← The Metabolic Classroom with Dr. Ben Bikman
The Metabolic Classroom with Dr. Ben Bikman
Why Women Enter Ketosis Faster Than Men - What the Science Reveals
00:26:55
More Knowledge, Better Health
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Ben Bickman
Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Hey everyone, before we get started today, I want to tell you about something brand new that our team has created called Dr. Bickman's Digital Mind. It's an AI version of me that can help answer your questions about the science behind metabolic Health. It's been trained using nearly 3 million of my own words from my lectures, published research, my books, interviews and even unpublished private Q and A sessions. You can chat with it or even talk with it, using your voice to try it out. You'll get five complimentary responses and five minutes of voice conversation time just to see how it works. After that, you can decide whether or not you'd like to have unlimited access by becoming an insider. You can find it right now on my website, and there's a direct link below at the top of the show. Notes welcome to the Metabolic Classroom. I'm Professor Benjamin Bickman, a biomedical scientist and professor of cell biology. Today we're unpacking a very interesting topic, the differences in ketogenesis between the sexes. In other words, how men and differ in the way they mobilize fat, produce ketones, and even respond to low carbohydrate or ketogenic diets. As we start, we will begin at the source, namely the fat cell, and then we're going to trace how nutrient energy moves from stored triglycerides to circulating fatty acids and then to ketones. Then we'll explore where the paths of men and women begin to diverge from hormonal regulation and enzyme activity to differences in how we store fat, the unique metabolic consequences of that, and even the unique metabolic situation or milieu of interesting physiological states like lactation in women. By the end, you'll see why one size fits all. Metabolism rarely does, in fact, fit all, and why sex differences play a larger role in metabolism than most people realize. Let's start, as I mentioned, with the foundation being the fat cell. Every fat cell, or adipocyte, is like a tiny savings account holding onto triglycerides as a compact form of stored energy. When we've eaten a carbohydrate rich meal and insulin levels are high, the body happily deposits energy into those accounts through a process called lipogenesis. But when energy becomes scarce, like between meals, during a fasting window, or even just when carbohydrates are restricted and insulin is allowed to drop those same adip, lipocytes will switch roles. They start withdrawing energy through lipolysis, the opposite of lipogenesis, now breaking triglycerides down into its component parts, namely free fatty acids and that glycerol backbone. The hormonal controls here are beautifully balanced. Insulin is the break. It slows lipolysis anytime it's elevated. On the other hand, counter hormones like glucagon, epinephrine, and norepinephrine act as the accelerated accelerators kicking fat breakdown into gear when the body needs fuel. Once released into the bloodstream, the free fatty acids don't just aimlessly drift. They're carried to tissues like skeletal muscle, the heart, and most especially the liver, which serves as the metabolic crossroads. I've long referred to the liver as the, the tissue at the nexus of all nutrient metabolism. But once again, insulin matters here. If insulin is high and blood free fatty acid levels are high, not only does that reflect an insulin resistant, an insulin resistance at the adipocyte at the fat cell, but those free fatty acids are then going to simply be stored in the tissues that I mentioned. It's high insulin plus high free fatty acids that results in, say, the storage of fat in the liver or in the pancreas, or in the heart or in the skeletal muscle. But when insulin is low, the tissues cannot store fat. It becomes impossible. Thus they have to burn it. And inside the liver, fatty acids, as they're being burned for energy, rather than being now repackaged into triglycerides for storage or export, they are now transformed into ketones through the process of ketogenesis. That transformation happens inside the mitochondria. And, and remember, it only happens when insulin levels are low. Fatty acids are broken down. So the fatty acid itself is a product of the breakdown of the triglyceride. But then when you break down the fatty acid, it is broken down through a process called beta oxidation into its component parts or its building building blocks called acetyl coa. When acetyl COA starts to accumulate faster than the citrate cycle can