levels of blood glucose relative to normal, then that is an indication of diabetes. So diabetes is essentially a condition where you have chronically and consistently high blood glucose levels, both in the fasting and in the fed state. Insulin is a peptide hormone that promotes the absorption of glucose from the blood into cells, particularly of the fat, particularly of the liver, fat cells and skeletal muscles. So those are the cells that are responsive to insulin. This is obviously important because you want to make sure that your cells don't have too much glucose floating around inside them. that causes problems for the cell, causes problems for metabolism, as we'll see later.

But you also need to make sure that your cells have enough energy. So there needs to be a mechanism to regulate how much glucose your cells take up, and insulin is the hormone that does that. And insulin is regulated by a whole bunch of processes, which we won't get into too much detail here. That's part of endocrinology. You can refer back to the system we did, the episode we did on the endocrine system if you're interested in that. But what we will say here is that the pancreas is responsible for producing insulin, particularly beta cells in the pancreas, and these beta cells are sensitive to blood sugar levels.

So essentially what happens is that these beta cells sense the glucose concentration in the blood. They secrete insulin when blood glucose levels get too high, which is an indication that we need that there's too much glucose in the bloodstream needs to be taken up by the cells. And conversely, the beta cells inhibit secretion of insulin when blood glucose levels are too low, which is an indication that cells have enough or too much glucose and that they don't need to be taking up as much. So, as I mentioned, diabetes is a condition characterized by chronically high blood glucose levels. There's two types of diabetes. In type 1 diabetes, the beta cells in the pancreas that produce insulin are destroyed by an autoimmune reaction.

So insulin can no longer be synthesized or secreted by the pancreas, and people with type 1 diabetes then need to take artificial insulin in order to make up for that deficit. it. But the type of diabetes that we're interested in today, and by far the most common type of diabetes, is type 2 diabetes. And in this case, the beta cells usually are still there. They may be somewhat damaged, but usually they're still there in producing insulin. But instead, what happens is that peripheral tissues, like the muscles, for example, and the liver, develop a resistance to insulin. So insulin is still around. In fact, often there's more insulin produce than usual. But the cells no longer respond to it appropriately. They don't respond by

taking up the insulin as they need to. And this increases the blood glucose concentration, right? Because normally high glucose would lead to secretion of insulin, which would lead to take up of glucose by the cells, and then the blood glucose levels would go down. That's what normally happens. But in type 2 diabetes, cells develop a resistance to insulin, and so the insulin is there, but the cells don't respond enough by taking up enough glucose, and so blood glucose levels remain high. That's what's involved in type 2 diabetes. Here I'm just going to give a little bit more background about the molecular mechanisms of how insulin works, because we'll need to understand this later when we get to talking about the pathophysiology of metabolic syndrome specifically.

So normally, again, what happens when things work properly is that insulin molecules, it's a peptide hormone, so it's fairly small. The insulin binds to an insulin receptor on sensitive cells. There's a few different types of these receptors, but not going to right. Not going to about that for our purpose here. So once the insulin binds to the insulin receptor, this triggers a conformational change in the receptor, which then leads to a signaling cascade within the cell. We've talked about this in previous episodes. You can refer back to those if you're interested in the details here. All we need to know for our purposes is that this intracellular signaling cascade terminates with a signal delivered to special vesicles, which are found inside the cell,

so bits of cell membrane essentially that are hanging around waiting inside the cell and these vesicles contain special channels called glute four channels or g l-ut-4 channels. There are actually different types of these channels but we're just talking about one of them here just to illustrate. So glute four channels are channels that allow glucose molecules to be transported into the cell. So normally there'll be some of these on the surface of the cell membrane right, but most of them are sequestered inside the cytoplasm on these little vesicles waiting for the insulin signal. So when they receive the insulin signal mediated via the secondary messages cascade inside the cell,

these vesicles then are transported. They're translocated to the surface of the cell. They merge with the cell membrane and then the glute receptors are accessible and able to transport glucose molecules into the cell. So that's how insulin regulates the intake of glucose in the cells. You need insulin in order for these glut4 receptors to be displayed on the surface of the cell and therefore allow the glucose to be transported into the cell. Without insulin, the glut4 receptors will be translocated into these vesicles located inside the cell and therefore not able to actually move the glucose in. So that's what happens normally.

We'll get to what happens in the pathological state in just a moment. But before we do that, we need to talk a little bit about blood pressure. Blood pressure, shockingly enough, of circulating blood against the walls of blood vessels, usually measured in the brachial artery in the upper arm. So for most adults, normal blood pressure at rest, so when you're not exercising or anything, is within the range of 100 to 140 milliliters of mercury at the systolic measurement. So that's just after a heart contraction. So 100 to 140.

and 60 to 90 millimeters of mercury in the diastolic phase, or just when your heart relaxes. So often this is reported as like 100 over 60 or 120 over 80 or something like that, right? So numbers around there are a good, healthy normal blood pressure. Again, that's at rest. Blood pressure arises because of the operation of the heart as a pump. So it squeezes, it's a muscle that squeezes out the blood through the aorta and then through all the arteries to deliver oxygen. oxygenated blood to the systemic tissues and the rest of the body, right? And so in pushing that blood out through the aorta and through the arteries, that blood is under pressure. It's being pushed

with a velocity, right? So that delivers some force against the walls of the arteries, and that's what generates the pressure. Now, hypertension just means a high blood pressure. And it's classified into primary hypertension, which means there's no clear identifiable cause, and secondary hypertension, where there is a specific cause such as a kidney disorder or endocrine diseases or pregnancy, something like that. About 90% of hypertension is primary and is caused by lifestyle factors such as obesity and excessive salt intake. And so it's primary hypertension that I'm interested in here, just like type of diabetes is the relevant type of diabetes that we're interested in. Hypertension is often called the silent killer because it often has no

noticeable symptoms at all. But over time, it causes damage to organs and blood vessels. and we'll talk about the mechanisms of that in a little bit. Now blood pressure, or mean arterial pressure, is determined by the product of the cardiac output, so this is essentially how much the heart is beating and the force of contraction, and the systemic vascular resistance. So this is the resistance provided by the vascular, the arteries around the body. So that means that blood pressure will increase if cardiac output increases, and or if systemic resistance increases.

