Four Days to Metabolic Flexibility: What a Danish Crossover Trial Reveals About Carbs, Fat, and Fatty Liver

A 35% drop in liver fat in under a week sounds impossible—until you see how a simple macro shift can redirect your metabolism. We dive into a Danish crossover study where calories stayed equal, protein held steady, and the only real change was carbohydrates versus fat. The result: rapid reductions in hepatic fat, lower triglycerides, improved insulin sensitivity, and clear signs of metabolic flexibility, all in four to five days. We unpack what that means for everyday eating, how to use CGM feedback to reduce glucose spikes, and why outcomes like organ fat and fat oxidation should trump a single lipid reading taken out of context.

From there, we widen the lens. Fatty liver—now recognized as a hallmark of metabolic dysfunction—is staggeringly common, yet highly responsive to nutrition quality and distribution. We break down why modest carb moderation paired with quality fats and robust protein can stabilize energy, support endogenous GLP-1 signaling, and protect lean mass. We also confront a common confusion: “high fat” isn’t a license for ultra-processed oils or low-fiber meals. When fats come from olive oil, avocado, nuts, eggs, and fish—and plants supply fiber and polyphenols—the microbiome, mitochondria, and glycemic control can all improve together.

We close with practical implications for anyone using GLP-1 medications. Pharmacology can provide short-term traction, but it doesn’t guarantee nourishment. A protein-forward, lower-glycemic template plus resistance training helps preserve muscle, sustain satiety, and potentially reduce medication reliance over time. If you’re ready to swap shaky biomarkers for meaningful outcomes—and to see changes fast—this conversation offers a clear, evidence-backed roadmap. If it resonates, follow the show, share with a friend, and leave a quick review to help more listeners find The Health Edge.

www.thehealthedgepodcast.com

Transcript

Framing the Study and Why It Matters

SPEAKER_00 0:00

Welcome to The Health Edge, translating the science of self-care. I am Mark Pettis, and I'm with my friend colleague, John Bagnulo. John, good morning, my friend.

SPEAKER_01 0:09

Good morning, Mark. It's great to see you, buddy.

SPEAKER_00 0:12

Great to see you as well in this beautiful fall season that we're in right now. And uh uh and good to just be connecting, John, and sharing the science that we love. And um our podcast, uh, as we sort of resurrect um some of what we've been doing from a recent hiatus, uh, often focus around a paper, something that gets our attention. And uh a research paper that we've been looking at is one that uh I think is really aligned with many of the principles that we've discussed in the past, John, around nutrition that focuses more on moderation of carbohydrate and liberalization of healthy sources of fat and protein. Uh and in this particular study that we're we're going to look at, this was not designed to be a ketogenic trial. This isn't very low carbohydrate, ketogenic. This was just moderation, uh, low carbohydrate. And a small number of men, these were um men, adult men who um, none of whom had diabetes, but many of whom had uh obesity and um fatty liver, which we've talked about, uh fatty liver being a uh really important um attribute of metabolic syndrome and and disrupted metabolic health and insulin resistance. And uh and so this study just took uh uh a small group of men and uh uh randomized them. Uh one one group got uh very low carb, high fat. The other group got what we we would consider sort of the standard American diet. They got um much more carbohydrate, about 50-55 percent, typical of the standard American diet, with lower fat and moderate protein. And calorically they were the same, so it's not like one diet had fewer calories than the other. And in just a matter of days, right, four or five days, as we'll

Design: Low-Carb vs High-Carb Crossover

SPEAKER_00 2:20

show, John, they showed very striking differences. So let me just I'm gonna share my screen and uh just pull up this paper. And this was um uh published recently. This is uh a group from Denmark and uh the this is from the American Journal of Clinical Nutrition and looking at the impact of short-term, again, this was just a matter of days, uh caloric, meaning equal caloric intake of both a low and a high carbohydrate diet on these men that had liver fat, a liver triacylglycerol, it's fatty liver. This is accumulation of fat in the liver that is associated with insulin resistance and obesity. Uh and that and as we've talked about often, John, this is um epidemic. Uh you know, this is a huge, huge issue. Some might say that it's public health enemy uh number one. And um and just very briefly, uh just so people have a sense of how this study was designed, John. Uh you know, they were all on a uh sort of a standard American diet. Um, and then they get uh baseline testing, and and you and I will talk about the testing that was done here. And then they're put on either a high carbohydrate, low-fat diet. This has been really the standard of nutritional recommendation for uh, to me, John, it feels like forever, um at least for the last couple generations, uh, or they got a low-carb, high-fat diet, again, equal amount of calories. And then they were retested. And then the beauty of this uh uh with a with a small study is they then sort of wash out uh all of the participants uh go back on sort of a standard American diet, and then they repeat the study uh where the prior group that had high carb then goes to the low carb side. So uh this is a um a study where uh you get crossover and you know, so very powerful and

