Did you know that adding MCT oil to your pasta is more ketogenic than restricting your carbohydrates to ten percent of calories?
Many people think of carbohydrate and insulin as central to ketogenesis, but the direct biochemical event that initiates ketone formation is actually the oversupply of acetyl groups to the TCA cycle during conditions of oxaloacetate depletion.
While largely a biochemistry lesson, in this episode I also teach you the practical implications of this. There is more than one route to ketogenesis, and while they all produce ketones, they are fundamentally different in important ways.
Adding coconut, MCT oil, or exogenous ketones allows you to reap benefits of ketones without necessarily restricting carbohydrates and insulin, and that may be useful if you are also trying to reap some of the benefits of carbohydrate and insulin.
On the other hand, certain conditions that respond to ketogenic diets, for example refractory childhood epilepsy, need stronger degrees of ketogenesis than you can achieve simply by adding MCT oil to pasta.
Understanding the difference allows you to better make practical decisions about your diet that are most consistent with your priorities.
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In this episode, you’ll find all of the following and more (these times refer to the podcast, and they may be different in the YouTube video):
- 01:00 An announcement about the paleo event I am speaking at in Brooklyn on August 9th.
- 03:17 The cliff notes.
- 04:55 The Snapchat discussion that inspired this episode.
- 05:44 Why the idea that protein suppresses ketogenesis by forming glucose makes no sense.
- 12:01 Overview of TCA Cycle and burning carbohydrate for energy.
- 14:48 How we burn fat on a mixed diet.
- 15:44 The meaning of the phrase, “fat burns in the flame of carbohydrate.”
- 17:58 Loss of lean muscle mass can occur if dietary carbohydrate and protein are too low; neither fat nor ketones can spare muscle mass from this effect.
- 22:20 Under carbohydrate restriction, oxaloacetate (OAA) is not repleted by carbohydrate and is used for gluconeogenesis, while more fatty acids reach the liver to make acetyl CoA.
- 24:38 The oversupply of acetyl groups in excess of OAA initiates ketogenesis.
- 26:40 Insulin shifts fat to adipose tissue, but this doesn’t cause obesity.
- 28:00 The effect of insulin allows us to look at how medium-chain and long-chain fats differ.
- 29:41 MCTs go straight to the liver and avoid effect of insulin in the blood.
- 30:26 Insulin suppresses the carnitine shuttle, but only long-chain fatty acids require it.
- 33:12 MCTs at breakfast suppress food intake at lunch.
- 35:14 Pasta topped in tomato sauce and MCT oil increases beta-hydroxybutyrate.
- 39:05 Two ways of getting ketones: selective deprivation vs. abundance.
- 42:12 If you are trying to get ketones, but having negative effects of carbohydrate restriction, you can add MCTs (or exogenous ketones) to get the ketones without carbohydrate restriction.
- 43:45 MCT oil-topped pasta is more ketogenic than a 10% carb diet, but much less ketogenic than the diets used to treat refractory epilepsy.
- 46:00 Exercise is ketogenic.
- 46:22 As a gym rat with a fondness for coconut eating the Warrior Diet , my pee turned keto-stix purple even after a three-course carbohydrate-inclusive meal followed by a frozen pizza and a pint of ice cream.
Links Related to Episode 22
If you want to see me, Dr. Akil Palanisamy, and Dr. Kelly Brogan, speak in Brooklyn on Tuesday, August 9th, you can purchase tickets here, and use the discount code “CHRISMASTERJOHN” to receive 20% off.
How to follow me on Snapchat.
The section on ketogenesis from the 5th edition of Biochemistry by Berg, et al. This is not the most recent edition but is freely available on NCBI Bookshelf, as is the case for a number of great second-to-last-editions of textbooks. This book is fantastic if you want something with exhaustive detail to occasionally reference. As a standalone book, though, it’s not a great cover-to-cover read.
For something where cover-to-cover reading is a worthwhile goal, I highly recommend the Lippincott Biochemistry Illustrated Review. The Kindle version is called an “e-textbook,” and I would highly recommend it if you have public transit commutes you could use for reading and studying or if you have a need to use the images for teaching.
“When Fat Burns in the Flame of Lean Muscle Mass,” an old blog post I wrote on this topic.
The study I discuss showing MCT oil at breakfast is ketogenic and suppresses food intake at lunch.
An example of the beta-hydroxybutyrate levels reached on a 10% carbohydrate diet.
An example of the beta-hydroxybutyrate levels reached on ketogenic diets used to treat epilepsy.
Although it did not compile beta-hydroxybutyrate levels, my article “We Really Can Make Glucose From Fatty Acids After All” compiled blood acetone levels reached on a variety of different conditions.
A Question for You
Transcript of Episode 22
This transcript was generously provided by Cassandra Barns.
This is Chris Masterjohn and you’re listening to episode 23  of Mastering Nutrition.
Before getting into today’s topic on why ketogenic diets are not all about carbohydrates and insulin, I want to briefly make two announcements. The first is for everyone, and that is that in an episode like this where there’s a lot of biochemistry, if you find that you would learn it better if you were watching a video that shows the biochemistry, I did make a YouTube video that goes along with this, and you can find that embedded in the page for the show notes at chrismasterjohnphd.com/22.
