PUFAs in Brain Health & Disease, Dietary Fats, Brain Lipids, Nutrition | Richard Bazinet | #165

About the guest: Richard Bazinet, PhD is neurochemist and nutritional scientist at the University of Toronto. His lab studies brain lipid metabolism in health and disease.

Episode summary: Nick and Dr. Bazinet discuss: lipid metabolism in the liver and brain; dietary fatty acids (saturated, monounsaturated, polyunsaturated); fatty acids in brain health & disease; endocannabinoids; omega-3 PUFAs, seed oils & diet; and more.Related episodes:

* Seed Oils, Omega-6 PUFAs, Inflammation, Obesity, Diabetes, Chronic Disease & Metabolic Dysfunction | Chris Knobbe | #136

* Omega-6-9 Fats, Vegetable & Seed Oils, Sugar, Processed Food, Metabolic Health & Dietary Origins of Chronic Inflammatory Disease | Artemis Simopoulos | #134

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Richard Bazinet 3:47

Sure. So I'm a professor at the University of Toronto. And I'm in the department of nutritional sciences, which I'm sure we'll get to the significance of that a little later on. And I'm a neuroscientist, maybe an old breed of neuroscientists, which you might call a neuro chemist. And we're really interested in in brain neural chemistry with a focus on the lipids, you know, you might know this, but if you exclude water, your brains pretty much half fat. And that's almost as fat as your body fat. So we're interested in, you know, how does the brain get to be like that, that comes back to the part to nutrition? And then the ultimate question is, why is it like that, and that's, you know, are brighter. So we use a variety of, of model systems, including human clinical studies, to try and get at the answers to some of the questions we have.

Nick Jikomes 4:41

And just just to give us a like a bird's eye view, like what, what components of neurons and the brain generally is is fat used to build and how does that compare to the rest of the cells in our body or do neurons have more fat than other cells or less fat and is it Just the cell membrane, or is there are there other components there that are made out of fat?

Richard Bazinet 5:04

Yes, so there's a few things there. You know, from from a lipid chemistry perspective, if you stand out far enough and you look at a cell, they're they're quite similar in that the phospholipid membrane is phospholipids, which is a lipid. And then there are fatty acids in there. They vary from tissue to tissue, the brains a little unique, and we can get into that. But the brain is also a little unique in that lots of our tissues would also have a fair amount of trace of glyceride, or triglycerides, kind of a storage fat that people would think of. Either that they're using it for energy when they're exercising, or it's a thing that's, you know, putting on a few too many pounds, our brain doesn't have that. The other thing with fats, though, is they they're in this membrane, but they also can come out of the membrane. And in that respect there, they're involved in a lot of signal transduction. So we, we study them, kind of both of those levels, because there actually are some big questions on how the the composition of the membrane affects the amount of fat that's released for signaling afterwards.

Nick Jikomes 6:11

Okay, so they're not they're not just structural things. No,

Richard Bazinet 6:16

no. If you picked up a textbook in biochemistry from about 1975, the year I was born, Len injure would say, they they keep you warm in the winter. They have structure. You know, they're used for energy, something I'm probably forgetting, because I'm trying to count to four on the spot right now. But they have no unlike nucleic acids and proteins at the time, they have no ability to share information. And that's not true. Right in. In 1982, the Nobel Prize was given out for the discovery of a molecule called prostaglandin E to backstep, a little bit prostaglandin e two is made from cyclooxygenase. That's the enzyme that aspirin inhibits. And if you step back a step further, that comes from arachidonic acid, which is a fatty acid derived from essential fatty acids. And that, you know, classically was thought to relay information about inflammation. arachidonic acid is one of the fatty acids, it's, you know, in the neuronal membranes, and the micro glial membranes and all of the different type of membranes. And, you know, that has a fluidity in a structural function, but it also gets released in response to signals and relays further signals. So there, they have a very important role structurally, that's been, you know, probably the focus of 4050 years of research. But more recently, we're getting into these nuances of their derivative, sometimes called bioactive lipids, and their role in signal transduction. Yeah,

Nick Jikomes 7:52

definitely want to get into a bunch of that stuff at some point, stepping back a little bit. So when we when we think about fatty acids, generally, people maybe are most familiar with, you know, seeing some of these things on nutrition labels and things like that. There's different types based on their chemical structure, you've got saturated, monounsaturated and polyunsaturated fatty acids. Can you give people just a general sense for what the major differences between those types of fatty acids are?