handle it, and I'm getting nitty gritty with some biochemistry, and that's basically, the citrate cycle is replete, it's full, and now you have an excess of acetyl CoA. Well, now the liver looks at that excess acetyl COA and says, well, I know what to do with you. And it will shunt that into ketogenesis. That's where you have enzymes like HMG CoA synthase, HMG CoA lyase, which will turn the acetyl COA molecules into acetoacetate, which then plays into beta hydroxybutyrate, the main circulating ketone, bhb. These ketones are capable of fueling the brain, heart, muscles, the tissues I mentioned earlier, and indeed every other single cell of the body that has mitochondria. This is a fairly elegant circuit where we have fat breakdown in the adipocyte. It's transported through the bloodstream as free fatty acids. It undergoes oxidation or breakdown in the liver, and that gets shunted, those pieces get shunted into ketogenesis. It's one of biology's more sophisticated metabolic adaptation systems. But as we'll see, it doesn't operate identically in all bodies. Sex matters when it comes to releasing stored fat into circulation. So that's at the beginning of this, of these steps that I outlined. Women and men operate on slightly different settings. Numerous studies show that during fasting or endurance exercise, women consistently have higher circulating levels of free fatty acids on the and this is not a small amount. It's on the order of about 20 to up to 40%. So in some instances, you have a gal who has can have Almost up to 50% higher levels of free fatty acids than her male counterparts. In fact, this is so known and identifiable that in clinical settings, women will have a different range of normal for fasted levels of free fatty acids because they're going to be a lot higher. That's just a normal sex difference. So it might not sound dramatic, but it does have significant downstream effects on what the body does and how it handles energy. Part of the difference between the sexes comes down to where the fat is stored. Women typically carry more subcutaneous fat, particularly around the hips and thighs. And while men will tend to store more visceral fat. So that's the fat that's deeper around the internal organs. The subcutaneous depots, though often viewed as maybe being stubborn, where the gal may be complaining about her fat, they're very metabolically active and even very metabolically beneficial. For reasons that I won't really elaborate too much. Those are fat depots that are designed to store fat and thus store fat in a much healthier way. This is again at the heart of why a female can both be fatter than her male counterpart and healthier. Because remember, it's not fat mass that matters most, it's how we store the fat. So with these differences in mind, men and women will respond differently to different hormonal cues because these fat depots will respond differently to hormonal cues. So for example, the catecholamines that I mentioned earlier, epinephrine and norepinephrine, they have a powerful lipolytic stimulus on the fat tissue that's subcutaneous. So hormones sit squarely at the center of these patterns. Estrogen, and I'm just going to say estrogen for the sake of conversation, but please know that what I really mean is estradiol, the primary estrogen, it shapes not only not only determines both the location of the fat storage, but also the behavior of that fat. Estrogen promotes fat storage in subcutaneous regions, which is likely a design in order to help the woman store not only store fat in a healthy way, but also have it not be in the way. Right. Imagine the problem if a gal had a lot of visceral adipose tissue, the tissue, the fat tissue deep within her organs, and she's also trying to grow a little baby there. Well, those volumes, those masses are going to come at odds with each other. So it's a very intelligent system to have the female store more fat out of the way. So estrogen helps with that, but at the same time, estrogen enhances the enzymes and the signaling pathways that stimulate fat breakdown when energy is needed. So we have this. This dual effect can seem a little paradoxical, encouraging both lipogenesis and lipolysis. But perhaps one way to look at this is to understand it as a hormone that's promoting fat turnover. Estradiol can increase the flux of the energy in and out of the adipose, allowing this fairly dynamic storage, rather than a more static or lethargic system of storage like you might see more in a male. So when conditions call for it, like fasting or exercise, or as we'll get to even lactation, the higher metabolic throughput of the fat tissue allows women to mobilize and then burn that fat much more rapidly. Now, testosterone