Hi, everyone, and welcome to today's hands-on seminar, Tips to Improve Diabetes Care. Today, our panel will share their expertise on heat and cold, point-counterpoint, and we're glad you're here. I'm Steve Mallon, and I'll be moderating today's webinar. To share a little bit about myself, I'm currently the co-chair of the Exercise Physiology Interest Group, and I'm an associate professor at Rutgers University, studying the effects of exercise on type 2 diabetes, in particular, with emphasis on understanding insulin resistance and how exercise can interact with factors like nutrition as well as pharmacology. We're going to spend the next hour together on a really interesting topic. We're going to be using interactive features during today's session. So in the chat box, we will send you important information and links throughout the entire session. We also want you to get engaged. We'll have two polls pop up during the presentations, so please keep an eye out for them and get involved. We'll use Zoom Q&A at the end of the presentation for panel discussion and questions. If you think of a question throughout the talk, please use the Q&A box on your control panel to type in your question. With that said, don't forget about next time. Join us next month on May 13th for the next installment of the hands-on webinar series. You can scan the QR code, as you see on the screen, or check out the link in the chat box to register. Now, I'd like to introduce our panelists for today's webinar. You can see a bit more by clicking on the references at the bottom of the toolbar to see their biographies. But briefly, I'd like to share that Dr. Paige Geiger received her bachelor's of arts in chemistry and English literature from the University of Kansas, graduating Phi Beta Kappa and from the Kansas Honors Program. After graduating from Kansas University, Paige obtained a PhD in physiology from the Mayo Clinic Graduate School in Rochester, Minnesota. She was awarded a National Science Foundation postdoctoral fellowship to continue her research training at the University of Florence in Italy for one year before completing her postdoctoral training at Washington University School of Medicine in St. Louis. She began her career at Kansas University Medical Center as an assistant professor in the Department of Molecular and Integrative Physiology in 2005. Now, Dr. Matt Lines is a faculty scientist at Maine Health Institute for Research, specializing in systematic energy balance and metabolic tissue signaling. With expertise in brown adipose tissue biology and lipokine signaling, he has led research identifying 1213 dihome as a biomarker for brown fat activation. As a principal investigator on a K01 Research Scientist Development Award, his work bridges preclinical discoveries to human application. In 2021, he established a lab at Maine Health Institute for Research, focusing on the development and origins of brown adipose in mice. Now, at this time, I'll let the panelists introduce themselves, state their disclosures, and get started with their talks. Thanks again. Hi, I'm Paige Geiger. It's nice to be here. These are my disclosures. Good afternoon, everyone. My name's Matt Lines. Thanks for having me, and these are my disclosures. Alright, I have a slide here showing a beautiful thermal spa to get us in the right mood for the beginning of this session to talk about heat therapy. And I'm going to go through a few main objectives. I want to introduce to you some ways that heat is thought to be an alternative for exercise to improve mitochondrial function and glucose regulation and the prevention of type 2 diabetes. And then I'll talk about some current research being done in different heat therapy modalities, which is pretty exciting right now. The field is exploding. So heat therapy is really an ancient practice, going back to the time of the Romans. And really, I think it's helpful to think of it in terms of how it compares to exercise just for practical reasons, and I'll explain that as I go. But really, sort of the modern interpretation of heat therapy that I'm going to be talking about today, I attribute to a study that was done in 1999 by Dr. Phil Hooper out of Colorado. And at that time, Dr. Hooper was seeing patients in his endocrinology clinic, and he was just wondering about, he actually told me later that when I met him at a conference that he was sitting in the hot tub one weekend, thinking that he felt warmer and that maybe his blood flow might be improved as a result of that heat. And so he decided to put some of his patients in a hot tub for three weeks. He took them every day for about an hour over the course of three weeks, and he didn't change anything about their diet or their insulin therapy at the time, just put them in the hot tub every day for an hour. And so this was a small sort of perspective study that he did, and he managed to get it published in the New England Journal of Medicine back in 1991. And what was significant about that very small study was that in just those three weeks, he saw improvements in HbA1c of all the individuals, and