Richard Bazinet 8:17

Yeah, so you now that there, we've got saturated fatty acids, which which the, if you can picture a structure in your head, right, now you've got a series of carbons connected to each other, and carboxylic acid at the end, when they're in a phospholipid, they're no longer an acid, because there's, there's an ester linkage there. And saturated, you know, at least when I visualize a fatty acid, I don't do this innately I just see the carbons, but there's hydrogens all there, right. And so saturated, will often be referred to as there's no double bonds. True, but not quite accurate. What it means is saturated saturated with hydrogen, so therefore, there are no double bonds. And if you had a double bond in, you've removed hydrogen, so it's now unsaturated, or mono unsaturated. And then if you remove multiple, you get these polyunsaturated ones, and the brains are a little unique in this respect, and that there's one of these polyunsaturated fatty acids, called docosahexaenoic acid. dokolo means 22. hexa means six. And so it's 22 carbons long and it's got six double bonds oncology DHA. And that one's you know, really unique in the sense that it's highly abundant in neuronal membranes. And we find it that the level of the signups quite enriched in some specific phospholipids, you know, it can reach 40 to 50% of the composition of that phospholipid. So there's spots in the brain where this molecule just just lives, so to speak, and that's unique composition. So we don't see that and in the Liver and the muscle, you know, there's DHEA in those tissues, but not quite at that level. And it begs the question, you know, why is that how to get there? And why is that?

Nick Jikomes 10:08

And so in terms of the saturation, you know, we're talking about how many double bonds exist between the carbons in sort of geometric terms, what is the level of saturation mean, in terms of the overall shape of the fatty acid, whether it's sort of straight or bent or highly curved? And what significance does that have. So

Richard Bazinet 10:28

two things so the in, you know, in a simple model system, it's easier to pack saturated fatty acids on top of each other, you can make them more tight, tight. So we talked about the membrane being more rigid or less fluid. And the implication of that is that proteins or receptors, or anything in the cell, will have different patterns of movement, maybe slower patterns of movement, in a more rigid membrane. But there's also something and then you add increasing unsaturation, the membrane becomes more fluid, and things can move around a little easier, so to speak, in a very simple model system. But it's also very important for signaling, because a lot of these molecules like prostaglandin E to essentially require oxygenation or hydroxyl groups to be added to them. And those are typically added at the sites of unsaturation. So you can't make a prostaglandin e two from a saturated fat like Paul metate, Monetate 16 carbons, but even if it was 22 carbons, recall, or 20 carbons, we call it a shidduch acid. Similar to arachidonic keep, but you probably heard that even with my little French Canadian accent, typically that the difference, you can't you can't add hydroxyl groups to ever shidduch acid, but you can add add them to arachidonic acid, because it's got the double bonds there. And that becomes very important in the in the signal transduction afterwards. So membrane fluidity, and signal transduction are reflected in this saturation, or unsaturation. And the various indices around those

Nick Jikomes 12:08

I see so so the amount, so if we, if we mentioned a cell, we have the cell membrane, there are proteins in the cell membrane, like, like receptors and different things, and they don't stay in one spot, they're kind of moving around in this membrane and the membrane, I don't know, if we think of an analogy or something I can, you know, I could imagine wading through a pool of water maybe, or a pool of molasses. And that would maybe, you know, the blast is gonna be harder to wade through, I'm gonna move around a little bit more slowly. That would be that would be akin to saying the membrane has, you know, a higher lower saturated fatty acid content, and it's more or less fluid.

Richard Bazinet 12:41

Yeah, so I like that, and I'm gonna steal that from you. Because it's better than how I teach it is, it's perfect. The one thing I'll say, though, is that, you know, it's a little more complicated than that, because if you, it depends on the fatty acid that's beside it a little bit. And then things can get really complicated because the membrane is made up of phospholipids. And there's specific types of these phospholipids, predominantly phosphatidylcholine, there's an endo and Ethan Olamide. And there's subtypes of those. And then there's inositol, and serine. And for whatever reason, they have their own biases, or affinity. So, so you, you, you, you kind of can't put two politics in a phosphor title searing in reality, right, it's usually got one of these DJs in one position, and something else in another position. So in and you know, I can't really explain all the biophysics of this, but sometimes you'd say, if I put a palmitate, I'm trying to do this in my head with something with with one double bind, would be might be much more rigid than something with to double, you know, it doesn't add up one to one to one for every he can't count the number of double bonds and say this is the fluidity of the membrane, because it depends on some interactions, I guess, is what I'm trying to say.