is relevant anytime we talk about metabolism, but it does play a different role. It very much promotes lean mass, so muscle mass, bone mass. As a, as an aside, I don't like the term lean muscle mass. That's very redundant. Just say lean mass, which encompasses like things like muscle and bone, or just say muscle mass. So it does promote muscle mass. But the differences in metabolism, largely driven by estrogen's promotion of fat burning. In women, it results in men relying more on carbohydrate oxidation for quick energy. So that greater muscle mass just means a hungry muscle and easily or more readily relying on glucose. Not to say that muscles can't rely on fat, they do so very readily. But in men, you could say men tend to be a little more glycolytic. Women tend to be a little more lipolytic. But the, the metabolic bias means that during fasting or exercise, men may be a little more glycogen burning, glucose burning, and less on lipid, which is the fuel, that or fat, the fuel that is more determining the metabolism in the female. The result is that men will often display lower levels of circulating free fatty acids, and as we'll get to even take longer to shift into ketone production. But with all of this in mind, the patterns do explain a consistent Finding across the literature, during fasting, women generally reach measurable ketosis sooner than men. And the higher availability of circulating fatty acids gives the liver more substrate to work with. So while both sexes certainly rely on the same fundamental metabolic machinery for both lipolysis and, and oxidation of those fats, the dials or the engine is idling at slightly. It's tuned a bit differently. And in fact, let's lean into that more. The story is a little more nuanced when we move from just fasting, you know, acute fasting, into longer ketogenic feeding scenarios. But let's, let's look at the early phase in a little more detail when men and women fast, which is I, I mentioned fasting, not that this was intended to be a lesson on fasting, but rather, of course, ketogenesis. But fasting is the fastest way to get into ketogenesis, making your own ketones. When men and women fast for the same length of time, women generally show higher circulating ketones at the same time points. At any given time point. And several studies now really show this plainly. During fasting, women exhibit higher levels of BHB and higher levels of free fatty acids than men, which certainly plays into the biochemistry that I outlined earlier where you see this faster ramp into ketosis because more fatty acid substrate is delivered to the liver for ketogenesis. A classic tracer study helps explain why. So a tracer study is one that has infused in this case a fat and it has a little tag on it, a little radiate radioactive tag that can be traced or followed through the body. In healthy young adults that were studied after an overnight fast, women partitioned more circulating fatty acids toward ketone production, whereas men diverted more toward hepatic or liver re esterification. So taking those fatty acids and turning them into triglycerides, whether the liver was storing it or then releasing it as vldl, which is the first triglyceride rich lipoprotein that comes from the liver. So functionally this means the same fatty acid traffic is really routed differently. More ends up as ketones in women, more is recycled back into stored fats in men. This partitioning difference is a direct human isotope tracer demonstration. So it's not just an inference, it's not an animal. Study supporting this head to head human fasting work shows women running with higher free fatty acids and lower glucose than men after a standardized 38 hour fast. The paper that I reference in the show notes the focus was not ketones per se, but the pattern more substrate like free fatty acids on board in women at the same fasting duration does align with why women tend to hit measurable ketosis much sooner. And as I noted, this really is largely hormone driven. Estrogen is just stimulating more fat turnover. Now once we leave the acute fast and move into chronic ketogenic diets, the picture it does actually grow a little more complicated. But that might just be a result of the difference between animals and humans, because in pre clinical or animal models there are studies to show that female animals on a mice don't respond the same way to a ketogenic diet. In fact, one 2024 paper found that the female mice actually stored more fat at the end of the ketogenic diet with with reduced glucose tolerance. But the male compared to the males, the males had a more typical response. They lost weight and were fine. So it kind of begs the question, do men Ultimately.