01:00 An announcement about the paleo event I am speaking at in Brooklyn on August 9th.
For those of you who are going to be in New York City or thereabouts on Tuesday, August 9, I invite you to come see me, Dr. Akil Palanisamy and Dr. Kelly Brogan speak at NYC Paleo evening, that’s at nycpaleo.eventbright.com to buy tickets, and you can use my name CHRISMASTERJOHN spelled as one word and in all caps as the discount code to get 20% off the ticket price. I’ll put the link to that and the discount code in the show notes. Again, that’s chrismasterjohnphd.com/22.
Alright, and with no further ado, here is the episode.
Alright folks, in this episode we’re going to talk about why ketogenesis is not all about carbs and insulin. And this is kind of going to be a biochemistry lesson because I really think that although you would definitely get the right information from a textbook, and there are definitely lots of great websites and blogs out there that do address the biochemistry properly, I also think that it is kind of commonplace to see the idea that the main driver of ketogenesis is insulin suppression. And this idea spills over into thinking that the reason protein suppresses ketogenesis is because it stimulates insulin. And I think this is a fundamental misunderstanding, and this is not just about biochemistry, this also comes to a really practical conclusion. Because there are other ways that you can – that you can induce ketogenesis that do not have to do with restricting carbs and insulin. So to illustrate this point, although I don’t necessarily recommend this as a breakfast, I will in this episode teach you how you can make a ketogenic diet based on pasta, or how you can at least boost your ketone levels after breakfast in the context of a meal based on pasta. Okay, once again I’m not advocating that as your breakfast, I’m just using this example to illustrate a point.
03:17 The cliff notes.
So for people who want the cliff notes, then here’s the deal. The cause of ketogenesis is that acetyl groups in the liver mitochondria – the supply of those acetyl groups is greatly exceeding the amount of oxaloacetate that is available that allows them to enter the TCA cycle. And that means that anything that supplies oxaloacetate, such as protein or carbohydrate, is going to suppress ketogenesis independent of insulin. And anything that allows more free fatty acids to reach the liver, if that can be dissociated from insulin, which it can in the case of medium chain triglycerides for example, or even exercise – those things will promote ketogenesis even in the presence of carbohydrate and insulin.
Okay, that’s the cliff notes. If that sounds interesting to you and you want more nuance and sophistication, then here we now dive in to the biochemistry, and then to the practical understanding of why you might want to think about, depending on your goals, if one of your goals is getting ketones, why you might want to think about the relative balance of using carbohydrate and protein restriction as a strategy versus using – supplying for example medium chain triglycerides as a strategy.
04:55 The Snapchat discussion that inspired this episode.
So this all began because on Snapchat I was kind of ranting about the paper – the Master’s thesis that I had reviewed in the last episode, episode 21. And that was about using a ketogenic diet for six weeks in the context of CrossFit . And overall, as I said in the last episode, I think that was a useful paper – I think the study was well-designed, I think the write up of the paper was largely good. But I – you know, I gave my reasons why I don’t think it was getting to the heart of the questions that I would be interested in in terms of how does a ketogenic diet affect sports performance.
05:44 Why the idea that protein suppresses ketogenesis by forming glucose makes no sense.
But I don’t want to give the impression I’m just knocking that paper, but there was this one sentence in the paper that was describing why protein is restricted in a ketogenic diet. And it first described why you need to restrict carbohydrate, but then it went on to say, and I’ll quote it here: “In addition (meaning in addition to restricting carbohydrate) protein consumption must not exceed fat intake during the low-carbohydrate ketogenic diet due to the additional glucose which can be produced from an excess of protein ingestion via processes such as gluconeogenesis.” And so on Snapchat I kind of ranted about this sentence because it doesn’t really make any sense. And in response to my rant I was getting – I got a private snap from someone that said, I really hope that you’re saving these Snaps so you can post them on YouTube because, you know, this is a great biochemistry lesson. And thus was born the motivation to produce this podcast. I know that – actually I’ve received nothing but positive comments about the level of biochemistry here. So if some people are asking for this, then probably a lot of people would want to hear it.