Nick Jikomes 14:07

I see. But you know, the sort of profile of fatty acids in the phospholipid to the membrane is gonna determine how fluid that membrane is how easily proteins and stuff can move through it. And presumably, this stuff, change the fatty acid composition of membranes in the brain and elsewhere in the body. Presumably, that changes depending on the fatty acid profile of our diet, or is that not true? Yeah,

Richard Bazinet 14:29

yeah. And that's why I'm a nutritional neuroscientists, right. And so we should take a step back and go there's another way to classify these fatty acids. We've got them saturated, monounsaturated, or polyunsaturated. We can also call them essential or non essential from from a biological function. Okay, well separate. I think they're all essential biologically, but dietarily essential. And that brings us into the field of nutrition and so these agitated fats and these mono unsaturated fats we can make okay we can we can eat them in our diet and absorb them directly POM from almost any sort of fat it's going to have palmitate in it oleic acid, one of the mono and saturates sounds like olive oil is famous for all oil butts and all kinds of things, you can eat them. Or you can use glucose and make them do lipo Genesis, and we have some enzymes that can make oleic acid because that double bonds in this specific position and we have an enzyme to do it, then you get into the polyunsaturates. And there's a couple minor exceptions to this that I don't think we need to get into. But there's roughly two types, there's the the Omega sixes, and then there's the Omega threes. And we eat in our diet, essential precursors. So there's two of them, and the naming is awful here, you gotta pay attention. There's little lag, and Lenovo lenok, it's sometimes I tripped up like so little lag comes from the Omega six side and little Lennox, sometimes called alpha linolenic comes from the Omega three side. And they have a double bind and a specific spot one in what's called the Omega six position, one in the Omega three position. And if you're in organic chemistry, right, now, you're going to be confused. Because you start naming the fatty acids from the carboxylic acid end of the molecule. In nutrition, we start on the other end, the methyl end. So if you if you say the bonds in the three position, you gotta tell people if you're a nutritionist or a chemist,

Nick Jikomes 16:36

so if someone's not a chemist, or nutritional chemist, the names, you know, you sort of you sort of said this in multiple ways already, the names these long, complicated names, and the numbers like Omega six versus three, that's just referring to like, how many carbons or the position of the bonds, it's referring to something about the chemical structure.

Richard Bazinet 16:55

Yeah, so typically, that there's the name kind of usually referring to where it was discovered. Or we get into Greek to make it a little more simple kind of thing. But the even some of the Greek names, you know, some of the names like DECOs, our, or, you know, PENTA something, that we have a common name for them, usually based on where they're discovered. But But these, these positions, are telling us, you know, the coza hexanoic acid, their six double bonds, there's nothing in that name that tells us where the double bonds are. And you'd have to know that the first one is in Omega three, because that's an Omega three fat. But anyways, going back, we've got these 18 Carbon precursors that we in our food right, in a variety of food sources, and then we can take them in our diet. Right bring them to our liver, we can make them a bit longer. And we can make in one case that arachidonic acid from the Omega sixes and DHA and some other steps in there, and we can eventually get them into the brain and into the membranes. The other thing to make it just a little more complicated is you can either make DHA or you can eat it directly. And it's famous for being in fish, so So you have a choice. You can either eat it from fish, or you can get the precursors and get it but you have to eat it. Okay, there's no glucose coming in here. There's no amino acids, there's no lipo Genesis, you have to get the the 18 carbon precursors started. And that's why we call them nutritionally essential, which, you know, doesn't necessarily speak to how biologically essential they are.

Nick Jikomes 18:30

Yeah. So all these things are essential. Biologically, our body needs all of them saturated monounsaturated, and the different polyunsaturated fatty acids. But as you said, the saturated and the mono unsaturated fatty acids are not nutritionally essential, so nobody can make them. But these Omega six and three fatty acids, the polyunsaturated ones are nutritionally essential, we have to get them from the diet. Is that sick? Like, does that tell us anything about their significance? Or how they're used? Or what why is it that some of them or body can make and some of them we can?

Richard Bazinet 19:01

Yeah, so it's a good question. And, you know, that reminds me my PhD exam. And I was very interested in DHA in my PhD exam. And so one of the neat things about probably in humans to some extent, but definitely, in animal models, if you if you remove it from the diet, you can lower the levels in the brain. And then we can use that to start to study its biology and its physiology, right. And so we're very, that's really exciting because there's wiggle room with this fatty acid, you can have higher levels or lower levels. And does that matter? Okay, so so we're really excited about that. But the question came to me as as a young PhD student from the examiner palmitate it's almost impossible to change in the brain, okay. And we've done some work on this. We've published some of this recently. It's so rigid, you can remove it from the diet, sprain level stay the same. We make diets that aren't even you know, don't even model what humans really levels basically don't change. in the brain. And so the question the examiner said to me, well, doesn't that mean it's more important? Because there's tight biological regulation on that. So it's a good question. At the time I did my PhD a long time ago, we didn't quite have the tools to answer that. I still think we don't have the answer. But now we've got biological tools with knockouts. And, you know, they tried to knock out the the enzyme fatty acid synthase, a long time ago when I was a grad student, and it was lethal. But now with tissue specific knockouts, I think we're gonna get a get a better idea. And you know, the lipid nerds can sit down and say this molecule is actually more important for that than that one. But the lipids have been really tough to study, largely for this reason, you can't knock out a lipid. There's no gene encoding for commentate. There's, there's genes encoding for its synthesis, but there's a variety of them. And there's no gene encoding for DHA, right? So you can't knock it out. So we've, we've struggled with it compared to some of the other fields not having those tools available to us.