Now, vascular resistance in turn can be increased by hardening and narrowing of the arteries, or atherosclerosis. We'll talk more about that later. Cardiac output can be increased by sodium retention by the kidneys, which results in fluid retention and hence increased blood volume. Although there's other factors that can increase cardiac output as well, but that's one of the factors. So these two different aspects here, sodium retention by the kidneys and hardening of the arteries are both can result from metabolic syndrome. And again, we'll talk more about the mechanisms

of those in the next section here, but right now we're focused mainly on the normal functioning, healthy functioning of blood pressure and how it's regulated. So blood pressure is regulated by the renin angiotensin-elodosterone system, or RAS for short, the RAS system. This is a hormone system that regulates blood pressure as well as fluid and electrolyte-electralight balance and modulates the vascular resistance around the body. Now, renin is an enzyme that's produced by the kidneys. It's secreted in response to decreases in blood pressure. So if blood pressure goes down, say if you're dehydrated,

blood pressure will go down because the volume is less, then the kidneys will respond by producing an enzyme called renin. In the bloodstream, renin is involved in producing another enzyme called angiotensin, which exists in a bunch of different forms. So there's angiotensin 1 through 4. Again, I'm going to simplify a little bit here just to make it a bit more comprehensible about what's actually happening. In fact, there's kind of a complex interplay between these different forms of angiotensin. But we're going to focus on angiotensin 2. Angiotensin 2 is a vasoconstrictive

peptide that causes blood vessels to narrow, which increases blood pressure. Now, that makes sense, right? Because remember, renin, which produces angiotensin 2, is released by the kidneys in a response to decreases in blood pressure. So a decrease in blood pressure leads to more renin, which leads to more angiotensin 2, which leads to constriction of blood vessels, which leads to increased blood pressure. So this is a negative feedback loop here. Now, angiotensin 2 also does something else. It stimulates the secretion of another hormone called aldosterone. So you'll notice we've gone through renin, angiotensin, aldosterone.

That's the RAS system. So this is our third one here, aldosterone. This is secreted by the adrenal cortex above the kidneys. And it causes the renal tubules in the kidneys to increase their absorption of, sodium. We haven't actually talked about the kidneys in this podcast before, but I will eventually do an episode on the urinary system and we'll talk about how they work. But basically, the kidneys regulate how much salt, how much sodium is retained. And by doing so, they regulate how much fluid is retained because we know that due to osmotic pressure, where there's more salt, you'll have more

fluid being kind of sucked in by the salt. They say salt sucks as a way to remember that. aldosterone causes more sodium retention which causes more fluid retention which in turn increases blood pressure so this is actually a second negative feedback mechanism whereby elosterone causes the retention of more fluid and hence increases the blood pressure so the end result is that the rass system operates as a negative feedback mechanism to modulate blood pressure if blood pressure goes down it triggers a series of hormones the ren in the angiotensin 2 and the aldosterone, which increases blood pressure by retaining more fluid and constricting the blood vessels. And conversely, if blood pressure is high, then the opposite will happen that

be less ran in, the blood vessels will be less constricted, which will reduce blood pressure, and the aldosterone that would less aldosterone produced, which will result in less fluid retention. If the RAS system is abnormally active, you'll get a high blood pressure because it will be abnormally overproducing the relevant hormones, which lead to increases in blood pressure. under normal operations, all of these hormones are doing their correct jobs and modulating the constriction of the blood vessels and modulating salt and therefore fluid retention to maintain blood pressure at the appropriate level. So, just to summarize this section where we've been talking about underlying biological processes,

essentially what we have are the three players here. We've got fats, sugar, and salt is one way to think about it. Fats in the form of lipids, which are circulating throughout the body. LDL particles are responsible for transporting fats around the body between different organs, and particularly to and from the liver, and HDL particles are responsible for cleaning up any leftover or excess bits of lipids that are left around the body or in the arteries and taking it back to the liver. Normally, those systems operate appropriately, and the flow and transport of lipids around the body is regulated appropriately. Blood sugar levels are modulated by

insulin, which is produced by beta cells in the pancreas, which ensure that when there's too much glucose in the blood, insulin is released, which binds to the receptor, which then triggers the glute four receptors to be displayed on the surface of cells, and then that leads to them taking up glucose and lowering blood sugar levels, and vice versa when blood sugar is too low. And so, again, this process ensures that blood sugar is mediated at the appropriate level and that cells get the energy that they need. Cidium is modulated by the kidneys and that in turn leads to the module, that's an important factor leading to the modulation of blood pressure and blood pressure is modulated by the RAS system,

so renin, angiotensin and elnostron, which is a negative feedback loop that ensures that the constriction of the arteries as well as the amount of sodium and hence fluid that's retained by the kidneys is modulated so as to balance blood pressure and keep the cardiovascular system working well. All right, so we've gone through the key biological processes that mediate lipids, glucose, and salt or blood pressure, and we've sort of hinted at what happens when they go wrong. So what happens when they go wrong is when we have high cholesterol, particularly high LDL cholesterol, when we have insulin resistance, hence high blood sugar, and when we have an overactive rash system, and hence high blood pressure.