So here’s the deal. It doesn’t make that much sense that gluconeogenesis is going to suppress ketogenesis. Because glucogenesis and ketogenesis tend to occur in parallel. Now, that’s not to say that they’re regulated precisely together and that one necessarily means the other, but as a general principle, the reason that you engage in ketogenesis is because carbohydrate supply is limited and you’re burning fat instead of carbohydrate. And the reason that you engage in gluconeogenesis is because carbohydrate is limited, and you need to make glucose for the cells that can only run on glucose. So carbohydrate restriction is the main thing that’s driving both of those, essentially, and because of that they tend to occur in parallel. So it doesn’t make any sense that gluconeogenesis itself is going to suppress ketogenesis. Because whenever you want ketogenesis, you also want gluconeogenesis, you know, by – almost by definition that’s true, because – the MCT oil that I will eventually get to is an exception to that. But along the traditional lines of producing ketogenesis during fasting or during carbohydrate restriction, in proportion to the degree that you’re running on ketones for fuel, that means carbohydrate is limited, that is exactly what drives gluconeogenesis. Now also in terms of what’s happening at the level of the tissue, ketones are being produced by the liver because fatty acids are going to the liver for that purpose. Gluconeogenesis is, not exclusively, but largely being produced by the liver because amino acids are going to the liver for the purpose of making glucose. Those ketones and that glucose are going to leave the liver and go into the blood because the liver’s making them for the other tissues. So glucose is produced by gluconeogenesis in the liver, it’s not produced there to get broken down for energy or to have metabolic effects shifting around the use of fuel in the liver; its destiny is to leave the liver. And it doesn’t make any sense that glucose is going to suppress ketogenesis in the liver when it’s made in the liver during these conditions as glucose in the diet would suppress ketogenesis. And so then you may ask, well, you know, what is it then that is the root cause of ketogenesis and why is it that you need to restrict protein?
So the actual fundamental cause of ketogenesis is not directly related to insulin, and it’s not directly related to carbohydrate as a stimulator of insulin. The fundamental issue that’s going on is that acetyl groups – which are two-carbon units that can be derived from fat, protein or carbohydrate, are being oversupplied in the mitochondrion – known as the powerhouse of the cell – the acetyl groups are being oversupplied in the liver’s mitochondria and exceeding the supply of oxaloacetate, which is the compound that allows them to enter the TCA cycle.
So let’s back up from this and flesh it out a little bit by describing how this works in a mixed diet, and then moving into what’s shifting around during a ketogenic diet. So let’s just imagine first how we would burn carbohydrate for energy. So carbohydrate during glycolysis is split in half and slightly oxidized to produce two molecules of pyruvate. For the sake of simplicity, you can just think of pyruvate as half of a glucose molecule. Pyruvate then enters the mitochondrion and generates acetyl groups that are carried by CoA to the TCA cycle. Because protein, fat and carbohydrate can all generate these two carbon units known as acetyl groups, and because CoA is the carrier of those acetyl groups, acetyl-CoA is basically acting at the intersection of all catabolic reactions for energy. We could even – if we were to move beyond this, we could even say that acetyl-CoA is lying at the intersection of all catabolic and anabolic reactions, because the acetyl group is a simple – simple, simple, simple two-carbon unit, CoA is its carrier.
12:01 Overview of TCA Cycle and burning carbohydrate for energy.
So what’s happening then when we’re burning carbohydrate for energy is that the acetyl group needs to enter the TCA cycle, and the TCA cycle is where we rip those carbons apart, we release the carbons as carbon dioxide, exhale that in our breath out into the environment, and we harvest the energy from the chemical bonds as hydrogen ions and high-energy electrons that we then deliver to the electron transport chain in the process of oxidative phosphorylation, to use the energy contained therein to make ATP, the general energy currency of the cell. Now in order to get the acetyl group into that process, we need a compound called oxaloacetate or OAA. And it will join to the acetyl group to form citrate. Because it forms citrate in the first step, that’s why we call it the citric acid cycle. Citrate has three carboxyl groups, that’s why we call this the tricarboxylic acid cycle or the TCA cycle, and there was this dude named Krebs who discovered a lot of this and that’s why we also call this exact same thing the Krebs cycle. I’m – just out of personal preference, I’m going to call it the TCA cycle going forward.
So the question then becomes, where do we get the OAA? Well, we call this a cycle because as a general principle, it just sort of goes round and round and round about, and we kind of don’t need new OAA. And that’s because OAA joins to the acetyl group, the acetyl group provides two carbons, it becomes citrate but then it gets re-metabolized, that acetyl group is ripped apart into two carbon dioxide and then you just wind up with OAA again, and you just restart the cycle, and it goes on and on and on and on and on. Well, that’s the clean story. Then it starts to get a little dirty, because OAA is also used to produce certain amino acids. If you know your biochemistry, you’ll know it produces aspartate. But that specific detail isn’t that important, because throughout the TCA cycle there are intermediates between citrate and OAA – we could call all of these things TCA cycle intermediates, and many of those can leave the TCA cycle to make other amino acids, for example alpha ketoglutarate can leave the TCA cycle to make glutamate. And then the net result no matter what TCA cycle intermediate is leaving to make some amino acid – no matter which one it is, any of them are going to leave you with less OAA, and that means you’re going to have to get new OAA from somewhere.
14:48 How we burn fat on a mixed diet.
And usually on a mixed carbohydrate-inclusive diet, in most tissues, most of that new OAA is going to come from pyruvate. Remember we got pyruvate because we split glucose in half into two molecules of pyruvate. A lot of that pyruvate’s going to generate acetyl groups that enter the TCA cycle, but some of it will generate the OAA or the oxaloacetate that can allow those acetyl groups to enter the TCA cycle.
I will stop here and just point out once more that if this all sounds really confusing, then you might want to watch the YouTube video instead of listening to the podcast, where you can actually see the figures as I’m talking about this. And you can find that at chrismasterjohnphd.com/22.