Nick Jikomes 21:04

Interesting. We're gonna spend most of our time I think, talking about brain, brain lipids, and and stuff to do with the brain health and disease. Before we get there, I want to talk about just some basic fatty acid metabolism, and probably just talking about what what the liver is doing here. So you know, I think you mentioned briefly before that, you know, the liver can do so it can metabolize fatty acids, it can make them longer, it can change them in different ways. I believe it can sort of make them from scratch, or process and change some of the ones that we can't make from scratch. But can you give us just sort of a basic Craske Crash Course and fatty acid metabolism? You know, what are these terms desaturate D saturation, elongation and oxidation? And what are those things mean?

Richard Bazinet 21:46

Yeah, maybe maybe we'll start from the mouth, right. Okay. Most most of the fats, we are in the form of triglyceride, I say triglyceride, you know, chemists would say try Aysel glyceride. Sometimes we call them tags, that's usually three fatty acids bound to a glycerol molecule. You eat others, you need some phospholipids use some of the things but you know, triglycerides, 98 99% of your diet. There's some enzymes called lipases that start actually at the Tookie lingual lipase and kind of make your way down. And they essentially break the fatty acids off of usually there's there's three positions, they break it off in the one and three position, typically leaving the two position intact, which which might be important for some things in development, there's that one molecule DHA in human breast milk, is in the two positions, suggesting it's protected, right. And it's important for neurodevelopment, it's just kind of a neat thing, we might go there. And then you take these fatty acids, and you bring them into the intestine. And you basically repackage them off. So you've broken them all down on one side, and you bring them all back in and you repackage them all into a pile of Viagra and you send them out, they drop into the lymphatics, and they go to a variety of places, including the liver, a notable exception, and you have to put them in these chylomicrons, because they're not soluble in your blood. And one of the things these kinds of microns are which are essentially lipoproteins, there's the outcome solubilizing in the blood, so we can transplant them around, transport them around, so we're not transplant them. But there are exceptions. You know, I my bias is I started thinking of fatty acids at about 14 carbons in longer. It's totally not true, they're shorter ones, and there's a lot shorter ones. And as they get shorter, they become more water soluble, even though we'll call them a fatty acid or lipid sometimes, and those ones have different absorption mechanisms through instead of through the lymphatics through the portal and they don't require Kyla micron. So keep that in mind. And then a fatty acid kind of comes into a cell, almost any cell with with some with some differences between tissues in the cell can say, hey, I'm going to take you and store you into triglyceride, something we don't really do in the brain. But you do in the liver, you do it in your muscle and others or I'm going to throw you into the membrane, or I'm hungry, I need some energy and I'm going to oxidize you beta oxidized you and that's I'm going to take you through, you know, a series of steps to break it down to acetate, and we'll put you through the TCA cycle, we're going to eventually make ATP out of this. And it's quite a rich process. If you've got double bonds, and you I can still do that, and there's some minor exceptions to the pathways. But just one thing for your listeners to be aware of, we can also auto oxidize you. And that's when oxygen reacts and makes oxidative products which are which you know, sometimes are considered bad things but they might also be signals for other cells that something's going on here. So don't just like to call them back. And so they get into the liver, and then eventually they get into the blood and to the adipose tissue in a variety ways and then You know, circle paths to the brain. And you know, I think the in the human, the blood brain flow is about two seconds, something like that it's just under a second and a rodent. And they have to cross the blood brain barrier and eventually get into the brain, assuming that's where they're going. And there's a lot of debate in that how that works in our field. Okay, I'm part of the debate, but I'll try and give you two sides of it. The fatty acids in the blood can be in lipoproteins, there's a variety of them, LDL being a famous one people might know about, but there's others. It could be as a free fatty acid, or as what's called a laser phospholipid, which is a phospholipid with a fatty acid missing on it. And so my colleagues a long time ago, could make artificial membranes with no proteins in it. And they could see free fatty acids crosses artificial membranes, so we realized that fatty acids might not need a transporter to cross okay, we came into the field and we started knocking out the candidate lipid protein receptors didn't seem to do much. So they didn't seem to be quantitatively a major role. These laser phosphor lipids can also cross and so now we've been debating whether the crossing just like free, or things, helping them. And this has been a massive area of confusion for our field because we named a whole bunch of proteins, fatty acid transport proteins, pretty clear by the name what they do. You know, you have a membrane of fatty acid on one side, you increase the amount of fatty acid transport proteins satps fatty acids go through it more quickly. Looks like a transporter smells like a transporter. Is it a transporter? No. They're a Sukhoi sensitizes, which are what are molecules that take a fatty acid and when it's in the membrane or other places, and you put a big coenzyme in on it. And coenzyme A is massive, and it's water soluble. And that does two things, it sucks it out of the membrane doesn't let it float back across and makes it kind of water soluble. But the problem is, if you look at this, because it's facilitating the uptake, it looks like a transporter. I like to compare it to glucose and hexokinase, or Glucokinase. glucose goes through a glute glute for a transporter gets six phosphorylated. And essentially disappear. So more can come back in. But if you looked at hexokinase activity or Glucokinase activity, you'd say, oh, that's facilitating the uptake. It's a transporter, until you get really close and you realize it's metabolizing, the glucose, allowing more to come in. And a lot of our proteins that are called fatty acid transport proteins are really involved in the metabolism of fatty acids and papers. And you could Google this right now. And you'd say you're wrong 500 times everybody's calling them transporters. But this is this is an area of debate. And there are some others as well called CD 36. And there's one called the MF s d two way that probably works on the lysophospholipid to help bring them into the brain. And eventually there's a series of enzymes that help them kind of get where they're going. And ours can't remember what the question was now. So