Rapid Results: Liver Fat Down 35%

SPEAKER_00 4:40

important data that emerges from that. And then I'll just jump to the conclusions here, John, and then I'll pause and let you weigh in. Um the low-carb diet reduced the fat content in the liver by 35 percent. These are really uh pronounced changes uh again over four to five days, uh whereas there was no change in the high carbohydrate diet. And again, they saw this with the crossover. So those that benefited uh when they then were switched to the high carb, low fat uh lost those changes. Uh and those that had no change initially on the high carb, low fat uh had significant changes when they were introduced to the low carb. So that crossover design um is very affirming. Uh and um, as we might predict on the low carb, there was much better burning of fat, this fat oxidation, right? This is the holy grail of what we would consider metabolic flexibility, the ability to quickly um burn fat as a fuel. Um the beta-hydroxybutyrate, even though this was not designed to be a ketogenic diet, they were producing more ketones in the low carb. And uh and not surprisingly, uh, you know, their blood triglycerides went down, their insulin concentrations, you know, which you and I might consider one of the most predictive blood markers uh today, uh, went down, and the ability for the liver to manage glucose, what we would consider insulin sensitivity, improved. So these were all sort of global, dramatic metabolic improvements over just a matter of days uh that were um confirmed in the crossover. So yeah, it this you know, these aren't the studies, right, John, that that make headline news, um, but they they offer affirmation and and mechanistic uh evidence that is really quite striking when you look at how quickly the body can adapt to these changes.

SPEAKER_01 6:59

Yeah, I mean, if this study doesn't pique uh your curiosity about just how dynamic uh really the effects are of

Metabolic Flexibility and Ketones

SPEAKER_01 7:10

shifting those macronutrient levels around. And I don't know, you know, I don't know if anything would pique a person's curiosity because you know, as you're saying, four or five days is um that's that's remarkable, remarkable. Uh and I, you know, I think how profound the effects are in addition to that, you know, just noticing uh, first of all, you you you already highlighted it, what an epidemic uh we used to call it non-alcoholic fatty liver disease. Uh now they had to, you know, it's it's always telling, right, when you have to rename uh a condition because of how prevalent it is and what an epidemic. So now it's metabolic associated liver disease. But it's you know, it's the same thing that for 30 years was called non-alcoholic fatty liver disease. And, you know, their numbers vary, but estimates are you know, anywhere from a third to 45% of people over the age of 40 have fatty liver deposits because their livers are basically drowning in carbohydrates. And that's the best way I could really summarize it is that the liver has a finite capacity with which it can, you know, safely process these surges in blood sugar levels. Um, and you know, you end up with these high triglyceride levels, which is I, you know, again, we can I don't want to digress here, but I think it's the one lipid that tells us the most about a person's health is triglycerides, not cholesterol and not the different fractions of cholesterol, maybe small dense LDLs, but those usually go hand in hand with high triglycerides. But you know, you've got um you've just got this really remarkable turnaround in uh liver health overall, and you know, using triglyceride levels as a surrogate for that, and you could also look at fibrosis, and yeah, it's just it's it's astounding. Um and it you know reminds me of a paper that was a little different but showed a similar turnaround in 10 days. This is it's around 20 years old now by Ian Frasetto. And in those uh subjects, and there was again it was a small pilot study similar to this, uh, where where the subjects were put on a Paleolithic diet, and in 10 days their fasting insulin levels went from 32 to you know under 10. Uh they didn't look at everything that was looked at here in this um in this Danish population, but it was also an incredible, incredible, uh, incredibly fast turnaround in the health of those that were following this paleolithic diet. Now, this is again not so much paleo, this is really focused on the levels of fat and carbohydrates. And when you look at those, uh, you know, I first of all, to your point, you know, well, well-constructed study in terms that that there were no differences in in the calorie uh intake. Because that's one thing that's always, you know, anytime a high fat diet has, you know, slightly less calories than some of the other studies, that's what's nitpicked by by the critics, right? They're saying, well, there was a difference in your your ketogenic population or your low-fat uh, you know, population, they had significantly you know different calorie levels, and so then everything is you know