You know, most people kind of know that having high cholesterol is bad, having high blood sugar and insulin resistance is bad, associated with diabetes, and having high blood pressure is bad. The question that we then want to answer here is, how do these systems of regulating blood lipids, glucose and blood pressure, how do they go wrong in response to obesity? So what is the connection between obesity specifically and all of these dysregulation of these important biological processes? So that's one question that we might ask. Why is it that becoming obese results in all of these other negative outcomes? The second question is how specifically does high cholesterol, high blood glucose and high blood pressure? How specifically do those things actually hurt us? I just mentioned that high blood pressure is often asymptomatic until it causes really negative problems.

But the same is often true for high cholesterol and high blood sugar. typically high LDL, high glucose and high blood pressure don't cause disease directly. They cause damage to organs and blood vessels in various ways, which then is what actually leads to the negative health outcomes. But how does that happen? Well, that's what we're going to discuss in the final section of today's podcast. But first, we're going to talk about what I call the pathophysiology of metabolic syndrome. So how is it that these underlying cluster of symptoms,

like abdominal obesity, high blood pressure, high blood sugar, high blood lipids, why are these connected together and what's the common linkage and why are they triggered by obesity? Why is that the underlying cause or one of the key underlying causes? So to understand that, let's start by talking about what happens with particularly abdominal obesity, so this is accumulation of fat deposits around the central region, and how it links into all of these other systems and how it leads to dysregulation of the lipids, glucose, and blood pressure. Okay, so let's begin with abdominal. obesity. Weight gain occurs when more energy, so calories from food and beverages, is

consumed than the energy that is expended by normal physiological processes and exercise. So we talked a bit about that in the previous episode, about calories in calories out, and how that is metated somewhat by differences and changes in basal metabolic rate. But it largely is affected by just the amount of calories that are consumed relative to your basal metabolic rate. Because exercise for most people is only a small, proportion of calories. And basal metabolic rate doesn't actually vary much between people. We saw maybe 5 to 10% if you control for differences in body size. So what happens when you consume more energy consistently over a long period of time than you use in physiological processes

or exercise? Well, that energy has to go somewhere and what normally happens is that it is stored in adipose tissue. So that's a fat cell or just fat. So adipose tissue is a loose connective tissue composed mostly of cells called adipocytes or adipocytes. So what happens is the energy will be converted from whatever form it was initially consumed in, whether it's carbohydrates or lipids or proteins. It will be converted into fatty acids, which are produced in the cytoplasm of cells mostly by the liver and also in adipose tissue itself. So this is why I mentioned before that the body needs to transport all of these excess lipids to and from the liver because the liver is mostly responsible for building for biosynthesis of fats from excess energy.

It also is responsible for metabolizing a lot of those stored lipids as well when they're needed. But anyway, this excess energy is stored in fatty acids and then transported in the bloodstream where it's ultimately stored in these fat cells and adipocytes. So what happens when you gain weight is it involves an increase in the number and size of the droplets of lipids in adipose cells. So these droplets, these droplets of lipids consist mostly of triglycerides and cholesterol surrounded by a membrane. So it's a little bit like these LDL particles essentially, except they're a slightly different version of that that's inside a cell. We call that a lipid droplet. There's a phosphate lipid membrane which surrounds,

or a similar lipid, which surrounds a central core of triacylaclycerides and some cholesterol. and there's a few proteins that will be associated with the outer membrane. So these lipid droplets are located inside, particularly adipocytes. I think they can be found in other cells as well, but particularly adipocytes are specialized for storing lipids inside these droplets. And what happens when you gain weight is these lipid droplets increase in size and also the number of them inside any given adipocyte increases. It's a misconception that when you gain weight, you increase the number of cells in your body.

In general, gaining weight does not mean that you're increasing in the number of cells. It just mostly means that those cells are increasing in size. And this is actually very important for the metabolic consequences of obesity. Now, another thing that's important to understand and has only been really properly recognized in the last few decades, is that adipocytes are not just passage storage vessels for excess lipids. They do store excess lipids, so that's important, but they do more than that. Adipocytes also are an important site for production and secretion of hormones. So adipocytes play an important endocrine function.

So they release hormones and other signaling molecules, including leptin, estrogen, resistant, and adipokines. And we're going to focus here on adipokines particularly. Adipokines are a type of cytokine, so that's a cell signaling protein, which is secreted by adipose tissue. and some of these contribute to a low-grade state of inflammation or development of metabolic syndrome. So just to go into a bit more detail about that, each cytokine has a corresponding cell membrane surface receptor, which is the case for most of these signaling molecules. There'll be a molecule and a shape-matched receptor that will interact with the signaling molecule when they come into contact. And that transmits a signal inside the cell, which then generates a cascade of intrastate of intramal.

cellular signaling molecules that can alter various cell functions. This can include things like up-regulating or down-regulating the expression of genes or transcription factors for other genes, which then in turn changes the production of other cytokines or other signaling molecules, which can increase or decrease the number of surface receptors for other molecules, or it can suppress some kind of metabolic effect in that cell directly. The point is that these cytokines can have lots of very complex interactions and complex effects on their target cells, and there can be many complicated interactions between these effects. And studying consequences of all of these different cytokines and their effects on different signaling processes

is occupy many scientists for a very long time because it's incredibly complicated. Now, I'm not going to go into the details of these messenger cascades and the different signaling molecules in this episode. That would take far too long and be very confusing. I'm just introducing the key concept that adipocytes are also signaling cells, one of the types of signaling molecules that they produce are called adipokines. That's a class, not a single molecule. And these adipokines travel around the body, find a matching receptor on the surface of a recipient's cell, and thereby trigger a signaling cascade within that cell that alters its metabolism in some way.

And this will become very important because what it means is that when there are changes in adipocytes, there can also be changes in various other metabolic processes throughout the body. So storing excess lipids in the dipocytes is not just a passive process of what it happens to be more in the lipid droplets. It actually triggers changes in these signaling processes, which has many important metabolic effects throughout the body, as we'll go through in detail. Now, specifically what happens when adipocytes accumulate larger and larger deposits of lipids, so those lipid droplets are expanding and spanning. The cell itself becomes expanded, it becomes enlarged.