Nick Jikomes 28:16

So Well, it sounds to me like basically, when one important part of what you just said, if I'm hearing you correctly, is that the type of fatty acid, we're talking about terms of its geometry, the number of double bonds, whether it's saturated, unsaturated, as well as its overall length, if it's short, medium, or long, those things are going to dictate how it gets absorbed and transported throughout the body. Yes, yes. And so one of the key steps in fatty acid metabolism and one that you know, certain corners of the internet in the world talk about a lot is oxidation, as you mentioned. So fatty acids can become oxidized, how many double bonds they have, is going to tell us how many places can become oxidized. And you said something that was kind of interesting. You said oxidation can have a negative effect that can produce, you know, my understanding is they can produce things that are toxic oxidative byproducts. But you said they can also produce things that carry information or active signaling molecules. Can you say a little bit more about that and the role of oxidation?

Richard Bazinet 29:13

Yeah, so two things I say about oxidation. One is that it a little bit better model on the periphery is that we think some cells can recognize immune cells, these oxidative products, and then you know, I don't want to overstate it but like chemotaxis, and they go there, and then they do things so they so they gave up a signal. That's not always bad. Clearly, you know, they can destroy memories and not help. One of the mysteries that I'm going to throw out right now is if I were designing a brain, or a body, I would keep these polyunsaturated fatty acids away from the sites with the most oxygen uptake right oxygens what's going to oxidize them. I put them in the opposite places. What do we see the exact opposite, right? There's a positive correlation between oxygen consumption of a tissue or or brain region and the polyunsaturated fatty acids, this DHA with six double bonds that would be most susceptible to auto oxidation, they're in the same place. You can ask me why I'm going to tell you I don't know, right? Nobody knows this. And I'll bring it back a little further, it's really wild because it jumps across animal kingdoms. And that two of the richest non mammalian sources of DHA are the Hemi hummingbird breast muscle, which has massive oxygen consumption. And the little muscle that I can't name on the tip of a rattlesnake tail that beats really quickly. That apparently also has a lot of oxygen consumption, there are rich sources of polyunsaturated fatty acids that are going to be highly susceptible to oxidation. So PhD thesis waiting to happen. I don't know why that is. I've had conversations with people. We have hypotheses, but I nothing other than I'm compelled to tell you right now, like this is the one that that we're betting on.

Nick Jikomes 31:09

Another another way that oxidation gets discussed this. So these things can become oxidized in the body as part of the chain of metabolic events that's happening, they can also become oxidized outside of the body before we consume them. So you know, one place people talk about these are, you know, french fries or something at fast food, it's basically you know, you're boiling these long chain fatty acids, they become oxidized before even put in your body. Does that have an impact in terms of how they're used by the body or their toxicity or anything like that? Yeah.

Richard Bazinet 31:38

So So you know, if you google this in the internet, you'll get the answer. And it's the this is the devil's oil. And this is the root of all evil, why everybody's dying. I don't think that's the case. But we're starting to do research. Now. There's somebody named Amir Taha, at the University of California Davis and others are really interested in this question, because they're studying, you know, the first question, these oxidized lipids, for a variety of reasons, we would have a hard time getting absorbed, okay, turns out are absorbed just in small quantities. We don't know the details of how they're absorbed. Like, I can't draw you that you can open a physiology textbook and find that you really can't even find a paper and find that, we assume it's similar, but we might not quite be right. But they're absorbed, they seem to be absorbed in relatively small quantities. So the body clearly has some mechanisms to try and keep them out or get rid of them, which might relate to the tox illogical properties. But yeah, you're absolutely right there, they can be found in foods, especially foods that had been exposed to oxygen or, you know, left that would their levels accumulate. Sometimes fats, and there's some little details here, I don't want to put my neck out too far, but smell bad. And it's not exactly clear to me, at the most minut level of it's just oxidized fats, or we need a mines in that mixture to make things smell bad fish being a great example. And that these are also cues for us not to eat these foods, that something's wrong with them. And then the debate we have there in the field, are they? Are they the toxin? Are they the canary in the coal mine? For something else? Or are they both right? And so we're working on that a lot of people are working on that. But there's clearly, you know, evolutionary programs signals where we tend not to like oxidized lipids from a nutritional perspective, with oxidized lipids in them. So

