The 75-Year-Old Obesity Riddle Science Just Solved

Hidden inside this letter is a secret, a scientific breakthrough 75 years in waiting. Now, I promise I'm gonna show you what's inside this letter by the end of the video. But first, let me be clear. I mean this literally because science have discovered that fat cells send secret letters to the brain and the information coded within them controls our hunger and our metabolism and the answer to a near century-old riddle that could reverse obesity. If our biology writes the right messages, We feel satiated, energetic. We stay lean and healthy. But if it writes the wrong messages to the brain, we become hungry and sluggish, and we end up sick and fat. The problem is that for 75 years we've been thwarted. We've had no idea what's actually inside the letter. What's the message? But the study we're going to explore today, the brand new study, changes that. It opens the letter. And what's inside is— I hope you appreciate the gravity of this discovery. Something truly consequential and fascinating. Obviously, you know, that's not the whole story. Biology thwarted us. Trillion-dollar question probably is why? These messages can be rewritten. Their brains lit up like Times Square. This is a genuine breakthrough in our understanding of obesity. Now, before we hit the body of this video, I just want to plug you can always find more nuances, details, references, and a written breakdown at the associated newsletter, not top secret letter but newsletter, at staycuriousmetabolism.com. With that plug over, let's back up to 1949. Researchers at Jackson Laboratory accidentally discovered mutant mice. These mice were deficient in a hormone called leptin that caused them to balloon up like their fat cells forgot how to say stop and develop severe obesity. In fact, there are humans with the same condition known as congenital leptin deficiency who also develop severe obesity. This makes sense since what leptin does is it signals to the brain to reduce appetite and increase energy expenditure. It makes sense therefore that loss of leptin would cause severe obesity. But the good news is that when you give leptin back to these obese mice or these patients with this genetic disorder, obesity reverses. So scientists were like, "Hallelujah! We discovered the cause and cure of obesity." Well, obviously you know that's not the whole story, and the scientists back then realized it too. Because unfortunately biology thwarted us. Giving leptin to these people with leptin deficiency worked, but giving leptin to normal fat mice or humans with diet-induced obesity doesn't have the same anti-obesogenic effect. And the million-dollar question—trillion-dollar question probably—is why? The answer is simple on the surface. But very complex underneath. You see, in run-of-the-mill diet-induced obesity, the type that affects most people, the body, and importantly the brain, become resistant to the hormone leptin. They become leptin resistant. Leptin levels typically actually go up in obesity, but the brain stops listening. And the result of leptin resistance is increased hunger, decreased energy expenditure, and a host of metabolic dysfunctions. Or if you want some analogy that might stick, leptin resistance is like if the fullness and satiety centers of your brain turned on do not disturb. And for decades, scientists have puzzled over what causes, what truly causes leptin resistance in the brain. And if we know the cause, we might be able to develop a cure. And this new study, just published in Cell Metabolism, this study found an answer. This study brings together both animal and human data to identify the specific letters— sorry, I dropped my secret letter prop— the specific letters that fat cells mail to the brain, and the contents of these letters, the molecular code that determines how the brain responds to leptin. Anyway, in obesity, these molecular letters become metabolically abusive. Writing the code for leptin resistance. But by discovering what they contain, we gain the ability to rewrite the message. So let's get into this exciting study. The researchers began with animals— mice— and a genetic strain with a defect specifically in their fat cells that prevented those fat cells from mailing out the letters. In the paper, these are called the RAB27 knockout mice, although the detail here isn't important for our purposes, but There's a detail for you. Anyway, now finally, I'm gonna tell you what these letters are, and then later what's within them. These letters are called extracellular vesicles. They're little membrane-bound packages that carry cargo around the body, including to the brain. Now, when the researchers knocked out the ability of fat cells, specifically fat cells, to send these extracellular vesicles letters out, the mice gained weight. Specifically, they gained fat mass. Not lean mass. And this was accompanied by an increase in food intake, decreased oxygen consumption, and decreased body temperature. So essentially, the mice got hungrier, ate more, and their metabolisms slowed, leading to obesity and metabolic dysfunction. Now, before we get to the human data—and we will get to human data—the researchers wanted to prove that these letters are part of a causal cascade. The experiment was pretty straightforward. Take healthy mice, extract their extracellular vesicle letters, and then inject these into obese mice that can't make their own extracellular vesicle letters. When you do this, what happens? The obese mice that can't make these letters, that receive the letters from lean mice, they lose fat rapidly. But here's the twist. If you repeat the same experiment using extracellular vesicle letters from obese mice that became obese through diet, this therapy doesn't work. Sorry if that's confusing, and I know this figure doesn't make it any clearer, so let me step back and try to make this clear. If you knock out fat cells' ability to generate the letters that communicate with the brain, mice become obese. You can treat this by giving the obese mice that can't make letters letters from lean animals, these extracellular vesicles. But when animals become obese through diet, normal obesity, Even though their fat cells still make these letters, the messages within the letters change. They're rewritten. The extracellular vesicle letters made by fat cells of animals that got obese through diet don't fight obesity, they perpetuate it. So in effect, diet rewrites the message in the letter. Now I promise I'll tell you what those are, but first let me get to the human element. So check