In this video, Nick Norwitz demystifies the popular but vague terms “fast metabolism” and “slow metabolism” by linking them to concrete cellular mechanisms. He explains that mitochondria, the cell’s power plants, constantly undergo fusion (joining) and fission (splitting), processes that determine how efficiently they generate energy. Recent 2024 research published in Nature Metabolism shows that obesity and a Western‑style high‑carb diet increase the activity of the protein RAL‑A, which activates DERP (also called DRP1), driving mitochondrial fission and fragmentation in white adipocytes. Mouse experiments where RAL‑A is genetically deleted reveal resistance to diet‑induced weight gain, larger mitochondria, higher membrane potential, and increased fat burning. Norwitz connects these findings to human physiology by noting that insulin stimulates RAL‑A; thus, high insulin (as in carbohydrate‑rich diets) may promote mitochondrial fragmentation, reducing energy expenditure. He speculates that the metabolic advantage observed in low‑carb diet trials could stem from lower insulin, reduced RAL‑A/DERP signaling, and a shift toward mitochondrial fusion, producing larger, more efficient mitochondria. The video blends detailed mechanistic evidence with broader dietary implications, aiming to give viewers a scientifically grounded understanding of what “fast metabolism” really means.
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He has a fast metabolism. She has a slow metabolism. We use these terms all the time, but they're hand-wavy as heck. What do they even mean? By the end of this video, I promise you, you'll have a better understanding about what fast and slow metabolism means than any of your friends. You'll be a master of mitochondrial morphology, and you'll probably annoy your friend group as well by lecturing them on fusion and fission while they're eating their pizza. And if you haven't already, you may try a low-carb diet. Welcome to my channel. Stay curious. Okay, so that pesky question: what does it mean to have a fast metabolism versus a slow metabolism? Well, as you probably know, when people say fast metabolism, they're generally referring to people who are resistant to weight gain. You know, those people that can eat whatever and they just don't —don't get fat— versus slow metabolism, those unlucky bunch who can gain fat basically eating air and lettuce, right? Or at least that's how it's portrayed. But at that point, it generally gets kind of hand-wavy. Everything is swept under the rug, and we just kind of assume biology is magical, gonna do whatever it wants. But we are not going to do that. No, sir. Instead, I want to talk to you about really cool new research that came out just recently in 2024 in Nature Metabolism, one of my favorite journals, that talks about how a Western-style diet and obesity can fragment mitochondria, literally take the powerhouse of the cell and break them up. The paper is entitled "Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RAL-A activation." But before we talk about RAL-A, the protein that's in the title, I want to fast forward to the end of their paper because I actually think it tells a better scientific story that's easier to digest for you. So a little background to kind of set the stage. Mitochondria are the powerhouse of the cell. Maybe you remember that from 8th grade biology. They generate energy. They are what burn our fuel, burn our fat, and consume oxygen so that we can turn that oxygen into water via the mitochondria oxidative phosphorylation and generate energy so we can walk around and do jumping jacks and stuff like that. Anyway, mitochondria are very heterogeneous, they're very complicated, and there are processes that control how efficient they are. Two of these processes are fusion, where mitochondria come together and generate super mitochondria, and fission, where they break apart, they fragment. And mitochondrial fusion and fission is dynamic and controlled by by various cell signaling pathways. And what you find is that in people with obesity, there is more fragmentation of mitochondria, more fission and less fusion. And one of the controls of this fission process is a protein called, wait for it, DERP. It's literally called DERP. DERP leads to mitochondrial fission, which can be, well, let's just say bad, lead to reduced energy expenditure, etc., etc., because the mitochondria are less efficient. And what you find in people with obesity, if you take their fat cells and look inside, that people with obesity have more DERP activity, more DERP expression, and that this actually is a dose-response relationship. So people with higher BMI— this is what you're seeing here in the graph— the higher your BMI, the more DERP. And the more insulin resistant you are, higher HOMA-IR, the more DERP. So insulin resistance and obesity actually correlate with more DERP activity, more DERP expression, which is going to lead to more mitochondrial fission. Literally, imagine the pizza inducing obesity and insulin resistance smashing your mitochondria. So if DERP leads to mitochondrial fragmentation, and we don't want that, what we want to know is what controls DERP. One thing that controls DERP