Nick Jikomes 33:45

based on how we prepare foods, you know, with a lot of the vegetables and stuff, they get heated, there's a lot of oxidized lipids out there that we put into our bodies. It sounds like you're saying most of those oxidized fatty acids don't get absorbed, and that it's probably a good thing that we only absorb a tiny little bit. One place my mind goes there is I assume it's under sort of baseline conditions. A healthy gut doesn't absorb a lot of those. What if there is some kind of a gut dysbiosis? And there's like a leaky gut, does that mean that some of those things could get in more than you'd want them to get in? Yeah, so

Richard Bazinet 34:18

great question. We don't know yet. Nobody's done that yet. Yep. At least to the best of my knowledge. I know a couple of people working on this. And and, you know, when you start these studies, you start simple, right? You don't, you know, go with a more complex pathophysiology. Very reasonable hypothesis. My guess is probably, but I don't know that. Interestingly, the, the, the infant, which would be another cause for concern with if I can call the easier term leaky gut, you know, usually is drinking human milk. And that would not be a major problem in human milk, right? Under normal circumstances, so it's It's a great question. I don't know the answer to that one. I think so. Sure.

Nick Jikomes 35:04

And before we dive into the brain more, one more question with the liver I want to explore is, does the fatty acid composition of our diet have an influence on things like fatty liver disease? And how much fat actually accumulates in the liver based on, you know, the based on which fatty acids we're actually giving to the liver? Yeah,

Richard Bazinet 35:26

yeah. So it does. And it's not always clear if the dietary fat is regulating that. So I think I think excess calories, in general can contribute to a fatty liver, and then, you know, disease states as well. But when we look at fatty livers, they tend to be more saturated, and maybe mono unsaturated. So if you if you took a fatty liver sample, and you ran it on an instrument, maybe I'll just recovered, you know, whatever Mass Spectrometer, or what we call the GC, you'd see that it's it's bias, and it's palmitate. And it's only eight. But it's not 100%, clear to me if those were the dietary fats in the liver that accumulated there, because those are the two you can also make from lipogenesis. And maybe somebody knows that answer, and I'm just, you know, unaware of those studies, but it seems to me, it could be either those two, or a combination of those two, nobody's reporting fatty livers up with omega three fats, right? Like we don't, we don't see that in the literature. If anything, there's a small literature that some of the dietary omega three fats Could, could maybe you know, mitigate or attenuate the effects of the fatty liver or shrink it just a little bit, not a not a sledgehammer, but a little little effect there. And

Nick Jikomes 36:47

then, you know, when we start to think about the brain, and we think about the fatty acids in the brain, how are they getting there? Are some of them made inside of the brain? Are they primarily made elsewhere, then they go through the bloodstream across the blood brain barrier into the brain out of the fatty acids in the brain? Get there?