The tissue becomes chronically inflamed. So basically there is a dysfunction that originates. The cells aren't supposed to be this big. It's not normal. This triggers release of chemicals, which are detected by immune cells, which come and infiltrate the tissue. Like, hey, what's up? There's something wrong here.

We've received a signal indicating that there's a problem. Human adipatisites can grow up to 20-fold in diameter and several thousand fold in volume. so they can expand massively. But there's a limit to this, and as I said, when they become too large, it results in a release of stress signals. Now, this is a normal process in the body that the body is sensitive to dysfunction in any tissue, really, and when things go wrong, it could be an infection, or it could be a cell becoming cancers, or it could be some metabolic process not occurring correctly,

it could be lack of nutrients. In this case, it's the adipocytes becoming grossly enlarged because of the excess lipid deposits. and when this happens, stress signals are released, which triggers the infiltration of immune cells. One example of a stress process is if the tissue becomes greatly expanded, there may be a deficit of vascularization, so essentially there isn't enough vascular structure to provide all of the nutrition that's needed, all of the oxygen and energy to maintain those cells. This can lead to hypoxia, so lack of oxygen, which then leads to release of these stress signals and infiltration of immune cells.

Although there's other processes as well, it's not just hypoxies. So there's many different things that can trigger the infiltration of the immune cells specifically, but all of them essentially are produced by the fact that the adipocytes have become grossly enlarged through accumulation of vastly excessive quantities of lipids for storage. Excessively engorged adipocytes can burst and die, which recruits even further immune cells, particularly monocytes, which ingest those materials. This then further exacerbates the inflammatory.

response. There are other factors as well. So inside the cell, the excess availability of lipids and lack of oxygen can lead to accumulation of misfolded proteins in the endoplasmic reticulum. So this can also trigger an inflammatory response. So as I've indicated, there's a whole bunch of different things inside the cell or just the size of the cell itself or lack of blood vessels. All of these things lead to problems, which then trigger an immune response to try to mitigate that. But the problem is that this isn't just a one-off. This is a chronic process. Like the adipocytes will retain their stored lipids until that energy is used. And so what ends up happening is a chronic inflammation of the adipose tissue. This chronic inflammation alters the expression of cytokines.

So alters the expression of the signaling molecules that they're sending out, which has a variety of effects on the rest of the body. This appears to be the underlying mechanism for essentially most, if not all of the rest of the metabolic syndrome. It's these chronically inflamed adipocytes because they have too much stored lipids and they get too big this causes a host of problems like misfolder proteins accumulating like lack of oxygen bursting and then the needing to be cleaned up by monocytes a vast variety of issues here which triggers an immune response and the accumulation of immune cells and that the chronically results in chronic inflammation of the tissue which in turn alters the expression of signaling molecules by the adipose

tissue. These inflamed cells and the immune cells that are surrounding them are all sending signals to each other, and that is what triggers the adipose tissue to change the balance of signaling molecules of adipokines and other molecules that it's sending out. Now, thinking of that as the core initiating trigger, let's talk about how this alteration of the signaling molecules and chronic inflammation of the adipocytes, how that affects the other bodily systems that we talked about. So we talked about regulation of blood lipids, blood glucose, and blood pressure. So we're going to talk about the effect of obesity and the chronic inflammation of adipocytes on each of these systems. And so the effect specifically of blood lipids is to produce a condition called hyperlipathemia,

or more generally dyslipathemia, which is just the dysregulation. But often it's hyperlipatemia, which means too many lipids in the blood, too much fat, essentially. And the way this happens is that the increased size of the lipid droplets in adipocytes means that, that there is a increase in the concentration or the quantity of LDL particles in the bloodstream. Basically, because there's so much more fat that needs to be regulated, that needs to be managed, packaged and transported by the body, this just leads to an increase in the traffic, if you like. When there's more people around, there's more people on the roads, there's more cars on the road, there's more congestion. Now, this is exacerbated by some of the other problems.

So I haven't talked about the mechanisms of insulin resistance yet, but I mentioned it before, with respect to blood glucose, what normally happens is that the liver detects high levels of glucose in the bloodstream, and it will send signals to anapose tissue to say, no more lipids needed thanks, we have enough glucose in the bloodstream, we have enough energy available, so we don't need any more of that fat to be sent over at the moment. But if the liver becomes, loses its sensitivity to insulin, again, which occurs in diabetes, then the liver will not be receiving that insulin trigger, which tells it that there's enough glucose in the bloodstream, and hence it will keep asking the adipose tissue to send more lipids, send more lipids, hey, we're running out of energy

here, we need to get more lipid so that we can process and break them down and produce glucose. So this is a feedback mechanism whereby, once you start getting, and we'll see in a moment, how obesity contributes to insulin resistance, insulin resistance can then trigger the liver to essentially be constantly signaling to release more and more of these lipids for break. down and conversion into glucose, that in turn increases blood glucose levels, which then has a variety of other negative effects. So this is an example of how we see there's an interaction between the hyperlipidemia and the insulin resistance and higher blood glucose levels. But anyway, back to focusing on the lipid side of things. So what happens to these LDL particles?

So we know that in response to increase in the antipose tissue that there's more LDL particles floating around the bloodstream, how does an increase in LDL particles cause problems? Well, LDL particles, when there's too many of them, and when they're around for too long, they can become oxidized, so they react with oxygen. And this can lead to activation of macrophages, so that's a type of immune cell, which eats other cells. These activated macrophages can absorb the oxidized LDL particles. They kind of eat them up. They recognize that, oh, there's some problem here. There's too many of these oxidized LDL particles.