Triglycerides, Insulin, and Better Markers

SPEAKER_01 10:20

kind of discredited. So here the researchers made sure that the caloric intake was was the same. Um, the protein was actually very similar. I was surprised that the high carb group was able to consume 133 grams of protein. I found that really, really interesting. Um, so they did a great job in terms of you know having this be, you know, limiting the moving parts here, right, to the carbohydrate and fat levels in each of these populations. And, you know, again, four or five days to to see that type of turnaround in liver health, it speaks to how resilient the human body and human physiology really is. Um the other thing that I find interesting that you know I I know I mentioned to you earlier was that you know the the total cholesterol levels uh they rose slightly in your in the low, lower carb high fat group. And so it shows me how useless that is when you have um a reduction in body weight, you have a reduction in triglycerides, your liver is getting better, um, you're burning more fat at any given intensity. And yet, because your cholesterol levels rise or your LDL levels rise, um, you know, again, all that is thrown out and it's it can be deemed as an unhealthy diet. It just it really shows you, you know, I think, and speaks to the overall lack of efficacy in terms of using that, you know, using that lipid as an evaluation for where someone's health is or how effective a dietary intervention is. So a lot of things we could talk about with a study, but I think the real headline here is like, wow, in just a few days, in just a few days, someone can really turn things around dramatically. Uh and yet, you know, again, it's like you like you said, this isn't the unfortunately, this isn't what receives the you know the headlines. Um we don't have enough people seeing this paper.

SPEAKER_00 12:20

Yeah, for sure, John. And the um extent to which these metabolic markers, as we've talked about often in the past, be it the amount of fat in the liver, be it uh your uh insulin levels, your glucose levels

Prevalence of Fatty Liver and Risk

SPEAKER_00 12:40

over time, uh they also gave these participants continuous glucose monitors, which I thought was pretty cool. Uh so they had some sort of real-time data while they were on these dietary interventions. But anyone who's ever worn a continuous glucose monitor uh would be equally amazed at the rapidity with which the the peaks, these excursions, which which may be the most telling uh in terms of of long-term risk, are dramatically reduced and stabilized. Um as we've often talked about, John, well, this um I mean it's it's uh compelling enough when you look at the prevalence as you as you talked about of insulin resistance, right? For 35 to 40 percent, that might be conservative with pre-diabetes, um uh another 10, 12 percent, and that may be conservative with type 2 diabetes. And I say conservative because these uh definitions really look at glucose only or hemoglobin A1C is a time average measure of glucose, as the uh, you know, that it's defined by that, and yet as we've always talked about, you'll see rises in insulin long before you see rises in glucose. So if if we were to re-establish the diagnostic guidelines for prediabetes and diabetes to focus more on insulin, you'd see much higher prevalence of both prediabetes and diabetes. So I think, you know, I think uh yeah, we would all agree that these are huge public health matters. Uh and then and then when you sort of extrapolate that, so so yeah, it's fantastic. You can lose weight and drop your sugar and um uh you know have these you would definitely drop your blood pressure, though that wasn't the focus of this study. Right. Uh you know, your lipids. The the um the long-term game, right? The long game that that that we we're all interested in is that these metabolic uh uh measures are one of the strongest predictors of all chronic complex disease risk over a lifetime. So um wouldn't it be remarkable if in a very short time, a matter of days to weeks, you could reduce your Alzheimer's risk with a huge magnitude

Rethinking Biomarkers vs Outcomes

SPEAKER_00 15:20

of reduction. You could reduce your uh cancer risk. You know, we know so many uh cancers are manifestations of insulin resistance from you know breast to colon to pancreatic, and so uh um this global um chronic complex disease risk reduction, improvement in health span, quality of life, compressing morbidity, uh all of these things uh can be extrapolated from what this study is pointing out in a way that no other medication on the market, no other lifestyle intervention exercises the holy grail. And when you combine dietary principles like this with you know lots of movement and some and some, as you would say, time under the load of resistance, um you're you are really profoundly changing the cards that you're holding. So this is a short-term study that that I believe would predict in the long term profound changes in one's health trajectory, quality of life, and possibly longevity. Um that's that's an even bigger headline. Uh and then as we've as we always talk about, John, it really does require for the individual a greater level of discernment when attempting to reconcile recommendations or guidelines, or maybe maybe uh um uh advice they are being given by their primary care doc or their endocrinologist or cardiologist with where the evidence is at today and and where it continues to to pivot and shift. And and that distinction for the consumer is huge, while for the uh the the establishment, right, those experts, um um you know, it can take some time before these things translate. And so that to me is uh is also the message here, John. You're as a consumer, you really um have to take matters into your own hands often when it comes to your health. Because it you know, some of this advice, the what we're talking about won't readily be forthcoming.