Richard Bazinet 37:04

Yeah, so this is, you know, I started off simple. And then I'm going to church and you know, confuse everybody because I'm a bit confused. And we just published a study on this, and the results were wild. So. So these these omega threes like DHA, and to the brain, through one of those kinds of mechanisms we spoke about a little bit, then it's really wild, because there's, there's another fish oil, if I can call it omega three called EPA Eicosapentaenoic acid, we haven't talked about it. It's barely detectable in the brain. So if I showed you like a readout of one of these Chromatographs, there'd be a little something that that you might call noise, and I might call a peak and we probably agree to disagree on so it's so low in the brain, you can barely detect it compared to the things are really clear. What we found, though, that was wild is it gets into the brain, at about the same rate as that one DHA roughly the same, but you almost can't find it in the brain. So it's metabolized, maybe I should use the word cat categorized very rapidly. How fast I'm not exactly sure, but probably within a minute, most of it is either destroyed or turned into something else. So so they get into the brain. But my point here is that the brain itself can help regulate its own composition, okay? It's, it's things are getting in there. And you'd predict to see them in there, but you don't find them in there. So the brain is doing something with them, okay. And then we've got this, this molecule, let me back up a step. So if you look at the brain, usually the most abundant peak, and I use the word peak interchangeably, unfortunately, with a mount is only eight. And then you've got one got late because there's 18, carbonyl, one double bond, and you've got one called stearic. Family and steers, it's 18 carbons, no double bonds. Paul imitates rate in the running, they're sometimes second, sometimes third. And then you get the DHA probably about fourth and this one arachidonic fifth and then things with the exception really dropped off a lot, right? So so they're there, but they're an order of magnitude lower. You know, what we've just discussed probably covers more than 80% of what's in what's in the ranges this few. And so some of them get into the brain, some get. We see them there. Some of them get into the brain, and we can't find them there. And then there's this molecule called palmitate, that I told is very hard to change in the brain, okay. And it turns out that the brain has these enzymes that can do lipo Genesis, so the brain can make palmitate okay. There's a lot of palmitate in the blood. And it turns out that it also comes in from the blood and enters the brain so the brain doesn't say I'm making use Stop coming in. It lets you come in as well. What we did that was a little wild and a little surprising is we gave rodents diets essentially palmitate, free, not quite, or very high palmitate and in the middle. And what we found was that even if we get these animals on these diets for a long period of time, we couldn't change brain palmitate levels, I hinted that never changes, right. So it's quite stable. And it what we found is that the the, using isotopes, if I can call it that, that there was more, when we remove palmitate from the diet, the parliament in the brain was more synthesized right from from the carbohydrates, the glucose makes sense. What doesn't make sense is we did a lot of work on this. And we found that it was actually the liver that was synthesizing and sending it to the brain. And so the brain MRI has the machinery to make it, okay. It can take it up from the blood. But when there's none in the diet, the liver up regulates its ability to synthesize it, not the brain, the brain is going to, I don't want to overstate it, but it really looks like a static level of palmitate synthesis, or lipogenesis going on. And if you give it more, it doesn't downregulate if you give it less, it doesn't operate late, it relies on the liver to do that. And I'm not sure why that is. But cancer cells do something very similar. They have a very critical level of lipid Genesis. And if you block that with a drug that inhibits it, you kill them. And then the textbook experiment is well, I'm going to stop it from making palmitate with this drug. So if I had palmitate, back, I'll rescue it right. You can't rescue it, cell still dies. And then the wild thing is there's there's tons of you know, I don't know why it's making the palmitate because there's tons in the blood and the vasculature could just take and what it makes its creats back out into the blood. So it's kind of useless, like, we're missing something. Yeah. And the brain looks a little bit like breast cancer and are the studies were MCF seven cells, which are breast cancer cells that I'm thinking of. But the brain looks a little similar to that, like it has to make palmitate for some reason, and it doesn't change that right. So we're missing a little something going on there. And it doesn't seem to change its regulation.

Nick Jikomes 42:24

Interesting. So the brain has this sort of constant level of palmitate unsaturated fatty acid synthesis, it never really changes. But the amount of palmitate made in the liver will change based on your diet. And that's going to influence how much it gets into the brain from the outside. But but somehow through all of those changes, the brain is sort of like holding the poverty levels constant.

Richard Bazinet 42:44

Exactly. Exactly. And so I don't mind hypothesizing too much. But I think sometimes we you know, we can measure palmitate. And that becomes the that's, that's the point of Label Genesis. That's why we call it lipo Genesis lipogenesis. But there's a lot of little reactions in there that balance things like NAD pH and NAD ratios. And without data, speculating that that might be also very important. And maybe we should recall that, you know, NAD regulation agenesis.

Nick Jikomes 43:20

So maybe it's sort of a byproduct of something else is going on. Yeah, it

Richard Bazinet 43:26

looks like it looks like a good hypothesis and the cancer cell that secretes it back out in the brain, I have to add on another layer to say and the brains evolved the mechanism to store it in the membranes, right? Why waste it will put it in the membrane? I gotta add that little pardon? Yeah.

Nick Jikomes 43:43

And so I would imagine that in the brain, from a structural perspective, obviously, you've got your phospholipid bilayer of the neurons themselves, it's gonna be made and other cells is gonna be made out of Bette acids. Presumably, it's also a component of the myelin. And I would guess that maybe there's some differences there in terms of which fats get used for cell membrane versus mileagelands.

Richard Bazinet 44:06

Yeah, a big difference actually great for bringing this up. The myelin is really enriched in all metate and another one got all the aid so it's so it's relative to the you know, if I can say the rest of the brain, it's quite rigid or would not be a very fluid membrane. very biased in that respect,

Nick Jikomes 44:31

because it's got mostly saturated monounsaturated and very little polyunsaturated. Yeah,

Richard Bazinet 44:35

yeah, not none, but very little. So So, roughly speaking, you know, if you look across the whole brain, a molecule like DHA would be 10 to 15%. It would drop down to about 1% in the myelin. So someone people say the brain composition and this is this it does vary a lot by cell type and architecture of the cell. Now, with the palmitate, and the all the eight jumping up even higher in the myelin the myelination?

