Welcome to the Metabolic Classroom podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical, and engaging. Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today's brief lecture explores a topic that intersects neuroscience, endocrinology, and metabolism, some of my absolute favorite topics. and with these topics in mind and the intersection in mind that means we're speaking about the vagus nerve and its role in controlling how your body handles nutrients with a particular focus on the pancreas and insulin secretion now lest you think i am speaking about some sin city in nevada when i say vagus. I don't mean V-E-G-A-S, but rather V-A-G-U-S, the vagus nerve. We'll examine what happens when the vagus is cut surgically and what we have learned from devices designed to either block it or stimulate it. The vagus has been called the wandering nerve. In fact, vagus in in Latin literally means wandering. It is the longest and most widely distributed cranial nerve. So a nerve originating from the central nervous system in the body. And it reaches all the way from the brainstem down through the neck and the thorax and then into nearly every organ of the abdomen. This includes things like the liver and the gut and the pancreas and all the rest. For our purposes, the vagus is the primary nervous system cable connecting the brain to the metabolic machinery of the viscera or that space within your abdomen. If you want to understand how the brain talks to the pancreas or how the gut tells the brain how much has been eaten, the conversation is largely happening along this nerve. Okay, now let's start with the anatomy. I've already given you a little bit of a hint of what we're talking about. The vagus is the 10th cranial nerve, and it contains two very different kinds of fibers traveling in the same bundle. Efferent fibers carry signals from the brain to the peripheral organs. So this is when your brain is maybe telling your pancreas to do something. afferent fibers will then in turn carry sensory information from the peripheral organ up to the brain so this might be a signal where the gut is sending something up to the brain an important point that often surprises people is that the vagus is predominantly is predominantly a sensory nerve now estimates vary by the branch that we're talking about but roughly 80 percent of the fibers in the abdominal vagus are afferent, meaning they are carrying information up to the brain, not commands down to the viscera. So when we talk about the vagus in metabolism, we need to remember that its dominant job is to keep the brain continuously informed about what is happening in the gut, liver, and pancreas. Below the diaphragm, the vagus splits into an anterior, so front, and posterior or back trunk. These trunks give off the major abdominal branches that concern us today. The hepatic branch, the gastric branches, and the celiac branch, the last of which ultimately provides innervation to the pancreas, the small intestine, and then the first part of the large intestine or the colon, what we call the proximal colon. Now, one counterintuitive anatomical detail is worth mentioning. The hepatic branch is somewhat misleadingly named. The majority of its fibers actually innervate the proximal small intestine, the pylorus and the pancreas, with only a very small minority actually going to the liver. So even though the hepatic branch is named for the liver, it has very little to do with the liver. Now, that's just important because later I'm going to mention the hepatic branch, and I just need you not to think about it as something that's just driving liver regulation. Now, let's talk about how this anatomy translates into metabolic control. I want to cover three broad areas before we drill down into the pancreas. The liver, I want to talk about the gut-brain axis, and then the integrated response to eating. So let's start with the liver. The liver is the metabolic switchboard of the body. I've sometimes referred to it as the metabolic soccer mom. It can do everything. It produces glucose during fasting. It stores glucose as glycogen in a fed state, and it can release fatty acids and fats and ketones as needed. Vagal input will modulate all of these things. blocking the vagal trunk or the vagal signal can has been shown to reduce basal hepatic glucose production by suppressing the breakdown of glycogen so you block the vagus you're blocking glycogenolysis now it can do so without affecting the production of new glucose or gluconeogenesis surgical hepatic vagotomy so when you're snipping that vagus has been shown to increase endogenous glucose production during fasting and it reduces the glucose production from the liver when the glucose is loaded with when the liver is getting loaded with glucose so in other words an intact vegas seems to help the liver appropriately throttle glucose release and throttle it down when nutrients are coming in and appropriately then sustain glucose in contrast when there is less glucose coming in like during a fasted state all right now let's shift to the fascinating brain to liver circuit when researchers inhibited fat oxidation in the hypothalamus of a rat model an animal model using rats the animal's livers dramatically reduced gluconeogenesis and glucose output but only if the hepatic branch of the vagus was intact you sever the hepatic branch and then the signal from the hypothalamus to the liver was lost This is a clear demonstration that the brain uses the vagus to regulate the liver glucose output in response to central nutrient sensing Now let's move to the gut. Vagal afferent endings are densely found within the intestinal wall where they sit in very close proximity to a series of cells called