← The Metabolic Classroom with Dr. Ben Bikman
The Metabolic Classroom with Dr. Ben Bikman
Why Your Bones Affect Your Metabolism
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More Knowledge, Better Health
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Your bones are doing more than holding you up. They're part of your metabolism. Bone is living tissue. It's constantly being broken down and rebuilt. And that process responds to insulin and blood glucose. When insulin works well, it helps build and maintain bone. But when glucose stays too high for too long, it can damage the collagen inside bone, making it stiffer and more brittle. That's why someone with type 2 diabetes can have normal bone density, but still have a higher fracture risk. The bone looks dense, but it doesn't behave strong. Bone may also send signals back to the body, influencing insulin, fat cells, appetite and energy use. The science is still developing, but the takeaway is clear. Your skeleton is part of your metabolic health resistance training. Stable glucose and good nutrition don't just help your metabolism, they help protect your bones. This is lecture 155 of the Metabolic Classroom. Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today we are going to explore an organ you almost certainly don't think of as metabolic at all. Your skeleton. For most of the history of physiology, the study of the systems of the body, bone was treated as inert scaffolding, simply a mineral frame, like big pieces of chalk that just holds everything up. Well, bone turns out to listen closely to the metabolic state of the body. It responds to insulin and even to the level of glucose in the blood. And the bone talks back. It releases hormones that can travel to the pancreas, they travel to fat tissue, they even get to the brain. So to get started on this mini lecture, I just want you to understand why anyone even was interested in looking for a metabolic role for bone in the first place. So what were these biomedical scientists and clinicians even thinking about? Well, before we get to that, I just want you to understand what bone is actually is. Far from being a static or set piece of calcium like, like a piece of chalk, the skeleton is living tissue. It is undergoing constant renewal. It's broken down and it is rebuilt throughout your life by two opposing teams of cells. One team is the team of cells that lay down or create new bone. And then there's another team that dissolves old bone. And it's that perpetual remodeling that keeps not only the bones healthy, but it is also what demands a metabolic relevance. These are energy demanding processes. They need fuel. This work has to be paid for from our own, from, from within the economy, if you will, of the body's metabolism. Anything that costly to run and rebuild. Thinking of the constant breakdown and rebuilding of the Bone relies on some relevance or has a position in the overall metabolic milieu of the body. Okay, so the first clue that bone is wired into metabolism came from the opposite direction, actually from fat. It was already established that a hormone released by fat tissue, leptin, signals to the skeleton and it shapes how much bone gets built. Now, you're of course familiar with leptin at this point, you studious students of the metabolic classroom. We've talked about it abundantly. It's interesting how often leptin among which is common among hormones, where you, you. We think we know what it does and we've assigned it a singular role. In the case of leptin, it would be satiety, when in reality the actual satiety effects appear to be somewhat modest. Maybe in a different universe, leptin would have been discovered for its role on bone metabolism and we would have called it a bone hormone. In this case, leptin stimulates an overall net synthesis. And I'm going to talk more about that net balance in just a moment. But leptin stimulates bone formation. Once you accept that fat can give a signal to the skeleton, then there are some logical questions that follow from this. The first is how much bone responds to the rest of the body's metabolic signaling. And the second is whether the bone is capable of sending its own response, whether the bone can answer back. All right, now let's start with insulin, of course, because insulin is not only a glucose hormone, but primarily it is a growth hormone. Let me just emphasize that insulin is so often. Once again, it's one of those instances where we think we know what a hormone does and we just assign all of its value to that one single thing for far too long. Historically, insulin has been considered as nothing more than a hormone that regulates blood glucose. That is wildly unfair. Insulin has many, many talents and its thematic effect is to tell something to grow. Bone is no exception. Bone is one of the tissues that insulin will signal to build. The cells that form new bone will carry their. They have their own insulin receptors. So they're insulin responsive cells, like every cell of the body is. And when the insulin signals to these bone building cells, it tells them to promote bone formation. That means the skeleton is a very big genuine insulin target tissue. It responds to the same hormone that governs the rest of fuel handling and fuel metabolism in the body, again namely insulin. When that signaling is intact and it's working well, bone is built and it is maintained in step with the body's metabolic needs and overall other signals. Now you can see how much this matters by watching what happens when insulin signaling breaks down in type 1 diabetes, where the capacity to make insulin is lost. So in the absence of insulin, bone pays a visible price. There is a significant reduction in bone density and a deterioration of the final effects of this. All of the minute internal architecture that gives the bone its strength, it's eroded. This is a direct consequence of removing insulin's building signal. Now again, in this instance, in this body, in the absence of type 1 diabetes, there would be other signals, there would still be some leptin signal, there would be some growth hormone signal, some insulin like growth factor, IGF1 signaling, all of these anabolic signals. But in the absence of insulin, it doesn't matter. It's not enough. Type 2 diabetes presents a bit more of a more nuanced but also I think more instructive