Nick Jikomes 45:08

Yeah, and as you mentioned before, these fatty acids, they're not just used for structural reasons. They're not just, you know, building physical structures, they're not going to use as an energy substrate to, you know, used, you know, used to make ATP for the cell, they can actually serve as signaling molecules themselves. And I'm wondering if you could start to tell us a little bit about that. So in the brain, how is some of the signaling happening? How is it affecting synaptic transmission? What are some of the major things we know about how some of these fatty acids are actually used for informational purposes? So

Richard Bazinet 45:41

two things and one I think you've covered nicely earlier is by changing the membrane fluidity, they change, you know, how the receptors whether their spatial orientation or their movement, so they can have those effects. But the other thing we've known for some time now, and I'll use dopamine as an example, dopamine is G protein coupled to D two receptors, G protein coupled to an enzyme called phospho lipase a two okay. phospho lipase, it's like phospholipid lipase, like the digestion lipase, we were talking about earlier. A to is when you look at a phospholipid, there's two positions, there's the one position the two position, and then the three position kind of doesn't count, because that would be a choline or an eternal life and the one in two position that'd be a fatty acid. And usually, or at least a high bias, the two position is a polyunsaturated fatty acid like this DHA or that other one arachidonic acid. And so dopamine binds to the D two receptor. You know, you've had a lot of neuroscientists on here, everybody's interested in what happens after that. One of the things that happens after that is phospho lipase, a two gets activated, and it releases the arachidonic acid, typically, depending on on on a few little things. And that arachidonic acid comes out, some of it gets converted to what we call oxy Lipton's now, which would include this prostaglandin e two, but this is a field that's blown up, and that there are many, many of these molecules. And then it does something. And in some cases, it might be you know, it's relaying the signals of dopamine. But we haven't worked that out systematically yet. So you know, the work that was done on olfaction, how much have they systematically worked that out? We need to do that with these molecules, because there are hundreds of them. And they're being released, and they're doing something and I'm not going to do a very good job right today and telling you what they do, right? I'm going to write that as a grant. But one of the wild things is that arachidonic acid that comes out, about 97% of it just goes right back into the membrane. We call that the land cycle name that there guy, the lands, and we don't know why that is either. So you see, you take a whole bunch out, you lose about 3%. And you bring 97% rate back into the membrane. And we do that with other fatty acids as well. What

Nick Jikomes 48:09

about things like? So I know that certain fatty acids that are ultimately of dietary origin, they connect to endocannabinoid production? So can you just remind listeners, what are endocannabinoids? And what's the connection here between dietary fatty acids and endocannabinoids? And what they're doing to regulate synaptic function? Yeah,

Richard Bazinet 48:32

and what will go back, maybe a little bit to some of these axelent. And so, so we use we've got fatty acids, and then we get fatty acid derivatives. And we use these terms like bioactive fatty acids, and there's a lot of different types. And we haven't touched that. I don't think I've ever had to define endocannabinoids on the spot, but they're essentially, you know, people found the, the CB receptors, the and the cannabinoid receptors, CB one, CB two, which THC binds to, and then it was obvious, hey, they're not made for marijuana. There's something endogenous in there. And you know, the first big hit was a molecule called anandamide. And anandamide is actually derived from arachidonic acids. So it's an ethanol amide attached to arachidonic acid and that's an end of mine, and it binds to the CB receptors. Huge discovery really elegant stuff. And that that really helped us understand its role in appetite regulation and a lot of the things that people would be familiar with. Then it turns around, it gets the story gets a little more complicated because arachidonic acid is an endocannabinoid because it binds to CB receptors. It's to chemists, it's an ethanol amide it's just what you would call it okay. And then we find that I think all of these fatty acids, or everyone we've looked at, can make these Ethan Olamide derivatives. So if you're chemists, you're like, I got this no problem. They all make them, there's these these enzymes, there's a series of enzymes that do this, and you make them, where the biologists maybe gets a little annoyed with this is they're not all endocannabinoids, you know, no meaning endogenous cannabinoid. And that they don't have affinity for the CB receptors. Maybe they bind to paper, maybe they they bind to something else. Some of them we don't even know yet what they do. But they're involved in in a lot of the synaptic transmission as well. They're produced locally on demand, especially in neurons. And they really, you know, seem to be very important for synaptic plasticity and models of memory and learning. And interestingly, some of them you can change a little bit with your diet. And, you know, one thing I think we have to be careful with nutrition with nutrition is if you look at something and it's one is higher than the other, I don't know if the one's higher, or the ones lower, okay? It's just always a problem. We have a nutrition, if I say this one's higher, your listeners would say, Well, how does he know the ones not lower? fairpoint. Okay, we just use the language to get us by so, but we can change the levels of some of these with diet, if you One of them's derived from DHA, and we would call it d H, E, AE, which is terrible if you study hormones, because it's not that one, but it's because the hexanol Ethan Olamide, not not, not the hormone. And, and that is really important for us synaptic plasticity. And at least in animal models, we can change this level and change those functions. So there's a whole cascade of those molecules, my lab does