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Ben Bickman
Respond better to a ketogenic diet well, the animal literature does trend that way, but the human data are mixed. For example, a 2025 review concluded that men do frequently lose more weight under ketogenic diet conditions. That's not overly surprising. Men tend there's just more mass to lose. And we have the hormones, the sex hormones that just generally push towards greater fat loss. Whereas women's female sex hormones, which of course both sexes have both sets of hormones but relatively higher in females, it does promote an overall greater fat storage, especially a hormone like progesterone. So you're not going to have a uniform response. And in fact that might be at the heart of some of the conflict where one of the studies that I've cited here actually highlights that some of the differences between men and women might just be a degree of adherence that sometimes you might have a bias for one, sex adhering a little better menstrual status influences this. The amount of protein that these free living subjects are eating also influences this. But all of it just kind of plays into muddying the water a little bit, which is always a problem with human studies. But we want human data. We just have to accept that that's going to come with some caveats. Now how might we sum it all up? So I think a fair synthesis of all the available data would look something like this. In short term fasting women will rise into ketosis earlier and higher than men at any given time point. This is going to be driven by greater free fatty acid supply and the liver partitioning those molecules, the substrates towards ketogenesis. With sustained ketogenic diet, sex hormones may help determine some degree of a steady state. Males often display more favorable changes in fat storage in, in rodent models, whereas the females will accumulate a little more of that in humans. The that steady state picture is a little more mixed. Men may lose more weight on a ketogenic diet, but the ketone levels themselves will really vary by protocol depending on what else is happening. With several studies supporting the evidence that women will have higher levels of BHB now seen through an evolutionary lens. And I'm always loathe to invoke an evolutionary perspective just because I feel compelled to remind people that all of evolution is theoretical. That doesn't mean it doesn't have value. But I don't like people speaking in absolute terms when it comes to this, because there are none. We simply do not know how we came to be what we are and and why. And I'm attempting to kind of explore the why question, which a biomedical scientist is never suited for. So we are stepping into the realm of pure speculation and even philosophy. But let's step into that because it, it is a fun place to explore. But when we wonder why we see differences between the two sexes, it could be, it could make sense. Women's physiology might be one or such to emphasize greater metabolic flexibility, shifting into fuels as well as reliability. So for example, getting ketones up swiftly when food is scarce. And even in, in instances of, of fertility, invoking evolution. After all, evolution is seen through the lens of trying to get a competitive advantage for reproduction, at least in part. But then you have pregnancy and lactation, which I'm going to come to More in a moment. Those demands are very high. And then we want to perhaps the female in the female form, in the female body avoid unnecessarily deep continuous ketosis when it could compromise things, it might make health worse. Men's physiological trends perhaps push more towards sustained higher oxidation once adapted with greater lean mass and different hormonal cues supporting longer stints at more of a fat burning. Now neither pattern would be better. They're just simply going to be optimized for different biological properties. Okay, so a couple times so far I've mentioned lactation. I need to mention lactation in this context of the differences in keto, ketogenesis and ketones between the sexes. Because lactation offers such a vivid example of female metabolic adaptability. Producing breast milk is hard work. It requires about an extra 500 calories per day and much of that energy is coming from her, from mom's fat tissue. So it's no surprise that lipolysis, lipolysis accelerates which is going to be releasing more fatty acids into her blood. With more fatty acids comes the greater potential for the liver to convert it into ketones. And so those ketones are then actually can be enriched into mother's milk, acting as an energy source for the infant. If we are going to revisit any evolutionary perspective here, I invite everyone to read the book by Dr. Stephen Cunain called Survival of the Fattest, where his theory of human evolution is that we needed ketones to enable to facilitate rapid and significant brain development because the brain, including that in infants, loves ketones. In fact, he posits that the primary reason why humans are the only land based mammal born obese, because we are, is because the human infant can burn that fat so quickly and get into a very deep state of ketosis, which in turn fuels the brain. And with that perspective in mind, it's. It also sheds light on why it is that a prematurely born baby who is going to be much leaner, much less fat tissue on the body will have a much higher risk of developmental delays like things like reading disorders, et cetera, where if baby doesn't have enough fat to make enough ketones, baby's brain might not quite develop. Well. All of that is encapsulated in Dr. Cunane's work. So I just refer you to his findings. Now back to this topic. With lactation, if carbohydrate intake drops low, you could say the adaptive metabolic response goes a little too far. This is real, it's not common but, but it does happen. There are published case Studies of postpartum women who follow ketogenic diets but are also lactating to breastfeed their baby, and they develop something called lactation ketoacidosis, a state in which the ketone production outpaces the clearance, which leads to a genuine metabolic acidosis. It is incredibly uncommon for a person to get to ketoacidosis if they are not a type 1 diabetic. And even then, it's because of underdosing insulin. So in a person who makes insulin, it's very uncommon. But lactation is an uncommon metabolic state. So even though this situation of lactation ketoacidosis is uncommon, it is well documented. So the combination of very high fat mobilization and these hormonal shifts, including prolactin and lower levels of estrogen, it creates a perfect storm for producing an incredible amount of ketones very quickly. So the takeaway here, I wouldn't want it to be that ketosis is unsafe, but that she does need to be more mindful in that she needs to be more mindful of her carbohydrate consumption and indeed not be quite so strict during lactation.