picture. People with long term type 2 diabetes often have a bone density that will read normal on a standard DEXA scan, and yet their risk of hip fracture is increased significantly by up to as high as 50%. So this seems to be a bit of a contra, a contradiction. I think it's kind of a striking one that in fact it's so common, it's so commonly seen, and this contradiction is so commonly reconciled or have is dealt with that it has its own name. It's called diet the diabetic bone paradox. Again, the paradox being the bone looks normal and yet it's not. It is fracturing at 50% higher rates than it, than it would be in someone without type 2 diabetes, even if they're the overall same body size. The resolution of this apparent conflict is that the scan measures quantity of bone. While the problem is really a quality issue, chronically high blood glucose levels, in addition to myriad negative consequences, they drive the formation of advanced glycation end products. So these sticky cross links that form when excess glucose reacts specifically with the collagen scaffold inside the bone. Often when you think about collagen, you think about maybe skin or, or other tissues. Even the bone has collagen, but that makes these cross links stiffen. So this collagen scaffold within the bone gets a little harder, but it also means it gets more brittle. And so it's the toughness of that bone becomes compromised. What would normally let the bone bend slightly with a load now cracks. So the bone looks dense, but it behaves like glass. But of course, I can't go too long in a conversation on glucose without talking about insulin. Glucose is only half of how the metabolic state Affects bone because insulin is that growth signal and bone is one of the tissues that it will build. As I noted, the cells that lay down new bone carry those insulin receptors, as I said a moment ago. And when insulin signals to them, it drives this bone formation. That dependence is exactly why insulin resistance turns against the bone. Being able to build a skeleton in a state of insulin resistance has less of the building and renewal work. And bone turnover, rather than increasing, is now suppressed. That's a pattern that is measurable in insulin resistant people independently of how much fat or mass they carry. This is a second blow separate from the glycation that I just mentioned. High blood sugar will stiffen the existing scaffold from the, from the outside, if you will, while the loss of insulin signaling starves or deprives the cell that would build and renew it. The the bone from within. The dense brittle bone of that that occurs with long term diabetes is the product of both of these insults. So there's a two pronged attack, the glucose and glycation on one hand than the insulin resistance and the loss of anabolic signaling on the other. Now, we don't know the specific mechanism of the insulin resistance I would suspect, so I'm unaware of any study that has measured the molecular mediators of bone insulin resistance. But I strongly suspect it's going to be the same microscopic molecular mediators that we see when we identify insulin resistance in tissues like the brain or muscle or liver, et cetera. And that's going to be the accumulation of that sphingolipid ceramides, something I've discussed previously, although it's been a little while. But when you wonder at where the rubber meets the road within the cell. In other words, what is the last mediator or the last molecule that actually prevents the cell from responding to insulin? Well, ceramides is usually going to be the answer. Now there is a final piece to how insulin signals to the bone and it's the one that sets up the entire second half of this mini lecture. When insulin signals to the bone building cells, one of its effects is to lift a break that's or, or remove an in an inhibitory signal on those cells that normally keep on the bone dissolving team. So it allows a measure of the bone with, with bone resorption proceed. So let me, as I stumble through that, let me just kind of restate some of that resorption of bone matters. That's part of the turnover when we are breaking down to build back up. But that resorption further matters beyond just bone mass itself for a chemical reason, because the same cells that are involved in bone dissolving work also in the process create a little pocket of a more acidic PH on the bone, on the surface of the bone. That's part of eroding the bone. Again, that's not on its own directly pathogenic. You do need to break the bone down. But that acidifying aspect of the bone ends up stripping off a chemical tag on a molecule called osteocalcin. When that happens, when the ph change has stripped off this tag on osteocalcin, it converts the osteocalcin from a locked in form. So a form that would keep the osteocalcin locked into the matrix or the mesh of the bone, now into a released or active form. And so it then gets released into the bloodstream. So let's now talk a little bit about osteocalcin because that's part of this bone metabolism story. Osteocalcin is the most abundant non collagen protein in the bone. And it's made by the same bone building cells that we've been discussing. As I mentioned, it exists in two forms. Most of it is modified in a way that lets it bind to bone mineral and stay fixed in the matrix of the bone. But a small fraction of it will have been modified. And so this, this now modified form is able to leave the bone and now circulate. And now as a circulating protein, it acts like other circulating proteins. In other words, it acts like a hormone. Some of this further modification of osteocalcin depends on vitamin K. So vitamin K status influences how much osteocalcin stays in the bone and how much enters the bloodstream as a signal. And of course, vitamin K is found mainly in animal foods and then some fermented foods. Once this modified form of osteocalcin gets into the blood, it can go to the pancreas. And there are some animal studies show that it can increase the ability of the beta cells to respond to a glucose stimulation. So it's not going to be pushing insulin up artificially or even I would say pathologically, it's enhancing the ability of the beta cells to respond when they should be responding. Now one thing that you'll find interesting because it's so timely is that osteocalcin also acts on the gut, specifically