SPEAKER_01 17:49

Yeah, I mean that's an understatement. You really have to, I think, for you know, in in so many areas of health medicine, stay curious. Stay curious, uh and always appreciate the difference between outcomes

Continuous Glucose Monitoring Insights

SPEAKER_01 18:11

and maybe a biomarker that doesn't necessarily equate to a different outcome. And I think like a study like this should pique our curiosity, to say the least. And you know, again, it's uh what's this, about a year or two old now? I think it was like January of 24. So exactly. Yeah, so I mean I'd be curious to see if these uh if these investigators are gonna do something on a broader scale that may at some point uh you know receive more attention or a headline. But I think stay curious, um, and you know, again, always appreciate that if like in a study like this, if the subjects are losing weight, burning more fat, their liver, their liver health is improving. Like you have to take those things as outcomes, right? You're you're changing the outcome, you're changing the trajectory of a of a population's uh of their health, their life. And you know, so if you put this in comparison to a study that examines a high fat, and there's a lot of these studies now that are very myopic. They're going to look at one biomarker that may not translate to an improved outcome or health. But so again, we could pick on total cholesterol. That's something that's you know often investigated and it's misinterpreted as as you and I have spoken to. I think the microbiome is another area where I repeatedly see, you know, it's it's pointed out that a high fat, low carb diet undermines the microbiome. And that, you know, again, that's in my opinion, the the investigators are first of all, the high fat, low-carb diets are often made with all the wrong types of fats, right? And they're void of any fiber. And there, you know, there's nothing, there's no life rafts for the microbiome, so to speak. And even then, though, even you know, even in studies where maybe everything is misconstructed in that comparison and it's unhealthy, what you notice is that that the families of bacteria that are investigated or looked at in the microbiome don't necessarily translate to a better microbiome, right? So I just think that there's uh so many misconstructed uh comparisons between high fat or high carb and the other. And I think that what's remarkable about this study is not just a four or five day turnaround time for improved health, but it's your improving outcomes. You're actually changing organ health. You're getting the types of changes that we want on the broader, like you know, big population type uh level.

SPEAKER_00 20:50

Yeah, those are those are such great points, John. And it and it made me think of um, you know, when you look at the the explosion of GLP1

Long-Term Risk: Brain, Cancer, Lifespan

SPEAKER_00 21:00

agonists and the the combined GLP, GIP, gastrointestinal peptide, um, you know, these these uh uh very effective uh small molecules uh you know it it the sometimes I I worry um that you know once there's a pharmacologic uh um answer, yeah uh that it it makes uh sort of what one might otherwise be trying to promote in terms of non-pharmacologic interventions a bit of a harder cell. And you know, while the researchers here didn't measure this, uh my speculation is that you would have found significant changes in the um uh GLP1 production of the biome in the gut uh of participants on the lower carb, higher fat. And and we know that uh more protein and more fat can be important um attributes to enhance endogenous production of GLP1, which is why those macronutrient proportions are more satiating. And people often do consume fewer calories. Right. Um and and as you pointed out, John, often that is is you know considered the reason why somebody might lose weight. Uh and it's it's a reason, um, but it's you know, it when you look at the global sort of metabolic improvements, I think that it's a reminder for me that there are many natural, if you will, ways to enhance one's own GLP1. The the whole microbiome uh story here, John, which is so fascinating and and still really kind of a black box, I think is a is a big one for further exploration. Um and uh, you know, I meet a lot of people on GLP1s and and it's changed their lives, and there's a lot to be said for that. There are some people who are just in free fall and need to need to gain traction. Uh but when you look at the opportunity to develop a uh a really thoughtful lifestyle uh holistic integrated health program in conjunction with what might be a GLP1 intervention, um the it it's the long game, right? Of eventually you've got to come off these meds. Uh you know, you uh we we know how to put people on meds. We really have very little insight as to how to get people off these meds, and and that we know that they can be problematic long term. So um all of that all of that is to say that that for me, these are powerful strategies to offer uh in conjunction with um pharmacologic interventions that could allow people to get off these medications more quickly, or maybe to um uh find a lower maintenance dose that they can coexist with with fewer side effects. Um and so you know the body is pretty much designed to do much so much more than what any drug generally can do for us. But I do th I do worry

Reconciling Guidelines with New Evidence

SPEAKER_00 24:20

sometimes, John, that once there's an easy pharmacological answer, um that um again all of the uh sort of passion for lifestyle and and healthy food and and really getting into to you know what's happening, what's really going on, and how can I how can I assume more effective sort of oversight of that gets uh further marginalized. And um I don't know, I it's uh we'll we'll see how things play out. But for me, this is um uh uh uh should be required consideration in anyone thinking about a GLP one.