So they absorb them and form something called a foam cell. It's called a foam cell just because of how it looks under the microscope. But a foam cell is basically a macrophage that's eaten up a lot of these lipid particles, LDL lipid particles, and then become itself sort of engorged with a lot of the lipids that it now contains. And these foam cells can accumulate in the blood vessel and gradually contribute to atherosclerosis. We'll talk about the mechanisms of that specifically in the next section. But basically the point here is that increase in the amount of LDL particles floating around the bloodstream, eventually gives rise to accumulation of these foam cells, which then leads to atherosclerosis,

the hardening and the constriction of the diameter, the internal diameter of blood vessels. It's not limited to that, though, because LDL cells, when they're taken up by hepatocytes in the liver, and the free fatty acids are released from inside the LDL particles, excessive amounts of these lipids can actually overload the oxidation and storage pathways of the liver and other organs, which leads to accumulation of this fatty acid intermediates, which can then in turn have further effects on signaling pathways. So all of these signaling and metabolic pathways are based on a sort of a baseline level

or usual levels of concentration of different signaling molecules and different intermediates. Too much of these lipids overloads oxidation and storage and other pathways, which leads to just further accumulation of these fatty acid intermediates, which kind of bungs up the system. again, as I said before, there were many signaling pathways. We're not going to get into all of the details of them, but this can lead to a variety of negative consequences,

including insulin resistance, which we'll talk about later. But the bottom line is that too many lipids stored in the adipocytes leads to too much circulating in the bloodstream and too much that the liver is trying to process. And this causes problems to the blood vessels, it causes problems for the liver, and it also interacts with other problems like insulin resistance and exacerbates them.

As we'll see later as well, accumulation of these foam cells in blood vessels leads to accumulation of plaque inside the lumen of the blood vessels which leads to narrowing of the arteries which contributes to high blood pressure so all of the we're seeing how these different problems then interact with each other one leads to another which then exacerbates the first and so forth in these sort of negative feedback processes so let's move on and we'll talk about now insulin resistance insulin resistance is sometimes thought as being the prime underlying issue or the sort of core central mechanism behind metabolic syndrome. Incident resistance, as I said before, refers to a loss of the

sensitivity of cells to insulin concentration. So the insulin is still there in the bloodstream. It's still released by beta cells in the pancreas, but it doesn't have the same effect as it should or it used to on causing cells to take up glucose from the blood. And this includes skeletal muscles, the liver, as well as adipose tissue. So all of these types of tissue have their own slightly different mechanisms, like they have their own different glute transporter, which brings the glucose in, but they all function in a similar way. And all of these different types of tissue tend to acquire resistance to insulin in a similar way. Now, one of the big questions in nutrition, health science, is how is it that being overweight, that accumulating lipids in the adipose tissue?

how does that lead to the development of insulin resistance? Not everyone who is obese develops insulin resistance, and there's clearly a genetic component. So it's not one single process or a terminative procedure that always happens. However, we do know certain things about it, which is what I'll outline here in broad terms, but just bear in mind that I'm only scratching the surface here and there's still a lot that's unknown.

But it seems that at least one important mechanism that leads to insulin resistance is the dysregulation of specific signaling processes that are important for regulating the intracellular response to the insulin receptor detecting that insulin hormone on the cell surface. So let me explain how that works. Remember, I said before that adipocytes accumulate lipid deposits, they expand. That triggers an inflammatory response, which in turn causes the signaling molecules, hormones, adipokines, and other signaling molecules that are released by adipocytes to change. So that's the core triggering phenomenon, which is the change in the concentration and the relative amounts

of these signaling molecules. In addition to these signaling molecules, there's also the accumulation of lipid intermediates. The liver is trying to process all of these lipids. It sort of gets overwhelmed. That leads to accumulation of these lipid metabolites, these intermediate products, which also have effects on a variety of metabolic processes. So lipid metabolites including diacyl glycerol, lysophosphatic acid, seramides, and acylkarnatines, I hope I pronounced that one correctly, all of these different metabolites are involved in the development of insulin resistance in liver and skeletal muscle particularly. So one specific mechanism that appears to be operative here is that there is an important signal transduction protein called IRS 1. This protein is involved

in the communication of the signal by insulin and via the insulin receptor, to the intracellular signaling pathway. So the insulin molecule binds to its receptor. This then triggers a confirmation change in the receptor, which in turn has an effect on IRS1. IRS 1 is found inside the cell. It's attached to the insulin receptor, but on the inside cell of the cellular membrane,

it then interacts with another protein enzyme called a protein kinase, which then helps to trigger the intracellular signaling process, which ultimately ends up in, remember, the glute 4 channels, or other transport of proteins being translocated to the surface and then enabling the glucose to be moved into the cell. Now, the problem is that when you have an accumulation of these lipid metabolite intermediates accumulating inside the cell,

these lipid metabolites induce an activation of certain serene kinases. So basically what this means is that lipids activate certain enzymes, which have an effect on other enzymes and so forth, which eventually leads to this IRS-1 signal transduction protein becoming phosphorylated, becoming activated, which means that in turn it doesn't work, it doesn't perform its appropriate function. So phosphorylation is adding a phosphate group, and that's what a protein kinase does, it phosphorylates. So these intracellular lipid residues trigger the phosphorylation of the serene residues of IRS 1, which in turn means that it doesn't actually fulfill its function.