is something called RAL-A, the protein in the title. RAL-A, through a cascade of events, activates DERP, and then DERP causes mitochondrial fragmentation. So we'd expect that RAL-A levels, expression, are going to be higher in obesity. And indeed they are. So RAL-A and DIRP are both increased in obesity, leading to mitochondrial fragmentation. And now I really need to nerd out with you because the data are just so cool. They really dig into the biology. So I'm going to go through some of the figures. And yes, these experiments were done in mice. They need to be done in mice because you need to do genetic manipulation and the sort of experiments that you just can't do in humans. So one thing they do is a RAL-A deletion. They just, just turn off RAL-A, right? And what they find is when they give mice without RAL-A the westernized diet, so high sugar, high carb, it's abbreviated HFD, little pet peeve of mine, that's an aside. When they give them a westernized diet, they are resistant to weight gain, and in particular, they're resistant to fat gain, which you see here. RALA deletion also increases fat burning, which you can see here from an in vitro study. And here, this is my favorite, this is where things get really cool. When you turn off RALA in these mice, which turns off DERP, right? You can actually use transmission electron microscopy, look at the mitochondria in the cell, and what you can see here so clearly, you don't need a PhD to see it, is that RAL-A deletion makes mitochondria bigger. It prevents fission, and you get these big, big mitochondria. Versus when RAL-A is more active, you get these fragmented little mitochondria. How cool is that? You can literally see the mitochondria. Now, does this translate into function? Well, yeah, and this is so, so beautiful. Look at this. What they're using here is a special stain to look at the membrane potential across the mitochondrial membrane. Now the way mitochondria work are kind of translating a concentration gradient of protons into the energy currency of the cell, ATP. So imagine it kind of like a waterfall. You have a 10-foot waterfall, you can produce a little bit of energy. You have a 50-foot waterfall, you can produce way more energy. So what you're looking at here in purple is the size of the waterfall. And what you see here on the right is a bigger waterfall. RAL-A deletion not only makes mitochondria bigger, but it increases their ability to produce energy. And you can literally see the mitochondrial membrane potential there, staring at you, or glaring at you, in purple. How cool is that? Now, that's— I mean, honestly, I hope you're just like now with me in scientific awe and thinking, "Oh my god, Nick, this is so cool. I get why you love this paper." But maybe there's a subgroup of you that are thinking, "Oh, well, yeah, Nick, I mean, this is cool and kind of nerdy and all, but what relevance does it have to me? How are we going to apply these mice findings to anything relevant to human beings, me? How is this going to influence my life and how I go about living my everyday, whether or not I choose to have a bagel or eggs for breakfast?" Well, there's a piece I've hidden from you. All right, we've established DERP1, fragments mitochondria, leads to more fission, less fusion. That means you are less efficient at generating energy, energy expenditure goes down. I'm translating this from the mouse data, but that's the implication. And that RAL-A turns on DERP, so lower RAL-A, lower DERP would mean better mitochondria, right? So now the question: well, what controls RAL-A? Ready? Drum roll, please. Insulin. Insulin. The hormone insulin stimulates RAL-A. So you have more insulin, you're activating RAL-A, you're activating DERP, you're fragmenting mitochondria. That's the implication. And here's what's really cool, and I will caveat, I am definitely speculating here. But if you look at the randomized controlled trials in humans, what you find is that there is a metabolic advantage to low-carb diets. Going low-carb, exchanging carb calories for fat calories, tends to increase energy expenditure. We see this in the longer-term, really well-designed human randomized control trials. But a question has remained: well, what is executing this effect? And also, why does it take time? It takes adaptation. It's not like tomorrow, if one goes from low-fat to low-carb, you get the metabolic advantage. There's an adaptation period, and we see that in the literature. If you do the meta-analysis of human trials, you see that in the literature. Well, I'm not saying this is the whole picture, but this is consistent with those human data. Imagine you go low-carb, your insulin comes down, so your RAL-A to DIRP signaling changes, it decreases. So then you get more mitochondrial fusion over fission, you get these big mitochondria, and you get a metabolic advantage. Now again, I am speculating, but it makes sense. It paints a picture. So this may be, may be, one part of a cumulative, but one element of a puzzle for how we get a metabolic advantage out of low-carbohydrate diets. Lower insulin, lower RALA-DERP activity, larger, more efficient mitochondria. Now, I think that's freaking cool. I don't know about you.