Okay if you are following this, listen on.
15:44 The meaning of the phrase, “fat burns in the flame of carbohydrate.”
So there is an old adage in biochemistry: “fat burns in the flame of carbohydrate”, or “fat burns in a carbohydrate flame”. And what that means is that because it’s predominantly carbohydrate that is providing the OAA under typical conditions, when you break fat down into acetyl groups in beta-oxidation, those acetyl groups need OAA to enter the TCA cycle and that means that if the OAA isn’t there, carbohydrate is going to supply it. So we can say entering the TCA cycle is burning, and OAA is the flame that allows it to enter the TCA cycle or allows it to ignite. And so then “fat burns in the flame of carbohydrate” means that acetyl groups derived from fat during beta-oxidation can only enter the TCA cycle to be fully metabolized for energy if sufficient OAA can be derived from carbohydrate. Now the reason that they single out fat is because it’s – actually protein can generate oxaloacetate as well. So fat is the only thing that generates acetyl groups but can’t generate OAA. Now that also means that because amino acids can generate OAA – remember it’s a two-way street, even though OAA leaves the TCA cycle to make amino acids, by the same way, just going backwards, these amino acids can enter the TCA cycle to generate OAA. So if that’s the case, it would be more accurate to say that fat burns in the flame of OAA, because it is carbohydrate and protein that can provide the OAA.
17:58 Loss of lean muscle mass can occur if dietary carbohydrate and protein are too low; neither fat nor ketones can spare muscle mass from this effect.
Now, one thing that that means as a practical implication is that if you are burning overwhelmingly on fat and you are not getting very much protein or carbohydrate in the diet, that can predispose you to loss of lean muscle mass. Because you’re going to have to get that OAA from somewhere. And if you can’t get it from dietary carbohydrate, and you can’t get it from dietary protein, you’re going to take it out of your lean muscle. And if you try to conserve lean muscle, that means that you’re not going to be able to operate the TCA cycle, and that means that you’re not even going to be able to use ketones. So if you’re severely restricting glucose and protein to this level, and you see ketones rising really high in your blood or in your urine, that could indicate not only that you’re making ketones but that you can’t use those ketones either, because you don’t have OAA.
So, in any case, the key – the two key things as I pointed out in the last episode to preserve lean muscle mass during a caloric deficit are, number one, exercise providing an anabolic stimulus that in the context of enough protein and calories would cause you to gain muscle, that same anabolic stimulus is going to cause you to conserve muscle during a caloric deficit. And in the same way, that exercise program is going to help preserve lean muscle mass during ketogenesis. The second thing is protein intake. Consuming enough protein spares lean muscle mass in a caloric deficit, provides a hypertrophic response with a caloric excess when that anabolic stimulus from exercise is present, and in the context of a ketogenic diet, it helps preserve lean muscle mass. And so if you think about the study I described in the last episode – chrismasterjohnphd.com/21 – if you think about that episode, I noted that the preservation of lean mass was really impressive in that study, and it was in the context of, number one, CrossFit providing weight training that provided that anabolic stimulus, and number two, it was in the presence of a diet that did not restrict protein. Right, so even though in that paper they talk about not consuming too much protein because it’ll stimulate – excuse me, it’ll suppress ketogenesis, and even though protein restriction is required when you want to get a very extreme ketogenic response, in that study the protein was not restricted in the ketogenic diet, they were eating the same protein as the control group was. So those two things would explain why there was a very impressive preservation of lean mass. And I’m not saying a ketogenic diet will make you necessarily lose lean mass. But what I’m saying is that the loss of lean mass is going to be triggered in large part by depletion of OAA, and only carbohydrate and only protein – or, I should say, only the two of those together – only those can supply OAA. The fat is not going to be able to preserve that. So, sure, if you have ketones, you’re going to preserve lean mass versus not having ketones, because the ketones are providing calories and energy to your muscles so you have less of a hypo – less of a caloric deficit. But there’s no effect of ketones in supplying OAA, and so if OAA is limiting because you’re not consuming dietary protein or dietary carbohydrate, there’s nothing that fat and ketones can do to fully preserve your lean mass in those conditions.
Alright, moving on, now let’s talk about why this is so important in the initiation of ketogenesis. So let’s think about how fat is burned in – first in the presence of a mixed diet. If you have beta-oxidation of fatty acids, that generates acetyl groups that are carried by CoA to the TCA cycle. If oxaloacetate is there, it provides the flame that burns that fat, so to speak, or allows the acetyl groups to enter the TCA cycle.
22:20 Under carbohydrate restriction, oxaloacetate (OAA) is not repleted by carbohydrate and is used for gluconeogenesis, while more fatty acids reach the liver to make acetyl CoA.