It needs to have those phosphate groups removed. in order to perform its function correctly. So these intracellular, this accumulation of intracellular lipid metabolites, these intermediate stuff, interrupts the signaling cascade process. So that insulin still buys for its receptor, the receptor still sends its signal, but IRS1 no longer transmits that signal. And so the signaling pathline is disrupted, kind of like cutting the telephone wire, although it's more complicated, and that's not a single wire, but you get the idea it's disrupting the signal,

which means that those glute four transporters stay sequestered inside the cell cytoplasm and don't move up and merge with the cell membrane and thereby allow glucose into the cell. That doesn't happen. And so the cell is insensitive or much less sensitive at least to the insulin signal. It still receives the signal, but it doesn't get transmitted. So this appears to be one mechanism by which insulin resistance is mediated. It's the disruption of the signal transduction pathway by these, fatty acid, these lipid metabolites that accumulate inside the cell. It also appears that the signal

transduction pathways can be disrupted by adipokines and other signaling molecules that are produced by the adipocytes directly. We talked about those before. Those also seem to play a role. And of course those signaling molecules then play a role in the processes that lead to the accumulation of these lipid intermediates inside the cell itself. So we can't give a precise description of exactly how we can't give a precise description of exactly how we all the processes fit together, but I indicated one of those, which is particularly related to the IRS1 signal transduction protein, but there are many other aspects to this as well. The point is it's a combination of accumulation of lipid metabolites, particularly in the liver and in adipocytes themselves,

obviously because the adipocytes have too many lipids in them. The liver is having to process all these lipids, so both of these accumulate too many lipids, therefore too many lipid metabolites. They're also receiving odd signals from the adipocytes themselves. Both of these things disrupt the insulin signaling pathway, which leads to insulin resistance. So now we've talked about the pathophysiology underlying hyperlipidemia and underlying insulin resistance. The final aspect we're going to talk about is hypertension. And as you might have imagined, one of the factors that contributes to hypertension is enlarged and as a result, chronically inflamed adipose cells, we said that that's at the basis of many of these,

many of these pathophysiological effects. So these enlarged and inflamed adipose cells appears to trigger an increase in aldosterone levels. Remember, that's the hormone that's responsible for increasing sodium retention by the kidneys and hence raising blood pressure. So that's one mechanism that contributes to hypertension. There are many more. Again, the interference appears to be that the signaling molecules that are produced by their inflamed adipose tissues interrupt the signaling pathways that mediate and modulate the RAS system, causes it to be overactive, which hence leads to increased aldosterone levels and increased sodium retention and higher blood pressure. But there are other mechanisms as well.

An overactive sympathetic nervous system also leads to vasoconstriction and hence increases blood pressure. And the sympathetic nervous system is the kind of half of the peripheral nervous system, responsible for the fight and flight response. So there's the sympathetic and the parasympathetic. So sympathetic nervous system is overactive in obesity. I'm not entirely sure why that's the case. I presume it's relating to the chronic inflammatory response and the stress that the body is sort of sensing. That triggers an overaction, overactive sympathetic nervous system and one of the results of that is vasoconstriction which further increases blood pressure. insulin resistance also damages vascular tissue because of the buildup of plaque and the high blood glucose

concentrations also cause vascular damage we'll talk about that in a moment so both of these processes basically too much lipid and too much glucose in the bloodstream makes artery in blood vessels make arteries harder and stiffer which increases vascular resistance by increasing the peripheral resistance that we talked about so that increases blood pressure and finally excessive dietary salt also leads to high blood pressure. Particularly when we talk about salt, we mean sodium here. High sodium intake leads to retention of water in order to avoid the toxicity, which will result from too high concentration. So if you have a lot of salt, you need to have more water in your system to compensate for that and retain a reasonable concentration of sodium.

This leads to a increase in blood pressure, which actually acts as a negative feedback mechanism. So your kidneys need a higher blood pressure in order to excrete all of this extra salt. So eventually that salt will be excreted, which will bring blood pressure back down, but the problem is if you keep consuming salt, then blood pressure is going to maintain at a chronically high level. So this is an interesting mechanism that's actually somewhat separate from the abdominal obesity, because you can have excessive salt intake, even if you aren't obese. So this is an example of where the mechanisms somewhat come apart, because this mechanism is somewhat distinct from the inflammation of adipose tissue. So I don't want to present metabolic syndrome as if it's all caused by that, though. the inflammation and enlargement of adipocytes does seem to be a very critical underlying mechanism, but it's not the only thing going on.

So to summarize, we've highlighted a number of processes that lead to hypertension. So inflammation of adipose tissues is an underlying factor in many of them. So this chronic inflammation and change in the signaling molecules released by adipose tissues results in an overactive sympathetic nervous system, which leads to vasoconstriction, and hence increase in resistance and increase. in blood pressure. It also leads to an overactive RAS system, which leads to an increase in fluid retention and increase in blood pressure. And insulin resistance damages and high lipid, high blood lipid levels. Also, both of those damage vascular tissue, which leads to narrowing of the arteries,

build off a plaque, which also increases vascular resistance and hence increases blood pressure. So all of those mechanisms are related. Excessive dietary salt is a little bit different because that can happen with or without a gain of weight, although highly processed foods also, tend to be higher in sodium. And so there does tend to be an association that if you eat a lot of high-caloric, highly processed food, it's likely you also have excessive salt intake, sodium intake specifically, but it's not, that's not guaranteed. And interestingly, consumption of other salts, of other salts like potassium, calcium, and magnesium is actually protective because the body uses these to essentially modulate its level of sodium. So if you have more like calcium

and potassium, it's easier to remove the sodium that you do have. But processed foods tend to have much higher sodium levels and much lower levels of potassium and calcium and magnesium, interestingly enough. So consuming a salt that has some of the sodium traded out for potassium or calcium can actually be quite beneficial for your health, you know, in addition to other changes, because it can help reduce the blood sodium levels that you have and hence reduce blood pressure. All right, so that concludes our section on pathophysiology, how obesity leads to hyperlipidemia, insulin resistance, and hypertension. and we saw that at the core of a lot of this was the enlargement and inflammation of adipocytes