the L cells. Now do you remember from previous metabolic classrooms what the L cells produce? They produce GLP1, that is that now famous incretin or gut derived hormone that we've Discussed now many times. All right, now osteocalcin isn't done in its effects as we continue the mini lecture to look at what the bone, how the bone affects metabolism. Because osteocalcin also acts directly on fat cells. And its effects there go well beyond just a kind of single hormone signal. The best established evidence here is that osteocalcin prompts fat cells to produce more adiponectin, a hormone that's released by fat tissue that has very favorable metabolic benefits throughout the body, namely including increasing insulin sensitivity as well as promoting direct fat burning. But the same work with the adiponectin showed a second effect alongside it. Osteocalcin can raise a main or activate a main cellular regulator of energy expenditure in brown fat. This is a signal we've talked about previously called PGC1alpha. And so osteocalcin stimulates PGC1alpha including and most especially in brown adipose tissue. And that's the tissue that's specialized for burning energy to produce heat. So the signal is pushing fat toward spending energy rather than storing it. Beyond these changes in what fat cells secrete and burn, osteocalcin alters how the fat cell handles glucose directly. It increases glucose uptakes, so it helps that glucose response and the rate at which the glucose is used both at rest and in response to ins insulin. It also lowers the fat cells output of inflammatory signals that's closely tied to of course, insulin resistance. And adipocyte hypertrophy does this all at the same time. Now this is some preclinical work and so we need to have further evidence later. But the evidence in the preclinical models, so fat cells growing in culture or adipose tissue from animals, shows that osteocalcin can signal the, the, the reduction in stored fat and it can make the fat cells shrink. So it's overall resulting in an increased mobilization and burning of fat rather than the lockdown or the storage of fat. Now I want to mention another bone derived hormone here. It's a second bone hormone in the, in this mini lecture because it's just, it's pretty interesting I thought and I figured if it's interesting to me, it's probably interesting to you. In this case, this hormone doesn't just signal to the pancreas or the fat, but it travels all the way up to the brain. The Hormone is called Lipokalen 2 and it's released by the same bone building cells that make osteocalcin. And in this case the output, it rises After a meal, which is the first hint of what it does, this bone derived hormone, Lipokalen 2, it will cross from the blood into the brain and it acts as an appetite suppressant. So it acts on the same appetite control center that a lot of these other famous appetite control hormones do. And so it influences how much you eat. And its effect is of course to signal a reduction in food intake. Isn't that interesting? So part of the signal that tells you that you've had enough to eat in real time, I mean immediately following a meal, comes from your skeleton and it does so in time, with meals rising, so you've eaten a meal, the bone releases Lipocolin 2. It goes through the blood, through the blood brain barrier, and it helps cap our appetite. Now, alongside that Effect on hunger, Lipocolin 2 acts on the insulin producing cells to support their function and survival, not unlike osteocalcin and it improves glucose tolerance. So it carries an appetite suppressing role and a glucose regulating role at the same time. Now, as much as I present lipocalin 2 as a brain signal, it does also signal to fat cells. And in some laboratory settings it also raises adiponectin and it switches on some of the insulin like signaling within those cells, so helping perhaps improve some of the insulin sensitizing effects. Now we can see this circuit where insulin signals to the bone building cells which lifts the brake on bone resorption. And that resorption releases the active form of osteocalcin, which returns to the pancreas to support insulin output under glucose stimulation, and to fat tissue to improve insulin sensitivity and reduce the inflammatory signals from that adipose. So in a way it's a little bit of a feed forward arrangement. It's a loop that's link the pancreas, the skeleton and fat cells in which insulin elicits the very bone signal that improves insulin's own sensitivity or efficiency. This is kind of a self reinforcing design that the body uses when it wants a process to stay coordinated rather than to kind of drift out of control. And the reorder we just walked through, from how the bone listens to how bone answers, is the only way the arrangement I think makes some sense. The loop also has a leverage point because the skeleton responds to mechanical load loading. The skeleton the demand that resistance training and weight bearing movement place on bone raises the circulating osteocalcin signal, so it increases osteocalcin levels. And the pooled results from human exercise trials show that training is accompanied by higher osteocalcin more adiponectin and lower or improved insulin resistance. That same signal improves the way muscle takes up and uses glucose. This lines the bone network up neatly with the levers. We already emphasize lowering the insulin load through how you eat, keeping glucose low and steady so the collagen scaffold is spared the glycation in the bone that makes it brittle, and supplying vitamin K that can influence osteocalcin's chemistry and loading the skeleton through training. That's a lot right there. But it all pulls in the same direction and none of it stands in opposition with a low carbohydrate diet. In other words, the perfect complement, if you are looking to leverage metabolism from the bone signaling in your favor, I would submit, is a low carbohydrate diet, one that helps keep insulin sensitivity in the body and glucose low, as well as resistance training, which of course has myriad benefits, one of which, as outlined here, will be that it stimulates the bone to release more osteocalcin and then you're further reaping the benefits of that bone derived hormone, all in defense and in favor of your metabolic health. That's it. Class dismissed. Until next time. More knowledge, better health.