enteroendocrine. enteroendocrine cells. These are cells that include some of the famous cells like L cells that produce GLP-1 and others. These afferents express receptors for those very hormones. So when a meal arrives in the gut and the enteroendocrine cells, like the L cells, release their signals like GLP-1, vagal afferents or afferent nerves will pick up that information and transmit it rapidly to the brain. This is the hardwired arm of gut brain signaling much faster than the hormonal arm. And it's responsible for a large portion of what we perceive as a satiety signal during a meal. Vagal afferents in the hepatic portal vein also directly sense glucose concentrations, giving the brain a real-time readout of nutrient absorption before the glucose even reaches the systemic circulation. So let me just say that again. So the vagus is able to sense the blood glucose level coming from the liver before the liver, before that glucose has actually made it to the brain. So this vagus is sending that signal, letting the brain know in real time, not a few minutes delay or something when that glucose is then getting to the brain. Now let's discuss the pancreas. The pancreas is richly innervated by the vagus and the effects on the beta cell and its function are substantial. But know that some of the literature that I'm going to be reviewing right now is much stronger in animals than in humans. You simply can just do more manipulation of the vagus when you are sacrificing the animal than you can in a living, breathing human. The basic pathway is as follows. The vagus carries a signal down from the brainstem to the pancreas, where it then releases acetylcholine onto the beta cell. And then acetylcholine acts on the beta cell to amplify insulin secretion. Importantly, the vagus doesn't override the glucose sensing. The beta cell is still sampling glucose in the blood to help it know how much insulin it should release. But this acetylcholine signal from the vagus works alongside that. It can lower the threshold and increase the amplitude of glucose-stimulated insulin release. Now, this brings me to the cephalic phase insulin response, or the CPIR. This actually was first described by Ivan Pavlov more than a century ago. and the cpir the cephalic phase insulin release or response refers to the small early release of insulin that occurs within a few minutes of some food related stimuli like when you see or smell or taste or even just anticipate you're starting to think about a meal so this is happening before any measurable rise in glucose has happened in the blood the pathway runs from the mouth and nose up to the brain and then back down the vagus to the pancreas. Pavlov himself showed that cutting the vagus abolishes the pancreatic secretory response to sham feeding in dogs. So when dogs were able to actually swallow something, but it didn't get into their stomach due to some surgical manipulation. And this finding has been replicated many, many times in other animal models. Now, in humans, the cephalic phase insulin response has been a little more controversial. The insulin rise from oral stimulation alone is exceptionally small. We're talking maybe just a few micro units per milliliter. But then the problem is that this can be just washed out with normal, spontaneous fluctuations in baseline insulin. If you're really finely measuring insulin, it's never just flat. In fact, no hormone ever really is. It's always kind of playing around and there's always a little bit of oscillation. So the problem with really identifying the cephalic phase in humans is that it's hard to determine whether it's just a natural little variability of insulin or whether it really is some cephalic effect. There was a 2020 paper that concluded that this cephalic effect is very, very small compared with spontaneous insulin fluctuations. And they questioned whether it was even real. Now, a meta-analysis that same year, 2020, reached a more positive conclusion where they found that food-related stimuli do reliably elicit a cephalic phase in humans, though with substantial heterogeneity depending on the stimulus. that's really important because a lot of people may find this is i think where we have some of the variability when it comes to things like a sweetener or why just some people are responding differently to different foods when it comes to weight gain or hunger it could just be within this heterogeneity and we do not understand the reasons for that heterogeneity and that pains me to say as your guest professor in this mini lecture i wish i had a more definitive answer for that now there is some evidence that gives us a little more insight even if we don't know how to manipulate it so some there has been some more recent mechanistic work that's added a layer of understanding to this where one group in particular found that the cephalic phase is modulated by interleukin 1 beta that is a pro-inflammatory cytokine in fact a very potent pro-inflammatory cytokine and they found that it was relevant in the brain's resident immune cells these these macrophages and that the cephalic phase is impaired in obesity potentially because of a dysregulated interleukin 1 beta signal that with obesity and the chronic systemic inflammation it has including in the brain you potentially are losing this cephalic phase response That last point I think matters for this metabolic classroom If the cephalic phase effect in humans is real and it small and it impaired in obesity then it may be a meaningful contributor to the postprandial hyperglycemia and the delayed insulin peaks that characterize early metabolic dysfunction. If you could restore an early little bump in insulin because of the cephalic effect, for example, you know, like