he also noticed that quite a few of them lowered their insulin dosage if they were taking insulin. And so again, at that point in 1999, he thought this was simply an artifact of improved blood flow due to the heat. And it wasn't until 2008 that a group in Australia led by Mark Fabrio followed up on this idea and really started looking at what might be happening in response to heat in different metabolic tissues. In particular, Dr. Fabrio observed that individuals that were obese or insulin-resistant had low levels of heat shock proteins in their skeletal muscle, and he noticed that if he were to activate those heat shock proteins with heat in mice or with a pharmacological compound, that he was able to protect those mice from insulin resistance in the presence of a high-fat diet. And so really, there was a series of studies that came out after that very first Hooper study in 1999 in humans, and the series of studies over the next decade really focused on sort of preclinical models in rodents looking at the response to heat almost as a way of understanding these heat shock proteins as molecular mediators of different pathways. And so again, that Fabrio paper was published in 2008, where they looked at these different aspects of glucose regulation in response to heat in mice. We followed that up with a study in 2009 showing an effect specifically in skeletal muscle of the heat intervention in a preclinical model. And what all these studies had in common in these early days was this focus on heat shock proteins and what they might be doing molecularly. So I'm going to spend a little time talking about that, because I think it's really the foundation of what we now understand about heat, and it laid the groundwork for what is now an exciting field of translational research looking at heat therapy for different patient populations. So this is a figure that probably makes a lot of sense to many of you. We're very familiar with the multifactorial benefits of exercise and the ways in which an about of exercise can impact all the different tissues in our body, from our muscles and our liver to the brain and our adipose tissue, and definitely our heart and our circulatory system. But actually, this is a figure from a paper published, again, by Mark Fabrio's group in 2014, showing the benefits of heat on multiple systems in the body. And we know that heat shock proteins, particularly one heat shock protein, heat shock protein 72, is upregulated in response to exercise and also in response to heat. Now these heat shock proteins are typically thought of as chaperones. They aid in protein folding, and that's sort of how they were originally studied and discovered. But we now know they have many different properties and very unique signaling properties, which we have explored in skeletal muscle as well as in the liver. And they also potentially interact with mitochondrial proteins, which I'll show you in just a second. So if we think about in terms of what's happening in metabolic tissue and in terms of glucose regulation and why we're interested in these heat shock proteins, on the left of this slide we have sort of what we think of as the typical insulin signaling pathway in muscle, primarily, by which glucose gets taken up into the cells. And so we have insulin attaching to the insulin receptor at the cell surface and setting off a series of downstream cascade signaling that results in glucose being taken up into skeletal muscle, for example. When we have insulin resistance due to either excess caloric nutrition or aging, we get a series of oxidative stress pathways that get activated in the muscle and the turning on of proteins like junk and IKK beta that can inhibit this insulin signaling pathway. And this is fairly well established in the literature. And this is really where my interest in this field started, is in thinking about how heat shock proteins might be able to interact with this pathway. So if you look at the figure now on the right, in response to either exercise, heat stress, or various pharmacological agents, the main heat shock transcription factor, HSF1, can be turned on and signal the upregulation of several heat shock proteins, of which heat shock protein 72 and 25 are the two that I've primarily studied. And they can directly interact with these stress proteins, the IKK beta and the junk, for example, that can turn down the heat on that stress pathway, if you will, and allow insulin to be restored in the tissue. And so we can see that the effect of this if we look at one of our in vivo studies in a preclinical model. So here on the left, you'll see we have a glucose tolerance test with blood glucose over time. And in the three different groups we have, we have normal chow fed rats, in this case, have the normal response to glucose, the lower line. And then we have a group of rats where we fed a high-fat diet to make them insulin resistant, which you see in the top line. And in that, you can see that their glucose response is blunted. And we see that insulin resistance that we think of as a pre-diabetic state. And then in