SPEAKER_01 25:03

Yeah, and to your point, Mark, I again it's it's triage, and I understand that there's a need for for people to sometimes you know use a pharmacological uh intervention short term to get the traction. I think the concerns uh just to kind of add to what what you were articulating is that you could go on a GLP1 program. Um long term though, it you know, it it doesn't necessarily equate to being nourished and to receiving all the different micronutrients or and even more importantly, macronutrient distributions that would be ideal for a person physiologically. So you could go on a GLP1 uh program and after several weeks, you know, respond favorably with respect to your weight, but are you consuming a biologically appropriate you know, array of foods? And the answer is clearly no. That's why there's this explosion of GLP1 diets and and foods to be used in conjunction, right? I mean, and and you know, a lot of these are again, they're they're a step in the right direction. They're offering a GLP1 user more fiber, more protein things to really help with the gut, because we know that a lot of people suffer there. But the high fat diet, and I hate to to limit it to that description, when you just say high-fat diet, automatically it it there's connotations for what that looks like. And you lose about, I'm gonna say you lose over half of your listeners, not our listeners, because our our listeners wouldn't be here if they weren't interested in this. But if you talk to the average person and you say high-fat diet, they immediately think, well, that just can't be good. Like that's that's bad. But the high-fat diet is biologically compatible with human physiology. And that's, you

Microbiome, GLP-1, and Satiety

SPEAKER_01 27:00

know, I I there's unequivocal evidence of that. From, you know, look at the digestive tract, look at our requirements. And, you know, what was great about this, and in and I'll leave it at that, um, is that the high fat, lower carbohydrate participants consumed about 160 grams of protein per day, which is what I know you and I would recommend for for the average adult. You know, we're not not the not the World Health Organization recommendation of 0.8 grams per kilogram of body weight. That leaves you with sarcopenia as an outcome. And a lot of GLP1 users are starting to exhibit sarcopenia, right? They're just not getting everything they need. They're turning off their appetite, and I understand that there's, you know, there's some there's some rewards to that short term, but long term you're going to end up with a different set of issues. Osteopenia, osteoporosis, sarcopenia. But yet if you eat this way, and again, maybe GLP1 is a stepping stone for people to get there. Um, but if you eat this way, you get the protein you need, you get the essential fatty acids you need, you support cellular physiology, you support your mitochondria, and you do it all non-pharmacologically. You do it all with what I think is a really well-balanced uh construct. So yeah, just to add to what you said, I think GLP1 gets people some traction, but it should not be looked at as like the long-term answer.

SPEAKER_00 28:23

That is a really good point to close on, John. Um uh nice discussion. And yeah, it's fun. I certainly would would um for people who might be new to the Health Edge, um, our website, the Health Edge Podcast.com, has uh a lot of uh I think great content on there, our older interviews, some great research papers. And so for anyone who might be interested in a bit more deep dive about um low carbohydrate, higher fat, uh, if you have concerns about your lipids, uh your you know, your cholesterol, your LDL, we we address a lot of that. That uh almost inevitably brings you to questions around statins. Do I take it or not? You know, we we address a lot of these issues, and they're not black and white, there are many shades of gray as we know, but um it's just it's a different context for how to think about one's health because what we're trying to offer is a uh a roadmap that's more empowering and and helps the individual realize that they're much more more powerful than they may perceive themselves to be. And uh as this study illustrated, one can begin to realize that in very short order. So um so please check that out for those who who want to take a deeper dive. And uh uh and John, I I know we talked about our next topic of looking at the biome and this interesting molecule, urolythine uh A, and and and and that sort of family of.

Meds as Triage, Nutrition as Strategy

SPEAKER_01 30:02

Yeah, everybody's excited about allagic acid, and you and I have talked about it in the past. I mean, it's an amazing phytonutrient, but you know, emerging science would suggest that not everybody can use that allagic acid the way they would hope. And uh so I think it'd be a really uh it'd be a really cool discussion about how the microbiome has such a strong influence over what we do with phytonutrients.

SPEAKER_00 30:26

Great. Well, we will we will have fun with that with that for sure. Um John, great to see you as always.

SPEAKER_01 30:34

Uh great to see you, man.

SPEAKER_00 30:35

Enjoy this uh uh weekend coming up and uh look forward to connecting very soon.

SPEAKER_01 30:42

Same here, bro. Take care.