using just a brief little subcutaneous injection. So if you can't do it in the brain, there was some way to get a teeny little dose of insulin in, then you could significantly improve the glycemic response to a glucose load. This is consistent with the idea that the loss of early, nearly stimulated or mediated insulin pulse can contribute to the glucose regulation after a meal. Now, beyond the cephalic effect, the vagus continues to modulate beta cell function throughout the entire post-prandial or post-meal period. Direct vagal stimulation in animals reliably increases insulin secretion. And this effect is blocked by a molecule or a drug called atropine, which confirms that the signal is mediated by what's called a cholinergic signaling like acetylcholine. The relationship with incretins is also important. And of course, the most famous incretin is GLP-1. Those of you who are longtime students of the metabolic classroom have heard me use that term previously. In fact, not even that long ago. When a meal stimulates GLP-1 release from the gut, part of that signal reaches the beta cell, not just through the bloodstream, but through a neural reflex loop involving the vagus. So there's kind of a direct ability to communicate here. One more idea is worth mentioning. There's a specific population of vagal sensory fibers that directly sense the pancreatic islet. So the islet within the pancreas are these little clumps of cells like the beta cells or the alpha cells that make glucagon. Because beta cells release serotonin along with insulin, and that's interesting alone because serotonin is a nervous signal. These sensory fibers appear to provide a real-time feedback signal to the brain about how much insulin the pancreas is actually secreting. So just think about that again. It is so fascinating to me that we typically would think, well, the brain only knows how much insulin is coming out when the insulin makes it to the brain. And yet, because serotonin is also released when insulin is released, that then affects the vagus, sending a signal directly to the brain, telling the brain how much insulin is coming out. Now, in the midst of all of this elegant neural control of the beta cell, there appears to be a bit of a breakdown in obesity and type 2 diabetes, and there are several lines of evidence worth noting. First, animal models of obesity-induced diabetes show a clear disruption of vaguely mediated insulin secretion. In lean animals, glucose arriving at the liver via the portal vein will trigger a vagal reflex that appropriately stimulates insulin release. In obese rats, this reflex is uncoupled and the animals now fail to mount a proper insulin response to an oral glucose load. So this is touching back on this fascinating nuance of how you might have a person who's not secreting a proper amount of insulin based on the glucose load. And it has nothing to do with the glucose getting to the beta cell, but it has everything to do with the vagus conveying that signal. Now, second, the cephalic phase itself is attenuated or diminished in obesity. People with obesity tend to have impaired cephalic release, if that is something that is real in humans. In the mouse model, the defect was traced to that dysregulated interleukin-1-beta signaling that I just mentioned. Now, notably, and I alluded to this a moment ago, chronic inhibition of interleukin-1-beta normalized that response in that animal model. This is a provocative observation because it connects the chronic low-grade inflammation, even neuroinflammation, which is well-documented in obesity, to a specific defect in the neural control of the pancreas. Third, resting vagal tone itself appears to be reduced in metabolic syndrome. Heart rate variability is something you've absolutely heard of, and there are many devices that measure it these days. It's a reflection of parasympathetic activity. The heart rate variability is consistently lower in people with insulin resistance, central adiposity, and type 2 diabetes. Lower parasympathetic tone is associated with higher fasting glucose and worse glycemic control. And these associations hold even after adjusting for something like BMI and age. Whether reduced vagal tone is a cause or a consequence of metabolic disease is still unclear. It's still debated, but either way, it fits a broader picture in which obesity disrupts the neural arm of metabolic regulation in parallel with its more well-known hormonal effects. Taken together, the picture that's emerging is that the vagus pancreas axis is not an ancillary modulator of insulin secretion. It's not on the periphery. It's not tangential, but it really is a meaningful contributor and one that is progressively lost in metabolic disease. Restoring it, whether through weight loss or anti-inflammatory strategies, or even perhaps direct neuromodulation, which I'll get to, that's a topic worth discussing. Let's move on to something that might be a little unexpected, which is surgical alterations. Now, given the extensive vagal involvement in metabolism, what happens when the vagus is cut? Well, we actually have decades of clinical data on this, mostly from an era when vagotomy, the snipping of the vagus was a standard operation. The metabolic consequences of cutting the vagus are interesting. When the vagal trunks are severed, the insulin response to oral glucose is diminished, while the response to intravenous glucose remains intact. So in other words, ingesting carbohydrates is now not eliciting a normal glucose response, but infusing glucose is working just fine. In this case the intrinsic beta cell function is preserved So the ability of the beta cell to sense glucose is maintained but what lost is the cephalic and the incretin those