response to heat treatment, so over the course of 12 weeks in response to the high-fat diet, we give them a heat treatment just once per week. And you can see that middle line, the dashed line, we bring that glucose curve down with just one heat session per week in this rodent model. And in addition to being able to lower that blood glucose over time, we do this. This resulted in a less taxing insulin response in these same animals. So you can see in the serum insulin response, the normal and the chow fed, the insulin resistance as a result of the high-fat diet. And then in response to the heat, we're able to lower that insulin level and get glucose lower in the face of a decreased insulin production. And then finally, the last point I want to make here is that we specifically showed that the primary effect of this heat is acting on skeletal muscle glucose uptake. And so down here, we see in the lower figure, we have 2-deoxyglucose uptake, which is an in vitro assay in skeletal muscle. And the basal levels of insulin uptake are shown in white. And then the dark bars show the glucose uptake that occurs in response to insulin. So this is the normal response that we might see in healthy rats. With the high-fat diet, that effect is severely blunted. And then in response to just one heat treatment per week, we are able to restore that insulin stimulated glucose uptake, which is really fundamental to preventing that progression towards type 2 diabetes in this model. So back to our idea of how heat can overlap with the exercise in terms of potential mechanisms, I point out this seminal paper by the late, great Dr. John Hallisey that was published in 1967, which was really our first measure of the effects of exercise on mitochondria, showing that the mitochondria in our muscles adapt to exercise by, in this case, increasing oxygen uptake and increasing cytochrome oxidase activity. And I've always had this thought that perhaps heat could do something similar in skeletal muscle, that it could not only improve glucose utilization, but that it might be impacting the mitochondria as well. And so we did a number of studies to look at this idea. And I'll just show you a real quick snapshot of some of that data. But to kind of steal our thunder a little bit, we did not see what we thought we might see. So in other words, I was hopeful that like exercise, heat might be beneficial or increasing the function of mitochondria. But acutely, that is not actually what we saw. So in this particular study, we were looking at mitochondria from the liver. And we gave the mice a whole-body heat treatment. So this involves, just like in the last study, that one heat treatment. We put them in a water bath, much like if someone were to sit in a hot tub, their waist down in the water bath. And we warm them up and raise their core temperature. And then we sacrifice them at different time points to really get at what's happening acutely in response to heat. And so you can see at the zero time point, the blue is our sham-treated or non-heated mice. And then the red is our heated. So that will be the pattern I'll show in the next couple of slides. And as you can see, in terms of their response to different substrates, whether it's pyruvate or acetyl-CoA, the response to the acute heat was a decrease in mitochondrial respiration. So the red bars actually showed a decreased function immediately after heat. And you can see that with time at the one-hour and the two-hour spot, that decrease sort of goes away. And the respiratory function is restored. But at least initially, we see a blunt decrease in the ability of the mitochondria to take up oxygen as a result of that heat treatment. So we were initially very surprised by this. Again, it's not what we expected. But we did a number of other studies looking at these mitochondria. And if you look here on the left, you'll see EM images of sham-treated or non-heated mice compared to the heat-treated. And these are their liver mitochondria. The circular shapes that you see of the mitochondria on the left is our typical striated mitochondria. And you can see the arrows, the red arrows, are pointing out mitochondria that are undergoing some sort of remodeling. So they're either fizzing together to make a larger mitochondria, or they're fusing apart to make smaller mitochondria. And this is something that, as you can see, occurs in the normal sham-treated. But it occurs to a much greater extent in our heat-treated mitochondria. And to follow this up, what we figured out what was happening is that initial fusing and fizzing that we were observing is a early step in the process of mitophagy, or the degradation of mitochondria. And so we were seeing changes in the signaling of these different mitophagy markers, like DRP1 and mitofusin-2, again, showing the blue being our sham-treated and the red as our heat-treated. So these signaling pathways by which mitochondria are degraded were turned up in response to the heat. So interestingly, we followed this up with a more long-term heat treatment, or a chronic heat treatment. Because as I