this out. That experiment we just described? You can do the same thing with extracts from human blood. The researchers showed you can give extracellular vesicle letters from lean humans to mice that don't make their own letters, and these mice lose fat. But again, if you use extracellular vesicles from obese humans, the effect disappears once again. And this is important. This is so important because it tells us this pathway is highly conserved across species. You can transfer letters between species. And we do need to use mice to dissect causal pathways using these experiments, we can't do it ethically in humans, but the biology is directly relevant to humans as well. Now. Next, the researchers wanted to confirm something I've been assuming so far. Do these letters actually go to the brain? So to test this, they generated mice whose extracellular vesicles, these letters, carry a fluorescent tag, like this red marker, but it glows. It's called em cherry. They then scanned the animals to see where the signal ends up. Where's the red glow? And guess where it is? When they scanned the mice, their brains lit up like Times Square. Clear, direct evidence that these letters reach the command center, the brain. So, summary so far: in a lean state, healthy small fat cells send out these extracellular vesicle letters containing specific instructions to the brain. This helps to maintain leanness, fullness, and energy expenditure. But in obesity, the letters become corrupted, the message inside changes, leading to increased hunger and decreased energy expenditure. So the next question is, what specifically is the message within the letters? And the answer? Small non-coding strings of nucleotides, sort of like mini strips of modified DNA, or more correctly RNA, called microRNA. Now these don't produce proteins. But they act as instructions, modifying gene expression and signaling pathways. And when the researchers chopped up these microRNAs, the anti-obesity effects of healthy letters disappeared. So simply put, the message within the letter—not this letter, but the message in the extracellular vesicles—is microRNA. Now here's the key point: in obesity, diet-induced obesity, the microRNAs that cause leptin resistance increase, and the microRNAs that promote leptin sensitivity and fight leptin resistance, they go down. Versus in a healthy lean state, the opposite is true: high levels of microRNA that maintain leptin sensitivity. And this pattern holds in both mice and humans, including a study of over 100 individuals examined across the BMI spectrum. You can see that here: the set of microRNAs in humans that fights leptin resistance? In people with overweight or obesity—BMIs above 25—they're depleted. Causing leptin resistance. And the relationship is even dose-dependent, meaning the higher the BMI, presumably the higher the body fat, progressively associates with lower levels of these microRNAs, these healthy letters that fight leptin resistance, and vice versa. Now sadly, the microRNAs' names aren't as exciting as their biology. For example, one's called mir148a-3p. It enhances leptin sensitivity and suppresses obesity, Boring name, but really extraordinary impact. And the researchers also showed that in patients, human patients with obesity, when they're treated with bariatric surgery, which induces a lot of weight loss, the leptin-sensitizing healthy microRNAs rise, promoting leptin sensitivity, fighting leptin resistance. Bottom line, these messages can be rewritten. And here's another really exciting element, a glimpse of the future. When the team synthesized these microRNAs— it's pretty easy to do, they're small simple molecules— then packaged them into the extracellular vesicles, it was sufficient when administered to animals to reverse obesity in these preclinical experiments. I hope you appreciate the gravity of this discovery, but if not, let's take a step back. Decades ago, researchers thought they'd solved obesity with leptin. Only to discover that leptin resistance stands in the way. And since then, for three-quarters of a century, we've been trying and failing to crack the code of leptin resistance. But this research identifies at least part of the answer. In diet-induced obesity, the extracellular vesicle letters that fat cells send to the brain get rewritten in microRNA code. This drives leptin resistance. But by intercepting the letters and replacing the message in these letters, we can enhance leptin sensitivity and potentially reverse obesity, addressing one of the core metabolic dysfunctions behind the disease of obesity. Now, in my opinion, as I know a lot of you are wondering, I think this is quite distinct from conventional weight loss drugs like GLP-1 receptor agonists, ozempic, Wegovy, which work by supra-physiologically dosing a hormone to cause weight loss, but here we're talking about identifying a root cause of a hormonal resistance syndrome, like insulin resistance, here leptin resistance, and I consider this a genuine breakthrough in our understanding of obesity, something truly consequential and fascinating. And even if the therapeutic utility is murky and not yet clinically available, what I think we have here is a glimpse of the future. I hope you agree. Now, finally, let me show you what's in my letter. Huh, it's a riddle. Okay, I'm going to read you this riddle. And here's the deal. For those who can answer it and leave a comment with one additional fact related to the answer that I don't already know, I'm going to enter you in a raffle to win a half year of free premium subscription to the Stay Curious Metabolism newsletter, which is now top 3 bestselling in science worldwide. I'm gonna have you on the honor code that you don't cheat, so here's the riddle: I am the headline general, commanding an army of diversely skilled knights, some floating like gilded barges, others sink like iron in the night. Yet whether courier, warrior, or smuggler, each bears my mark upon its spine. Count my soldiers if you wish,. But tallying me works just fine. At least that's what many say. The ones who wear ropes around their necks. And while some may call me a terror, my story is not complete. What am I? Drop the answer if you think you know it, don't cheat off anyone else, and another fact about the answer. See if you can win the Stay Curious Metabolism premium subscription for 3 months. Sorry, 6 months. You get 6 months. I'm not backing off on that. Anyway, stay curious. I hope you found this fascinating. This kind of science just excites me, thrills me, and I just love that I get to share it with you.