Okay, now let’s switch gears and suppose that carbohydrate is severely restricted. What’s going to happen? First of all, carbohydrate is not going to be able to supply OAA. Second of all, OAA doesn’t just leave the TCA cycle to make amino acids, it also leaves the TCA cycle to make glucose in the process of gluconeogenesis. So under conditions of carbohydrate restriction, you have less of a supply of OAA, and you have depletion of OAA in order to produce new glucose. And even if you have protein, that protein is overwhelmingly being driven in entering the TCA cycle so that OAA can leave for the process of gluconeogenesis. So although having protein is going to mitigate this, carbohydrate restriction in general is leading to depletion of OAA. If you restrict carbohydrate and protein at the same time, the more you restrict both of those, the more OAA becomes depleted. That’s primarily happening in the liver because the liver is the main site of gluconeogenesis, so OAA is especially depleted in the liver during carbohydrate restriction. Now what is also happening in the liver is that adipose tissue or fatty acids coming in from the diet are supplying fatty acids to the liver, the liver’s taking them up, they’re entering the mitochondrion, they’re getting beta-oxidized to acetyl groups, and because the burden of beta-oxidizing those fatty acids is primarily falling on the liver, you have this massive oversupply of acetyl groups in the liver. When you combine this massive oversupply of acetyl groups with this massive under-supply of OAA and depletion of OAA, then you just have this recipe for massive accumulation of acetyl groups that cannot enter the TCA cycle, because the TCA cycle is operating less effectively and there are more acetyl groups.
24:38 The oversupply of acetyl groups in excess of OAA initiates ketogenesis.
What happens in direct response to this is ketogenesis. This is the event that causes ketogenesis: oversupply of acetyl groups to a depleted OAA pool where the acetyl groups cannot enter the TCA cycle. And in that case you have acetyl groups that have nothing else to do except condense with one another to make ketones. And actually, you know, I’m leaving out some enzymatic steps here. I will link in the show notes – chrismasterjohnphd.com/22 – I will link in the show notes to texts that supply more detail, but for our purposes those acetyl groups are going to combine together to make acetoacetate. And acetoacetate can then be further metabolized to beta-hydroxybutyrate or to acetone. Acetone is what is responsible for ketone breath, and so that – you know, for the guys, ketone breath smells like paint thinner, for the ladies ketone breath smells like nail polish remover. And that’s caused by acetone. Beta-hydroxybutyrate is very often measured in the blood as a marker of ketogenesis and in fact, when we talk about MCT oil I’ll be bringing beta-hydroxybutyrate back into the picture.
Okay so, to summarize, the key event initiating ketogenesis is not directly related to carbs and insulin, it is because acetyl groups are oversupplied relative to OAA in the TCA cycle. Now doesn’t mean that carbs and insulin aren’t important. First of all, carbohydrate, of course, is actually a source of OAA, so it’s important that way.
26:40 Insulin shifts fat to adipose tissue, but this doesn’t cause obesity.
But also the degree of carbohydrate in the diet is causing greater insulin signaling, and insulin signaling is going to suppress the release of free fatty acids from adipose tissue and shift triglycerides from the blood into adipose tissue. So it is partitioning fat towards adipose tissue, and that means that there are fewer free fatty acids that can reach the liver and allow the liver to make ketones out of them.
Now I want to take a quick break, I’ve mentioned this in previous podcasts but I want to point out that some people say this is why insulin causes obesity. But insulin is promoting storage of fat in adipose tissue to the extent that carbohydrate is present in the diet, and to the same extent it is promoting the burning of that carbohydrate for energy, so it is not causing you to in net decrease your energy expenditure; it is causing you to – in proportion to the carbohydrate in the diet – preferentially burn that carbohydrate for energy by shifting your metabolism towards carbohydrate and away from fat. Okay, I said that before but it deserves reiterating.
Let’s come back to ketogenesis.
28:00 The effect of insulin allows us to look at how medium-chain and long-chain fats differ.
So at this point one key thing to point out is how MCT oil is very different here. So MCT oil is derived from coconut. Coconut is 15% fatty acids that are 8 and 10 carbons. MCT oil is 100% fatty acids that are 8 and 10 carbons. A small majority of fatty acids in coconut oil is lauric acid; lauric acid is 12 carbons. It’s often thought of as a medium chain fat but for the purposes of energy metabolism, it behaves more like a long chain fat. And so I’m going to simplify this and say that coconut oil is 15% 8 and 10-carbon fatty acids, and I’m just going to talk about long chain fatty acids versus fatty acids that have 10 or fewer carbons. Now, long chain fats, which are most of the fat, you know, with the exception of 15% of coconut oil fatty acids and about 6% of butter fatty acids, most fats are going from the intestines through the lymph into the blood, they’re packaged into chylomicrons, and as the chylomicrons circulate in the blood, the extrahepatic – meaning the tissues that are not the liver – the extrahepatic tissue get first dibs, the chylomicron remnants eventually make their way to the liver. And so what that means is that as they circulate in the blood, there’s plenty of time for insulin to direct them – the triglycerides – into adipose tissue and prevent them from reaching the liver.
29:41 MCTs go straight to the liver and avoid effect of insulin in the blood.