mentioned, when we did our in vivo study in the rats, we saw that 12 weeks of repeated heat treatment was beneficial to that glucose regulation. So we wanted to see if, over time, perhaps the mitochondria were adapting and there was actually some benefit to a more chronic heat treatment. And that actually is what we saw. So in this case, the same set of mice, a different series of them, but the same type of conditions. And this time, instead of one heat treatment, we gave them a heat treatment every 72 hours over the course of three weeks. So they got about 10 heat treatments over a three-week period. And as you can see now, looking at mitochondrial respiration and O2 flux, we see that if you look towards the right of this left figure, that again, the red bars represent our heat-treated mitochondria. And now mitochondrial respiration is increased in response to these repeated heat bouts. And this is supported by looking at H2O2 to O2 flux ratio, which, just to simplify that, is a sort of indicator of mitochondrial efficiency, how well the mitochondria are working at any given time. And a decrease in that ratio indicates an improved efficiency. So what we see in these mice is that, initially, we're turning on this mitophagy pathway, as you can see here, as a result of the heat shock protein activation, and as well as other cellular pathways that result in improved glucose regulation. But over time, what we think is happening is that, as a result of that mitophagy, those poor-functioning mitochondria are degraded and removed. And what's left is higher-quality, better-functioning mitochondria. And so we developed this into a bit of a model that, with an acute heat bout, much like an acute bout of exercise, you get some initial sort of stress response, much like muscle will produce reactive oxygen species in response to that initial exercise bout. We get a stress response to the heat that, over time, results in a more improved mitochondrial function. Now, one of the things I want to switch gears a little bit now is, after having talked to you a little bit about some of the mechanisms that we understand are happening in the tissue and at the cellular level in response to heat, I want to start thinking about how we're now translating that and applying that to different human studies. And so what evidence do we have in the humans of this benefit of heat on whether it's glucose or mitochondria? So we'll start to talk about that. And one thing I want to do is throw up a question here. And this is a little bit of a trick question because I haven't told you all of this information yet. But just imagine, after what I've told you already about the effects of heat, if you were to repeatedly heat muscle directly with, say, something like diathermy, which is a high electromagnetic source of energy that can heat up a muscle, and it's used very commonly in a rehabilitation hospital setting, if you were to use diathermy to heat the muscle directly, what effect would that have on mitochondrial function in human skeletal muscle? Do you think it would improve mitochondrial adaptation? So in other words, let me phrase it towards the question, repeated muscle heating would induce mitochondrial adaptation in skeletal muscle. And tell me whether you think that is true or false. I'll give you a second to think about that. So, for those of you that said true, that is correct. So in terms of what's happening, this is really exciting research that was published just a few years ago out of BYU, where they used this diathermy approach, which again is commonly used in muscle rehabilitation and physical therapy type settings, and they heated the muscle directly over two hours over a course of about a week. And they were able to show, by taking muscle biopsies at the end of that week, that the mitochondrial function within that muscle was dramatically increased and improved as a result of that direct muscle heating. So this leads me to thinking about what we know about heat on a cellular level, and now how can we apply heat and use this information to benefit different populations in which need an alternative to some of the other adaptations that we know are out there. And so this field has sort of exploded in the last decade, and really I attribute this to a paper that was published in 2016 by Chris Minson's group out of the University of Oregon. And this was the first study that sort of replicated that very first Phil Hooper paper that I talked about from 1999, and in this study they took some young, healthy individuals, put them in the hot tub every day for eight weeks, and then they looked at some outcomes that were related to cardiovascular function. They looked at blood pressure, for our blood flow, and they looked at endothelial function, for example, and they saw benefits in all those different measures that were on part, or in some cases even greater, than what eight weeks of aerobic exercise typically produces. And so this study really opened up a lot of new avenues of research by showing that hot tub immersion, or heat therapy, was safe in this population, and