leading to excess lipids and lipid metabolites throughout the body, a disruption of signaling processes, which in turn leads to insulin resistance and hypertension. So now I'm going to conclude the episode by bringing everything to a head and talking about how exactly all of these processes actually lead to negative health outcomes. We talked in the previous episode about how obesity, well, being overweight and then being obese and higher levels of obesity, progressively leads to worse and worse health outcomes with nearly all causes of mortality, with a few small exceptions, but almost every cause of mortality, the mortality rates are higher for obese people. The question is why? Because as we said before,

by themselves, high blood pressure, high blood glucose, and high cholesterol or high blood lipid levels, don't themselves generate symptoms a lot of the time. And they don't by themselves typically kill you. what happens is that these which lead to damage to various organs and the blood vessels, which then leads to a variety of negative health outcomes. So now we're going to explain how dysregulation of blood lipids, blood glucose, and blood pressure leads to the direct health effects. And before we get into that, though, we'll talk briefly about the direct, what I call the direct health effects of obesity.

So this is more the effects of just the excessive weight itself, rather than the effects that are mediated by insulin resistance or blood pressure. So increased adiposity has many, many effects on health, including decreased mobility. It makes it harder to exercise, which obviously acts as a positive feedback mechanism there. The harder it is to exercise, then the more weight you're likely to gain. Cause lower back pain, the buildup of fat around the neck can cause obstructive sleep apnea, which decreases sleep quality, which itself is a risk factor for weight gain. And so there's, unfortunately, many of these positive feedback effects in the sense that

some weight gain can contribute to further weight gain by reducing exercise or reducing sleep quality. Higher body weight also increases pressure on the joints, which makes obesity a risk factor for development of osteoarthritis. There is a more complicated relationship between obesity and bone health, because on the one hand, the additional weight that presses down on your bones and pulls on your bones can increase their strength, because bones do need resistance in order to stay healthy. And in addition, the excess fat can actually protect against fall damage, so if you fall over, you're less likely to break a bone or cause a serious injury because you're actually sort of padded. So both of those things are actually somewhat protective.

However, on the flip side to that, there's recent evidence that the inflammatory response which is triggered as a result of obesity that we've talked about appears to be maladaptive for bone health. So it's a bit of a mixed bag about the effect of obesity on the bones themselves. Another effect of obesity is fatty liver disease, so this involves buildup of fat deposits on and also within the liver. interestingly in obesity, particularly when obesity reaches the more severe levels, you don't just see an accumulation of lipid deposits in adipocytes.

What you really see is an accumulation of fat deposits almost everywhere within all of the visceral organs. So on the liver, on the heart, blood vessels, the digestive system, pretty much everywhere you can see fat accumulate. And fatty liver disease is just one sort of manifestation of that where fat deposits accumulate. in and on the liver. Now this doesn't cause, this is not symptomatic in and of itself, but it can lead to liver failure and contribute to liver cancer because these fatty deposits inhibit the function

of the liver. And as we've talked about before, accumulation of lipid deposits where they shouldn't be nearly always leads to disruption of signaling pathways, which interrupts normal cellular functions. A similar accumulation of fat around the heart, so pericardial fat can also increase the risk of heart failure. So these are sort of the more direct effects of obesity of just being larger and having more fat. Let's now talk about the specific effects associated with high blood sugar or diabetes.

So why is diabetes so bad? Diabetes means you have chronically high blood glucose, but what's the problem there? Well, chronically high levels of blood glucose are terrible for the body. They damage pretty much everything that they come in contact with, but over long periods of time, it doesn't happen immediately. The two main categories of the types of damage are often broken up into damage to macrobascular, and damage to macrobascular. So damage to microvascular specifically refers to damage to capillaries, like the smaller blood vessels. And this can cause damage pretty much everywhere in the body, as I understand it, but it tends to manifest most severely and soonest around the eyes. So that

leads to diabetic retinopathy, which can cause blindness around the kidneys. There's a lot of smaller, intricate components in the kidneys, which require blood supply. That leads to diabetic nephropathy around the heart, so diabetic cardiomyopathy. and around the nerve, so diabetic neuropathy. High blood glucose levels can also lead to damage in larger arteries and blood vessels. This can lead to coronary artery disease, stroke, and also diabetic foot. So that's a particularly common location of damage. That's why diabetics often lose toes because of the damage to the blood vessels in the feet.

So how is it that high blood glucose leads to so much damage to blood vessels? Well, there are a number of mechanisms operative here. So one is that it appears that excessive levels of glucose leads to interaction with proteins, lipids, and other molecules that are also transported in the blood. And so when they are exposed to glucose, they interact with sugars. And this can inhibit their function. This can cause damage intercellularly and intracellulally. One effect is that it can cause cross-linking of collagen, which causes stiffening of the

vascular, so this is one cause of hardening with the arteries that I mentioned before is exacerbated by glucose. It's not the only cause, but the glucose leads to, it interacts with proteins, causing cross-linking of collagen, which stiffens the vascular wall, and increases its resistance to blood pressure, and hence increases blood pressure. The hardening of the vascular walls also contributes to entrapment of low-density lipoproteins, so LDL particles, which leads to atherosclerosis. We'll talk about that more in a moment. So in addition to this damage by interaction with proteins and lipids, high glucose levels also increase production of free radicals, which are highly reactive molecules or particles that have an unpaired electron, and they cause

damage pretty much wherever they go. So there is a certain baseline of free radicals in the body that are necessary for breaking down and metabolic products and things like that. But high glucose levels artificially increase the quantity of free radicals, which causes damage, particularly to the endothelial cells of blood vessels, which in turn inhibits their function. The details are complicated, but basically excess sugar in the bloodstream causes damage to the walls of the blood vessel, and leading into stiffen and more readily accumulate and entrap lipopoprotein particles, which contributes to atherosclerosis. And this then progressively damages the blood vessels, inhibits the blood supply to the relevant region of the body.