Medium chain fats are very different. So 8 and 10-carbon fatty acids, or fatty acids that are even shorter, are going to go directly from the intestine into the liver via the portal vein. And because they go directly to the liver, they escape insulin’s partitioning of fat into adipose tissue. And what that means is that, even if you eat medium chain fats in the context of a carbohydrate-rich meal, they’re still going to the liver and escaping that effect of insulin.
30:26 Insulin suppresses the carnitine shuttle, but only long-chain fatty acids require it.
Now, once fatty acids are in the liver, most fatty acids – meeting long chain fatty acids, and this includes lauric acid – need what’s called the carnitine shuttle to enter the mitochondrion. And the carnitine shuttle is indirectly suppressed by insulin. And that means that insulin not only suppresses fatty acids being able to make their way to the liver, but insulin also suppresses burning those fatty acids for energy once they’re at the liver, because it indirectly prevents them from getting inside the mitochondrion, which is where beta-oxidation takes place. Now fatty acids that are 10 or fewer carbons make their way quite easily into the mitochondrion without the help of the carnitine shuttle. So here, again, insulin does not suppress the burning of those fatty acids for energy. So in some – if you consume 8 and 10-carbon fatty acids in the diet from coconut or MCT oil, or even shorter fatty acids from butter – from 6% of butter fatty acids – those fatty acids are going through the portal vein into the liver and they’re escaping the effects of insulin promoting storage of fat in adipose tissue. And then at the liver they’re escaping the effects of insulin suppressing entry of fatty acids into the mitochondrion. And so they just go straight from the intestines to the portal vein, into the liver, into the mitochondrion, and are burned for energy even in the presence of carbohydrate and insulin.
Now, let’s take this into a practical application as seen with MCT oil. There was a study, that I will link to in the show notes, where they gave people – this was 12 healthy male students of normal body weight, and this was a randomized crossover design, so all 12 students ate all of the meals, but there were four different breakfasts separated by one week provided in random order. And at every breakfast they had 300 grams of pasta and 100 grams of tomato sauce. The four breakfasts differed by whether they had a low-calorie fat substitute, or they had 40 grams of olive oil, 42 grams of lard, or 43 grams of MCT oil. And the weight is slightly adjusted because the caloric load is actually different in these different oils, so this was normalizing for calories. Now the one exception here is that the low-calorie fat substitute provided fewer calories at breakfast.
33:12 MCTs at breakfast suppress food intake at lunch.
Now what they did after this was they waited and said, okay, let’s allow them to just spontaneously ask for lunch, and let’s time them and see when they ask for lunch. And then at lunch, let’s measure what they eat. And so when they got MCT oil, they waited longer than any of the other meals to ask for lunch. And that means they were less hungry. And that’s true, you know, compared to the isocaloric diets of the other fats, and it’s true compared to the lower-calorie diet as well. Now, at lunch they then measured what they ate. And the MCT oil diet, fed MCT oil for breakfast, they ate fewer calories at lunch than any of the other groups, and that’s even though they waited longer to eat the lunch. Interestingly enough, this difference was much larger when compared to the diet that had lard. So they seemed to – although not all of these differences were statistically significant, but if you look at the data, the lard and the fat substitute had the highest caloric intake. I don’t know why that is in the case of lard; in the case of the fat substitute that’s not very surprising because they ate fewer calories at breakfast. The only difference that was statistically significant was this lower intake of calories at MCT oil compared to all the other meals. And if you want to be generous and compared it to olive oil breakfast where they ate the least at lunch, they ate 43 fewer calories at lunch when they had MCT oil for breakfast than when they had olive oil for breakfast.
35:14 Pasta topped in tomato sauce and MCT oil increases beta-hydroxybutyrate.
Now, why might that be? Well, I think it’s – actually it’s pretty straightforward, in, when you eat pasta plus MCT oil, you are getting carbohydrate but you are also able to burn the fat for energy and make ketones. And that’s clearly shown by the measurement of beta-hydroxybutyrate in this study. So before the breakfast, everyone was kind of floating around 0.05 mmol per liter or less, and so you have this low non-zero level of ketones in your blood when you wake up in the morning, so just an overnight fast is ketogenic, but these amounts are very low. And they eat the diet and pretty much everyone’s ketone levels sort of bottom out to this, you know, maybe not zero but really close to zero level, and then very gently start to rise after a couple of hours as they gradually ease back towards the fasting state. Now the MCT oil radically stands out from all these other breakfasts, because their levels rise from less than 0.05 to 0.3. So the beta-hydroxybutyrate is skyrocketing up sixfold in the MCT oil breakfast, and it’s bottoming out in every other meal. So even though pasta and tomato sauce was the base of every meal, it was doing opposite things depending on MCT oil. With the other fats it’s suppressing ketogenesis because the carbs and insulin are suppressing not only burning the fat in the meal for energy, but they’re also suppressing burning fat – fatty acids from stored adipose tissue for energy. You know, and why shouldn’t they? You just ate a meal, so of course you’re going to burn the meal for energy instead of your adipose tissue. But in MCT oil, yes the pasta is suppressing burning adipose tissue for energy because you just ate a meal, you just ate a caloric load, and yes, you are burning the pasta for energy, but because MCT oil is escaping the effects of insulin in the blood by going straight to the liver, and because it’s escaping the effects of insulin on the carnitine shuttle because it doesn’t need that shuttle, it – on top of the carbohydrate – gets burned for energy in the liver. So you burn glucose and ketones at the same time, and so no wonder you wait longer to eat lunch, and no wonder you eat less at lunch, because your brain is getting glucose and ketones. And, you know, I’m it sort of imputing my working paradigm of how this works here, but the way that I’m thinking about this is, the brain is just sort of like bathing in glucose and ketones and is like, you know, it’s like, imagine if you – sort of like someone gave you a million dollars, and you’re like, okay, I’ll budget like whatever for sneakers, and then I’ll take the rest and then just sort of, you know, just like take a bath in it, or, you know, have all my friends over and we’ll, like throw it in the air and like, roll up some of those Benjamins and smoke them, and whatever, you know, because, you know it’s like during an economic bubble or whatever and, like, the CEOs are like, yo, let’s have like this big party and just like burn this cash and whatever, and then, you know, eventually the bubble pops and whatever. But I’m getting off track. So I think what the brain here is doing is getting all this glucose and it’s getting all these ketones and it’s like, yo, tons of energy around, like, who needs to eat, right? And so for that reason the brain is coordinating this response that says, you know, plenty of energy available, we don’t need to eat as quickly and when we do eat, we don’t need to eat as much.