that it had dramatic effects on some really basic physiological outcomes that we're interested in in terms of different diseases. They followed that study up by showing that in women who are obese and have polycystic ovarian syndrome, that they could improve their glucose regulation as a result of the heat session. So if you look here, these are these glucose tolerance tests in individuals that have polycystic ovarian syndrome, and you can see they're divided into pre-heat during the middle of this 10-week study and after, and you can see that the closed circles show a benefit of the 10-week heat therapy on glucose regulation, much like those preclinical studies that I showed you from our RAP model. And so this has really resulted in the field thinking about what do we need in terms of ways to utilize heat, and what are the different options? And really, I think the important thing here is not to replace exercise, but to find alternatives for different populations who maybe can't exercise to the extent that they need to in order to get the benefit. So individuals who have some reduced physical capacity, say due to injury or recovery from surgery, or some other secondary complications of chronic disease, like aging or cognitive impairments. So there really is a need to try to find other alternatives. I like to show this slide, you know, just to kind of put out there that, of course, I know that there are certain populations that maybe need to think twice before just hopping in a hot tub to treat all their ailments, and of course, you know, those are things that we're still working out in the field. There have been a handful of studies looking at different patient populations and safety aspects. I'll show you some of the work that we're doing. And for our clinical studies, just to give you kind of a starting point, we utilize the ACSM risk score stratification as a way of looking at safety before we start our studies. And then we also will utilize physician clearance if we think that's necessary. So I'll show you some of the setup for a study that we are doing right now. This is actually a study looking at the prevention of Alzheimer's disease, but it's very relevant to our audience today because actually the way that we're looking at preventing Alzheimer's disease is through the control of glucose regulation, both peripherally and potentially in the brain. And so one of the main outcomes that we are interested in here is blood glucose regulation. And so in this particular study, this was a study that we did as a pilot where we did a four-week heat therapy intervention. And so we originally start with a visit where we look at some basic heart rate, blood pressure, things like that. We do a glucose tolerance test. Then we do an MRI to look at brain blood flow. And then individuals are immersed in the hot tub. We use the same protocol that was originally done by the Oregon group where individuals' core body temperature is raised one degree. So we try to get their core temperature increased by one degree. And then that takes about 20 to 25 minutes. After that occurs, they sit up higher within the hot tub for another 20 minutes. So the total intervention is about 45 minutes. And on this particular pilot, we did this every other day, so three days a week for four weeks. And then the follow-up visits were all the same. And if you're interested, we just published this pilot study in the Journal of Applied Physiology, and you can see more details about that there. But speaking more broadly in terms of, you know, we have used hot tub and hot water immersion, but there are a number of different options out there people are looking at for heat therapy. As I mentioned, hot tub and the finish sauna, which is a dry sauna that has a low humidity, those are the most commonly looked at right now. But there are obviously other options. And again, that direct muscle heating or the diathermy that I mentioned earlier is something that people are really looking at. And so while I'm a little cautious to throw up, you know, kind of global characteristics here of the way this could be applied, I think we're getting close to the point where we can start making these references on a very cautious basis of what types of heat modalities are beneficial and the temperatures, frequency, and duration. And much like the field of exercise, you know, which we've been studying for 40 or 50 years, trying to get at these exact, you know, frequency, duration, modality, you know, there's so many different versions and so many different approaches that work for different populations. So keep in mind that in terms of heat therapy, the field is in its infancy compared to what we know about exercise. But if I were to, you know, to make a educated statement about where I think we are right now, I think, you know, every other day, three times a week for hot water immersion, starting really low at the maybe 10 to 15 minute duration and working your way up. Like I said, we use 45 minutes in our clinical studies, but that I think is probably, you know, overkill. It's that to make sure