One Unexpected Cause of Obesity: Brain Goo?!

Could a newly discovered goo in the brain be contributing to obesity? It's a scary thought, but also kind of a hopeful one. For in advancing our understanding of physiology, and neurophysiology for that matter, we can innovate new approaches to solve the problems that plague us as individuals and as a society, namely obesity. In this video, I'm going to walk you through these new really cool findings about brain goo, starting first at a high level and then delving down into the nitty-gritty details before circling back to provide you with a summary and solutions to make sure your brain is goo-free and happy. And that rhymes. Anyway, at a high level, this paper, just published in Nature, finds that brain inflammation from an obesogenic diet leads to thickening of a matrix around a center in the brain that controls hunger and energy regulation. This thick gooey matrix then prevents insulin from signaling to the brain, leading to insulin resistance in the brain and throughout the body, also increased appetite, decreased energy expenditure, and overall fat gain and obesity. But you're not gonna wanna leave yet, that was the high level, because to really internalize what I'm saying and get this to stick with you, pun intended, I want to show you the data. And of course, end of note, end of caveat, these data were collected in mice, since you can't exactly chop off human heads for these forms of research studies. These experiments thus need to be conducted in mice. However, they are consistent with the broader literature on neuroinflammation in humans, so I think there's every reason to believe these findings would generalize to humans. But point being, these studies need to be conducted in mice. You can take that with a grain of salt if you want. With that, what you're looking at here, to dive straight into the data, is a stain for something called the perineuronal net, or PNN for short. The perineuronal net, PNN, is a specialized form of extracellular matrix, a network of proteins and scaffoldings that surround cells, including neurons, hence perineuronal. And this perineuronal net is effectively the goo and is shown here in white in a region of the hypothalamus, in a region of the brain's hypothalamus specifically called the arcuate nucleus, which helps control metabolism. It's one of the key regions in the brain that controls metabolism. And what you see here is when mice are fed a high sugar, high-fat diet over 12 weeks. The goo intensifies. Basically, the Western-style diet is making the hypothalamic arcuate nucleus region more gooey, more goo in the brain. And they discovered, the researchers discovered, this happens because of inflammation. Specifically, inflammation from the high-fat, high-sugar diet leads to a decrease in the proteins that would otherwise turn over and break down the perineuronal net goo. I.e. gobble up the goo, and this leads to goo accumulation. Now, if this goo is causing metabolic dysfunction, then breaking down the goo should lead to metabolic improvements. And indeed, when they provide an enzyme to the mice that specifically eats up the perineuronal net goo, the mice lost weight, as shown in yellow, as compared to the black line that controls eating a high-sugar, high-fat diet. And what's perhaps even more interesting, when the mice on the high-sugar, high-fat diet were pair-fed, meaning they were forced to eat the exact same amount of calories, the mice who received the GU breakdown enzyme treatment, comparing the red here to the yellow, the mice who received the GU breakdown treatment still lost more weight and lost more fat, even when calories were controlled. And this demonstrates that the brain GU, the perineuronal net brain GU, is doing much more than just leading to increased appetite and more eating. Although it does that as well. In fact, breaking down the brain goo led to decreased appetite, increased heat production, and increased energy expenditure, and improved glucose regulation, and improved insulin sensitivity. Man, this goo seriously sucks. I mean, sucks. Okay, that was actually intentional, because what does this goo get stuck? And the answer is the hormone insulin. The researchers hypothesize that the perineuronal NET goo would impair insulin delivery and insulin signaling in the arcuate nucleus of the hypothalamus in the brain, and that this would lead to defective insulin signaling and dysregulation of brain and consequently whole body metabolism. And indeed, they found this to be true, and the effect was relatively specific to insulin versus other hormones like leptin. So in effect, they found that negative charges on something called glucosaminoglycans, if you want a big word, in the perineuronal neuronal net goo were effectively entrapping insulin, clogging up the works. The goo was trapping insulin. All this goes to reveal an axis whereby inflammation from a high-sugar, high-fat diet can contribute to inflammation in the brain, leading to an increase, a buildup of goo around a key brain region, the arcuate nucleus. And this blocks insulin signaling. The goo traps insulin in the brain, leading to metabolic dysfunction in the brain and consequently the whole body, with whole body insulin resistance, increased appetite, decreased energy energy output and overall fat gain. So what's the solution? What's the solution for you? Well, first and foremost, I think the answer should be diet. Obviously. I hope that's obvious. If you eat a low-sugar, species-appropriate diet and are overall achieving good markers of metabolic health, like a good low triglyceride to HDL ratio, appropriately low insulin and insulin resistance HOMA-IR score, then These changes, or these markers, suggest your brain is probably in good shape and your goo levels are low. But beyond that, I'd also be surprised if exercise, sleep, and stress reduction didn't influence this brain goo process. So those are also always important to keep in mind as health essentials. But with that said, I should get more specific, and there should also be ways to specifically target perineuronal net brain goo with small molecules that you could just administer to the body. Perhaps administered through the nose, kind of like an inhaler, towards the brain. And indeed, in this study, they provided a proof of principle that this could work, administering something called fluorosamine, which is an enzyme inhibitor that can prevent neurofibrosis and prevent brain goo accumulation. And drum roll, it worked! Fluorosamine through the nose decreased brain goo and led to serious weight loss. It was really impressive. You can see that here in blue. All this is super cool and utterly fascinating and intellectually stimulating, but in closing, I guess I should provide an obvious caveat that maybe I should offer more often. These studies identify causal pathways and reveal new pieces of a really cool puzzle, but they're never the whole story. This is not the answer to obesity. However, it is a remarkable addition to the puzzle, a single piece, but it's a puzzle we need to keep working on together because frankly, standard of care and standard standard of care thinking is not working. So thank you for your curiosity and sticking with me through this brain goo video. I would love to hear your feedback, and also tell me in the comments what you do to keep your body healthy and hopefully your brain goo-free. Stay curious.