39:05 Two ways of getting ketones: selective deprivation vs. abundance.
Now, one thing to note here is that, take a moment to compare this way of getting ketones versus restricting carbohydrate and protein. When you restrict carbohydrate to get ketones, you are engaging in selective deprivation. It’s not absolute deprivation because you do have calories, but you’re selectively depriving yourself of the carbohydrate. And in proportion to the degree to which you do so, you get ketones instead. And so people can debate whether you want to run on glucose or ketones, but when you are restricting carbohydrate to get the ketones, you are acknowledging that the debate is all about should you run on glucose or ketones. When you supply MCT oil, what you’re doing is running on glucose and ketones. So instead of selective deprivation, this is a model based on greater abundance. And I think that becomes really relevant when you start asking the question, you know, why am I trying to get ketones? If the goal is because ketones are providing a benefit, you know, maybe they’re enhancing your cognitive performance or they’re enhancing certain types of athletic performance, and remember in the last episode I described why I think certain types of athletic performance can be hurt by a ketogenic diet. But, you know, maybe you’re getting some kind of performance benefit from being able to use those ketones as fuel. But maybe that’s coming at the cost of some other things, for example, maybe it’s hurting certain types of athletic performance that depend on anaerobic glycolysis. Maybe it is hurting your antioxidant status, because insulin plays an important role in supporting the antioxidant defense system. Maybe it is hurting your hormonal status, because insulin plays an important role in supporting thyroid hormone and sex hormones and in minimizing the degree to which you need to rely as much on cortisol. So if you are experiencing this trade-off, then maybe what you want to ask yourself is, can I get the same level of ketones by adding abundance here? And then, you know, of course it’s not just MCT oil; you could also get a weaker effect from coconut oil. And if you eat enough coconut, you could, you know, by eating enough – if you bring the 15% of coconut oil fatty acids up to the amount of MCT oil that you would otherwise supply, you’re going to have to eat six times more coconut fat to get that effect, but you can do that. Then of course, adding exogenous ketones is also another way, in the context of a mixed diet that is another way of adding more abundance.
42:12 If you are trying to get ketones, but having negative effects of carbohydrate restriction, you can add MCTs (or exogenous ketones) to get the ketones without carbohydrate restriction.
So if you can get the same level of ketones to provide that same benefit, but also get carbohydrate and also get insulin, then it may make more sense to opt for MCTs to get ketones, instead of restricting carbohydrate to get ketones. Now that is the same rationale of moving from the classical ketogenic diet to the MCT oil-modified ketogenic diet for treatment of refractory childhood epilepsy, for example. And in that case you’re trying to get ketones into the brain, presumably because the brain has some defect in using glucose. But you want to also get some of the benefits of insulin-stimulating foods. For example, if you can get greater diversity, if you can make the diet more palatable and easier to sustain in some ways, if you can get more vegetables that supply carbohydrate but also supply important micronutrients and polyphenols and other things of health value, then you can – then you can get that benefit by adding MCTs and relying less on the strategy of restricting carbohydrate and protein. I would add to that that, because I also think that insulin is important in supporting the antioxidant defense system and thyroid hormones and sex hormones, that that would also enable you to reap those benefits of insulin as well.
43:45 MCT oil-topped pasta is more ketogenic than a 10% carb diet, but much less ketogenic than the diets used to treat refractory epilepsy.
