How Your Brain is Weighing You Down

What's the difference between these two mice? Kind of obvious, isn't it? One mouse is fat and one mouse is skinny. But what I'm really asking you is, why is the fat mouse fat? The fat mouse is something called an OB/OB mouse. This is a mouse with mutations such that it doesn't produce the hormone leptin. Leptin is a hormone released by fat tissue and other tissues, but mostly fat tissue, that signals to the brain to decrease food intake and increase energy expenditure. And in that way, leptin signaling can promote a healthy weight. So what's supposed to happen is your Fat mass increases, the leptin says to the brain, all right, we got enough fat here, you can decrease eating. And vice versa, fat mass goes down, leptin goes down, maybe you get a little bit more hungry and you eat more. Again, maintaining a homeostasis. And when scientists discovered the deficiency in this mouse and how it led to massive increase in food intake and obesity in the mouse, they thought, yes, we have obesity solved. If we just give people back leptin or mice back leptin, then they will eat less, their energy expenditure will go up, and they will achieve a healthy weight. Spoiler alert, it didn't work like that. Unfortunately, bile biology foils us. And the reason leptin supplementation doesn't work in treating diet-induced obesity is because of leptin resistance. So just like in insulin resistance, where insulin levels go up because the body's just not getting the message, you have the same thing with leptin, where leptin levels do increase, but it doesn't translate into increased leptin signaling because the pathway is resistant. You can't just inject humans with leptin and have them lose a bunch of weight because they have leptin resistance in their brains. So a question that has dogged science in the obesity field is, well, what what causes leptin resistance at a molecular level, and how can we overcome that leptin resistance, restore leptin sensitivity, and thereby help people achieve healthy weight balance? That's what this paper and this video are about. Welcome to my channel, stay curious. So let's dig into the molecular elements straight away. This paper was recently published in Cell Metabolism and is entitled Central inhibition of HDAC6 resensitizes leptin signaling during obesity to induce profound weight loss. What is HDAC6? Well, inside the cell, there are proteins. Proteins carry out function. But proteins can have their function modified by putting tags on and taking tags off. And one of these tags is called acetyl group. And as its name suggests, HDAC6, histone deacetylase, the function of HDAC6 is to remove acetyl groups, deacetylate proteins, to thereby change their function. And one of the targets of HDAC6 is— wait for it— the leptin receptor, the protein, the leptin receptor. So what they first show in this really cool study is that HDAC6 binds to the leptin receptor, removes acetyl groups from it, and thereby inhibits leptin receptor activity, decreases leptin sensitivity. This actually makes sense when you look at states in which HDAC6 goes up and down. So for example, if you fast mice, HDAC6 goes up, and this makes sense because you'd want to inhibit leptin signaling so that the mice get hungry and eat when they're fasting, right? Now, the extension of this logic, the discovery that HDAC6 is a leptin receptor inhibitor is that if you inhibit the inhibitor, you should promote activity in that pathway. In other words, if you inhibit HDAC6, you should stimulate activity of the leptin receptor when leptin binds and thereby promote the downstream consequences of leptin signaling, which are decreased food intake and increased energy expenditure. So that's the hypothesis they're running with. They think, okay, you know, if you have diet-induced obesity and leptin resistance, If you just give Bacleptin, we know that doesn't work. But what if you gave Bacleptin along with a leptin pathway sensitizer, HDAC6 inhibitor? Because remember, again, inhibiting the inhibitor, inhibiting HDAC6, should improve leptin sensitivity and signaling through the pathway. So that's what they did. They took mice, mice with diet-induced obesity via a westernized diet, and they sensitized them with an HDAC6 inhibitor. And lo and behold, what they found was the mice lost weight. In fact, this weight loss was specific to fat mass. They preserved lean mass. The mice had increased energy expenditure along with decreased food intake. They had improved insulin sensitivity, and they had more relative fat burning as marked by a decrease in something called respiratory exchange ratio. Bottom line, in line with the hypothesis, inhibiting HDAC6 specifically improved leptin sensitivity and promoted all the consequences of high leptin sensitivity, leading to fat loss and improved energy expenditure, improved insulin sensitivity, which are really, really cool results. But there's a catch. At least there's a catch for me. When I read this paper, or when I read any papers like this, I want to translate into something that you care about. I want you to read it and say, "This is interesting." But if I can, I want to bring it to the next level where you realize, "Oh, this is relevant for me." So what I was very prepared to do when I read this paper, and the way I thought about this video initially, is say, "Let's connect this to ketogenic diets." Why? Because ketogenic diets have similar effects. They can improve insulin sensitivity, they can decrease fat mass, they can improve fat burning, and they can improve energy expenditure, even in human randomized controlled trials. And what's more, ketones produced on ketogenic diets are known class 1 and class 2 inhibitors. So HDAC6 is actually a class 2 HDAC, so it's very logical, right? Ketogenic diets would increase beta-hydroxybutyrate, a ketone level that would inhibit HDAC6 and result in the clinical phenomena that we see in humans in line with the mouse data I just shared. It fits together perfectly, and that's what I was about to share with you. But then, while I was just preparing the video, I thought I'd just do my due diligence and double-check, triple-check that ketones actually do inhibit HDAC6. So I went back to a Keystone Science paper that reported ketones inhibit class II and class I HDACs. Remember, HDAC6 is a class II HDAC. And there was a line in the paper that I caught, which was, yes, beta-hydroxybutyrate inhibits class I and class II HDACs, with the notable exception of HDAC6, which it does not inhibit. So that left me stroking my chin and thinking, huh, this is weird, because what we have here is something that would just make so much sense on a, you know, let's say clinical level. You have an intervention that raises a molecule, beta-hydroxybutyrate, that inhibits a class of molecules that are the target and the topic of this paper. And why would HDAC6, the one that is the specific target of this paper and results in the same phenomena in mice as we see in ketogenic diets in humans, why would that be the exception? Why wouldn't beta-hydroxybutyrate inhibit HDAC6? Why did— if you want to make it kind of anthropomorphize nature a little bit— why did nature select out HDAC6 as the one Class I or Class II HDAC the ketones don't inhibit? And I could have gone a little bit further, done my homework, come up with a compelling hypothesis, but I actually decided not to do that. I decided to pause here and record this video at that moment when I'm stroking my chin and thinking, what the heck's going on here? The reason being something my dad told me, which was, "Nick, the greatest thing about science, the most exciting thing in the life of a scientist, is not when you have data that confirm your hypothesis. It's when you have data that go and completely contradict what you expected to happen." So I'm in that mode right now, that mode of, I thought I had a story that made sense. I thought I had a puzzle that perfectly fit together, and it turns out I don't. I have the opposite. I'm profoundly confused and I don't have an answer. And I actually want to leave you with that, because if you're a true scientist, then you'll have the feeling I have right now, which is curiosity. That question of what the heck's going on here? And I think that while it can be an uncomfortable feeling for some, is actually the coolest feeling of all. That feeling of curiosity and that there's more to learn. So I may even post my developed thoughts in the comments below the video notes for those who do want them. But for now, I want you to just pause and feel that feeling, that curiosity of like, wait, wait, what goes on here? Why is this happening? Because I think that's really fun and really cool. I hope you agree. You can let me know in the comments.