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Mrs. Claus's Younger Sister
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Elf Drew Ski
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Ben Bickman
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Elf Drew Ski
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Mrs. Claus's Younger Sister
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- [29:03]
Ben Bickman
So there what are the implications here as we near the end Understanding I think I'd submit that understanding the biological differences between the sexes when it comes to metabolism can help shed light on why men and women do respond differently to ketogenic diets. For men, the classic ketogenic diet, very low in carbs and higher in fat, can produce very strong and sustained ketosis with significant fat loss, even if it does take him slightly longer to get into ketosis than his female counterpart. For women, it's a little more nuanced because the female metabolism already favors fat oxidation. Pushing deep into ketosis can sometimes lead to things perhaps getting complicated, and she needs to be very mindful of her menstrual cycles or if she's on hormone replacement therapy. Of course that's going to help with menopause, but menopause itself adds a complicating variable here, but nevertheless, adding small amounts of carbohydrates around exercise or at certain points in the menstrual cycle, like during the luteal phase, that might be warranted. But the point here, if there's one grand point, is that there are differences between the sexes. Not that one sex has a better than the other, but each is tuned for different priorities. Women's metabolism, you could say, favors flexibility and more steady, albeit shifting energy delivery, while men's leans more toward intensity and maybe fuel efficiency. It's whatever I can get in the moment when diet approaches can embrace these differences. I think that it helps a person start to leverage some of these metabolic tools for greater, if you will, systemic harmony rather than any sort of adaptive response. So men and women differ not just in how they store fat or where they store fat, but even how they access it and burn it. The distinctions really come down to hormones and how those hormones influence enzymes involved in the breakdown of fats and in the synthesis of ketones. When we can recognize these differences, I think it helps us move past a one size fits all, cookie cutter nutrition approach and rather gets us to strategies that can respect individual physiology. Class dismissed. Until next time. More knowledge, Better health.
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Mrs. Claus's Younger Sister
Guys, thanks for helping me carry my Christmas tree, Zoe.
- [32:29]
Elf Drew Ski
This thing weighs a ton.
- [32:30]
Ben Bickman
Drew Ski, lift with your legs, man. Santa. Santa, did you get my letter?
- [32:34]
Elf Drew Ski
He's talking to you, Bridget.
- [32:35]
Ben Bickman
I'm not.
- [32:36]
Mrs. Claus's Younger Sister
Of course he did.
- [32:37]
Ben Bickman
Right, Santa, you know my elf, Drew Ski here. He handles the nice list.
- [32:41]
Elf Drew Ski
And elf, I'm six three. What everyone wants is iPhone 17 and at T Mobile. You can get it on them. That center stage front camera is amazing for group selfies. Right, Mrs. Claus?
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Mrs. Claus's Younger Sister
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Ben Bickman
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Mrs. Claus's Younger Sister
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