Now I want to put this in context by just comparing this amount of ketones to what you would get in some of these other contexts. So I will post a study in the show notes where they put people on a 10% carbohydrate diet, 60% fat diet, 30% protein diet. They called that a very low carbohydrate diet – I would agree with that. And that caused ketone levels to rise, but they rose to about 0.2. And in the case of MCT oil here, we’re getting 0.3. So adding MCT oil to pasta is more effective at ketogenesis than restricting carbohydrates to 10% of the diet. By contrast, if you look at the classical ketogenic diet in treating epilepsy, you’re going to see beta-hydroxybutyrate levels rising to 4 millimoles per liter which is, you know, 6 times – or, excuse me, it is 12 times what we’re looking at here in MCT oil. And if you look at the MCT oil-modified ketogenic diet used in epilepsy, the beta-hydroxybutyrate levels are a little bit lower, maybe 2.7 or 3 in that the study that I’m linking to. And of course I’m sure there are variable results with different numbers in different studies, but my point is that if you’re trying to get the extreme level of ketogenesis that is needed to treat epilepsy, you’re not going to get that with MCT oil and pasta. But if you’re trying to achieve the level of ketones that you get with a pretty low carbohydrate diet – 10% carbs, 30% protein, remainder fat, you can get even better beta-hydroxybutyrate production by eating pasta plus MCT oil. So this effect of MCT oil is not negligible, it’s very relevant and competitive to diets that are modestly ketogenic with very low carbohydrate levels, but that are not ketogenic enough to actually, like, treat epilepsy with.
46:00 Exercise is ketogenic.
Now there are other things that are independently ketogenic, most notably exercise. So exercise, independent of carbohydrate intake, is creating a caloric deficit and it’s also providing a hormonal response that mobilizes fatty acids from adipose tissue. And exercise will make an independent contribution to ketogenesis.
46:22 As a gym rat with a fondness for coconut eating the Warrior Diet, my pee turned keto-stix purple even after a three-course carbohydrate-inclusive meal followed by a frozen pizza and a pint of ice cream.
And with that I’ll tell you a little story. About 10 years ago or so, I was on the Warrior Diet and I was also working out very intensely with a combination of powerlifting and bodybuilding techniques. And I was – when I was very lean I was 20 pounds more than I weigh now. And there was a point at which I was not at my leanest and I was probably 30 pounds more than I weigh now, but I was very muscular. So, you know, overwhelmingly this is sort of a testament to this extreme level of exercise that I was doing. I was probably spending an hour 3, 4, 5 times a week in the gym, spending an hour weightlifting with a 20 minute elliptical as is a warm-up. And I was on the Warrior Diet, so I also had fasting contributing to ketogenesis, but then in this four-hour window I would eat a three-course meal that was focused on nutrient density, then I would eat a frozen pizza that was like my post-game and then – or like my pre-dessert or whatever you want to call it – and then I would eat, like, a pint of ice cream – like, Ben & Jerry’s ice cream. And so – and I was not trying to restrict carbs. And then at the end of all of this, just for fun I would measure my urinary ketones. And I don’t know how reliable the keto strips are, but my keto strips were turning purple, so like, my urine was full of ketones according to these strips. And I was eating anything but a low-carbohydrate diet. So, you know, I think – when you think of just the dietary pattern with intermittent fasting and then on top of this, this extreme level of exercise, that also is causing a lot of free fatty acid flux to the liver that’s independently contributing to ketogenesis.
Anyway, to sum this all up, yes insulin and carbs play a major role here. But insulin is not directly controlling ketogenesis. Ketogenesis is about fat supplying acetyl groups that over-surpass the ability of the TCA cycle to accommodate them because the oxaloacetate or OAA pool is not being repleted by carbohydrate, and is being repleted even less if protein is restricted, and OAA and its precursors are leaving the TCA cycle to make new glucose. And under those conditions, you have lots of acetyl groups, little OAA, and that right there is the event that triggers ketogenesis. And that means that you can separate ketogenesis from carbs and insulin to a certain degree by, for example, providing 8 and 10-carbon fatty acids in the diet. Because even in the presence of carbs and insulin, they will go to the liver and oversupply acetyl groups. And even if you have normal amounts of OAA there, the oversupply of acetyl groups is still generating ketones even in the presence of 100 grams of tomato sauce on top of 300 grams of pasta for breakfast. And so what that means, I think, is if you don’t require the extreme level of ketogenesis used to treat neurological conditions, then ask the question: is my more moderate amount of ketogenesis that I’m getting from say a 10% carbohydrate diet, is that something that I need to restrict carbohydrate for, or am I doing it to get the ketones? If you’re doing it to get the ketones rather than to restrict the carbohydrates, then ask, you know, is there any downsides that I’m seeing, such as certain types of athletic performance or certain hormonal changes or antioxidant status declining that result from the carbohydrate restriction? And if that is the case, then think about whether you might want to readjust the approach to get the ketones while also getting the carbohydrate and insulin in the manners described in this podcast. If you’re not on a ketogenic diet – and I’m not on one – then if you made it this far, then that means that you really love geeking out on the biochemistry. Regardless, I hope you got some value of listening to this – if you’re still listening, obviously you did. Remember that you can get the show notes at chrismasterjohnphd.com/22, you can always get the show notes to all of the podcasts at chrismasterjohnphd.com/podcast. So thank you very much for listening, I really appreciate having you in my audience, and with that I will leave this to see you once again in episode 23.