gut hormone contributions that depend on vagal signaling. Notably, this disruption is confined to the fed state. Fasting glucose metabolism and just normal baseline glucose production and the adaptation to a fast, they're all unaffected. The vagus matters most during feeding and the early post meal or post-prandial window. It's not during the steady state fasting where hormonal systems are generally more dominant. This physiology is directly relevant to obesity where the vagus has become a therapeutic target. The clearest example is vagal nerve blockade or V block. This is actually the only FDA approved vagal procedure specifically for obesity implanted electrical leads are placed on the interior and posterior vagal trunks and they then deliver high frequency pulses that will intermittently silence vagal signaling to the upper abdomen producing what producing ultimately a reversible version of a vagotomy like rather than just going in and snipping the vagus this device can just release these electrical pulses to silence the vagus. And again, it's something you can turn on or off. With this device, patients have been shown to lose up to about a quarter of their excess body weight, so about 25% of their body fat sustained through two years with concurrent improvements in glycemic control and other cardiometabolic outcomes. The magnitude is a little, it's modest compared to gastric bypass or to even GLP-1 agonists these days. But mechanistically, it's a very clean proof that if just interrupting the vagus alone is sufficient to produce meaningful weight loss without any of the anatomical rearrangement of the guts. Now, the vagus is also cut like it is snipped surgically, but often inadvertently during bariatric or gastric bypass surgeries. sleeve gastrectomy um when you put in this when you when you adjust the shape of the stomach it will usually sever only the distal fibers of the gastric vagal branches whereas the more the more historical version the rouen y gastric bypass typically transects both the anterior and posterior branches which of course substantially disconnects the vagus signaling from the stomach to the hind back up to the brainstem some surgical groups now deliberately preserve that hepatic branch and preliminary evidence suggests this actually may improve glp1 responses and glycemic outcomes though the human data is still you know out it's remaining remains to be determined the broader point here is that the vegas is a genuine lever for body weight and glucose regulation, multiple lines of direct human evidence, whether it's vagotomy or V-block or bariatric surgeries converge on the same conclusion that the neural arm of metabolic regulation is not optional in really understanding normal metabolic function. Okay, so let's continue this line of thinking. If cutting or blocking the vagus has metabolic consequences, what about stimulating it? Well, a growing category of non-invasive devices is doing exactly that. What makes them possible is that the vagus is accessible to electrodes on the body surface in two places. The outer ear, where we have a small sensory branch that reaches the skin, and the side of the neck, where the cervical trunk runs close to the surface of the skin. The most established device is a handheld unit applied to the neck. It's marketed as GammaCore with FDA clearance for several headache indications, including things like migraines. In randomized trials, it reduces pain and attack frequency compared with sham or placebo with a very good safety profile. the mechanism involves modulation of the central pain pathways rather than anything directly metabolic but it's still a clear demonstration that the transcutaneous vagal stimulation can produce reproducible clinical effects now the second category is the transcutaneous auricular vagus nerve stimulation and that uses a small clip or electrode on the outer ear these devices are widely studied, but they're not FDA approved within the United States yet. The evidence varies based on the outcome you're looking for. There are some reported benefits for depression and anxiety and even insomnia, stronger effects for functional dyspepsia as well. So some stomach issue or digestion. And there are some documented acute shifts in heart rate variability. So suggesting that it's changing this, this autonomic or this parasympathetic tone for metabolic disease, specifically, the direct evidence remains a little preliminary. Pilot trials of the daily ear-based stimulation in impaired glucose tolerance have shown improvements in glucose tolerance, but these need to be replicated with larger, better controlled studies. For now, the external vagal devices are definitely a real technology with real benefits, but less so established with regards to metabolic benefits. all right let's summarize as we wrap up the vagus nerve is a central player in metabolism it delivers the earliest signal to the beta cell during a meal through the cephalic phase it modulates the hepatic glucose output metabolism during both feeding and fasting it allows the gut to communicate nutrient status to the brain within seconds and it even listens to the pancreas itself providing the brain with real-time feedback about insulin secretion. All in all, the vagus is a reminder that the brain is continuously influencing metabolism with every organ in that visceral space, and that anything which disrupts this, whether it's obesity-related neuroinflammation, whether it's surgical transection, or even age-related vagal decline, they will have downstream very real consequences for how well the body can handle nutrients. Thanks for joining me today. I'll see you next time in the metabolic classroom. Until then, more knowledge, better health.