we see something. I really hope that we bring that number down eventually with the additional studies. And then the sauna, which is used a little bit differently, shorter time periods, more like 10 to 15 minutes, and three to seven times per week. But the overall message being start with short intermissions and lengthening the time as the body adapts. And then finally, I'm just going to close with showing this slide, bring it back to this idea that heat therapy is really an ancient practice. This was a photo that was just released and they unearthed this hot, what looks like a hot tub to me, from the ruins at Pompeii. And this was just released within the last couple of months. And so, you know, Pompeii was buried by Mount Vesuvius in 79 AD. And so this was, you know, pointing out how long ago this potential hot tub was in existence. And they found this in what they think was, you know, a very wealthy home that had many rooms and it was part of a larger spa complex. And what I think is really interesting is they, next to this, what looks like hot tub, they have evidence that there was a cold room or a cold spa as part of this larger home spa from, you know, ancient times. So with that said, I'm going to turn it over to my colleague, Matt Lyons, to talk about the benefits of cold. I just need to be able to start my video, hoping to be able to do that so you can see me all here. I hope you can hear me start my video. And hello everyone, my name is Matt Limes, and I swear to God, it just started snowing where I am. So I don't think that Paige could have set me up any better. And what I want to start off with saying is that today we're called heat versus cold point counterpoint. But the spoiler is both Paige and I are two sides of the same coin because we're not actually counter one another. My learning objectives today are for you to identify the effect of cold temperature on total energy expenditure. And then to recognize the role of brown adipose tissue and how it's affected by age, obesity and physical activity. So I'm taking over where Paige left off. And the way that we think about cold exposure and relating to energy expenditure starts at this place that you don't want to be called the thermal neutral zone. So your body, because of obligatory energy expending protocol procedures or functions, has to generate heat. To stay alive, your body makes a certain amount of heat and at temperatures in the thermal neutral zone between about 30 degrees C and 27 degrees C ambient. This amount of heat from the obligatory metabolism required for life is sufficient to keep you euthermic. Now, below this zone, you maintain euthermia. However, your body must activate voluntary energy expenditure to supplement the obligatory energy expenditure. Now, again, my colleague mentioned this thing called exercise. Eating will also generate heat. But let's just, for the sake of our time together today, assume that there is no heating and no exercise. So where does this extra energy expenditure to maintain euthermia come from? Well, it comes from a process called non-shivering thermogenesis. And anybody in this talk right this moment wearing short sleeves and in office below 27 degrees C is indeed engaging in some amount of non-shivering thermogenesis. I'll explain what that is physiologically in a moment. At a certain point, though, we all shiver. And for today's talk, so this would be involuntary muscle contractions. Shivering can cause different things to happen. Sorry, that's not very specific. But for the sake of today's talk, I'm really going to focus on this place right here. So the Goldilocks zone below thermoneutrality. But before you start to shiver where you're engaging in this non-shivering thermogenesis. So this is a fight or flight response is a catabolic state that your body is in. And some very basic systems of biology is at play here. So peripheral sensory neurons would detect decreases in ambient temperature. And that signal is integrated in the central nervous system and then relayed to the rest of the body by the sympathetic nervous system, mainly in the form of norepinephrine and other catecholamines that are released. And the net response is this and this increase in energy expenditure to keep you warm. The cool thing about this, and I'll show this in a second, is that this is a systemic effect. It's it's not necessarily local, but you get because of the sympathetic nervous system, your entire body can feel the effect. And so what I'm going to talk about in my next couple of slides here is, first of all, how do you feel the cold? How does it how will it make you or your your patients feel? And then what I'm going to spend most of my time on is what are those target tissues and how do they work? And I'm going to end with there can be more to cold expenditure than just this simple energy expenditure vis-a-vis calorie burning. OK, so how do you feel the cold so you can put ice packs onto your body? And the cool thing about this, and I'll show some data later, is that this even though the ice packs are applied locally, because you're activating