And as I said before, the microvasculature around the eyes, kidneys, heart and nerves are particularly susceptible to this sort of damage. Diabetes also increases the risk of certain types of cancers, including pancreatic, liver, colon, bladder, rectal, and breast cancer. I'm not entirely sure about the mechanisms there or whether they're related to the vasculature or to other processes, but I thought I just mentioned those as well. So diabetes has a wide range of negative health effect. Now we'll conclude by talking about atherosclerosis.

So this is the process of the hardening and narrowing of the arteries. I've talked a number of times about how the accumulation, what happens when we talk about hardening and narrowing, we're specifically talking about accumulation of plaque on the inside lumens, so on the inside surface of the blood vessels. This plaque causes the lumen to narrow and by increasing the pressure. And eventually the arteries can become almost completely occluded, which if that happens on arteries that feed the heart, that can lead to a heart attack, or if it happens in the brain, that can lead to a stroke.

Now, specifically, you might think, where is this luck coming from? What is it? Why does it happen? Why does it form? So atherosclerosis, I mentioned this in the previous section where we talked about hyperlipedemia. The increase in LDL particles in the bloodstream, these LDL particles can become oxidized, and that's, as I said, worsened in the case of when there's glucose around, that can accelerate this process. And these oxidized LDL particles trigger an immune response, macrophages gobble them up, the macrophages turn into foam cells.

And these foam cells tend to accumulate. They can pass, what happens is actually pass through the endothelial cells, which line the inside of the artery lumen. So they pass over just the immediate inner layer, but not across the smooth muscle cells. So the artery has endothelial cells and then a bit of a gap, and then there's smooth muscle. cells surrounding it, the LD old particles and the macrophages can pass through the endothelial cells, but then once the macrophages eat up all of the oxidized, the LD old particles, they kind of get, and they turn into foam cells, they kind of get stuck there, and they accumulate there. They build up in this space between the endothelial cells and the smooth muscle cells.

And over many years, they accumulate and build up a larger and larger plaque in the wall of the blood vessel. And so these plaques are made up largely of these, accumulated foam cells with lots of lipids in them, but there's also other bits of cell residue. Some of these foam cells eventually will die, particularly in the center if they don't have enough oxygen availability, and this can lead to the formation of what's called a necrotic core. So there's a core of these dead cells and cell debris surrounded by accumulated but living foam cells, and then on the inner side there'll be the endothelial cells lining the actual inside of the blood vessel,

and then on the outside will be the smooth muscle cells. So you get more and more of this buildup, essentially of mostly residue fats, building up on the inner side of each side of the lumen, gradually narrowing and narrowing that lumen. Sometimes these plaques that are the buildup of these fatty cells and other tissues can become unstable, and they can rupture, so part of it can break off. and that broken part can become lodged in the remaining and narrowed lumen of the blood vessel. When this occlusion occurs, it triggers a... When this occlusion occurs in a coronary artery, it triggers a heart attack.

And if it occurs in arteries in the brain, like the carotid artery, it can lead to ischemic stroke. In many cases, this is one of the first symptoms of high blood pressure or of high blood lipid levels is actually a heart attack or a stroke. and by that point the process has been the process of arthroaccharosis and build up of these lipid deposits has been occurring for many years probably decades at that point and as i said the um different aspects of metabolic dysregulation interact with each other quite quite strongly because high glucose levels contribute to the buildup of plaque and damage to the to the blood vessels they can increase the infiltration of LDL particles and their oxidation causing them to accumulate more

rapidly and accumulate plaque that narrows the arteries. Narrowed artery increases blood pressure, which causes further damage to the arteries, which further increases blood pressure. And accumulation of these LDL particles throughout the body makes insulin resistance worse. It contributes to insulin resistance, and thereby increases the circulating blood glucose levels. So all of these processes are tightly interconnected to each other. And that's why the symptoms, as I mentioned, at the outset of abdominal obesity, hypertension, hyperglycemia, and hyperlipidemia are all tightly connected to each other.

And as we saw, it really all comes down, not entirely, but in large part, it comes down to too many lipids circulating in the body and stored in your adipocytes. Excess lipids over time, it leads to them accumulating on blood vessels, damaging them, causing high blood pressure, and it also leads to accumulation of intermediates, intermediate byproducts of metabolism in the liver and other cells, which disrupts the normal signaling processes and leads to insulin resistance. The chronically inflamed and enlarged adipose tissue also changes the signaling molecules that it sends throughout the body, which causes a wide range of disruptive effects, causing an overactive RAS system, which leads to hypertension, contributing to insulin resistance, and disrupting other

metabolic processes that normally regulate the amount of LDL and HDL and other things in the bloodstream. So it all comes back to excessive lipid deposits as well as salt intake and some other factors, leading to a systematic dysregulation in metabolism, leading to excessive levels of lipids in the blood, of glucose in the blood, and excessive blood pressure. And our bodies are not really built to mitigate these things. I mean, they don't cause disease immediately. It takes many decades to cause the damage.

But because we didn't involve in highly nutrient enriched environments, our bodies just don't seem to have the right adaptive processes to deal with a chronic excess of nutrients. And so the metabolic processes that normally keep things in balance go out of whack when we have a chronic excess of calories. So that concludes the discussion today. Hopefully you found that interesting. If you enjoy the podcast, feel free to support us by leaving a review on Spotify or the aggregator of your choice. If you would like to make a financial contribution, you can do so by becoming a Patreon supporter. Just Google Science of Everything, Patreon. You should be able to find us there. Or you can make a one-off donation via PayPal. If you would like to send

questions, suggestions for future episodes or other feedback, please feel free to do so. My email is Fods12 at gmail.com. F-O-D-S-1-2 at gmail.com. Thanks very much for listening, and I'll talk to you next time.