the systemic effect, excuse me, the sympathetic nervous system systemically, you can get benefits in areas of your body that you don't touch with the ice packs. There's new places opening up in strip malls here in Maine that offer something called cryo sizing. I haven't been into any of these places yet, but my technician tells me they offer a sort of wand that's cold that you can rub on your body again, similar to an expensive ice pack. There's anecdotal suggestions that you should finish your showers with cold water to the back of your neck. And I'll tell you why that sort of makes sense anatomically in a moment. Or you can just go for broke and do what people up here where I live do. They go surfing on New Year's Day at Higgins Beach. The other thing that I get pushed on me virally is the idea that I should be cold plunging all the time. And again, I can return to that at the end. In Nordic countries where my grandparents grew up, it's quite common for babies to be just sort of left outside to take naps. And there are colleagues of mine who study this because it really is a double benefit here. I don't know how green using a hot tub is, but if we could just sort of improve our thermal resilience, not use as much heat in our buildings, then presumably we could improve our energy expenditure and go greener. And thermal resilience, really, I read this as if people can just get a little bit tougher, we could all go greener. And why do I say get tougher? So how does the cold make you feel? Well, the cold makes you feel bad. And you should prepare for your patients to, I mean, nobody likes getting medicine, but cold is not unique. So if you turn the temperature down to 64 degrees and then ask people how it makes them feel, over time, you can see these bars creep up and up towards the top, which says uncomfortable. And so people get uncomfortable when you put them in the cold. And there are actual sex differences here. So in this study that I showed up top, you can see that the females report feeling more uncomfortable than the males. And I liked this study the best. So they asked thousands of people whether or not they were satisfied with the temperature in their work. And I was sort of surprised. I feel like most surveys, people say they're unsatisfied. Most people are satisfied with the temperature in their work. But the people who are unsatisfied, they are mostly females who find it too cold at their work. So it's not a pleasant feeling, necessarily, but I'm going to continue to make the case that it is a healthy situation to be in. So what about those target tissues? Well, again, I'm going to start from the ones that I rule out. So, of course, when you're cold, the muscles will respond through this shivering. But we already said we're not going to shiver and we're not going to eat. Again, I said this is a fight or flight response. This is a catabolic situation. So all of the energy that's stored in your body needs to be released so that the tissues that need it can use it. And so the first thing that would happen would be glucose would be released from the liver because of glycogenolysis. But maybe more well appreciated, and this is something that my lab studies, is an activation of lipolysis. So lipids that are stored in your white adipose tissue will be released into your blood so that they can be taken up by tissues and oxidized for fuel. So in the muscle, this glucose and fatty acids are oxidized because that oxidation is coupled to phosphorylation of ATP, oxidative phosphorylation. Remember learning about that? And so we take that ATP and we do work with it. And for muscle, that work is shivering or moving somewhere warmer. You can just move, right? And animals that are put in the cold will immediately move somewhere warmer. Again, you guys let me sort of make the assumption that nobody's moving, nobody's eating in this meeting. So the other place that those stored fuels can go is to this stuff called brown adipose tissue. So brown adipose tissue is where we think the majority of non-shivering thermogenesis occurs in man and rodents. And it occurs because the oxidation of those stored fuels, the glucose and the fatty acids, is not coupled to ATP production. It is uncoupled from ATP production. So if oxidative phosphorylation of ATP is the normal way to do it, brown fat uncouples oxidation from ATP production. And the way that it does that is with, for the most part, one single gene protein molecule. And that protein is called uncoupling protein number one, UCP1. So the way that it works is very similar to what happens if somebody sabotages your car. So normally your car burns gasoline, that combustion, the energy that's in the gasoline when it's combusted pushes up on the piston and your wheels move forward. Everybody in this meeting was in a biochemistry class at some point in their life where they learned how the electron transport chain works. The electron transport chain, I'm pretty sure, is not on the quiz for this class, so don't worry about that. But suffice it to say the electron transport chain inside every one of your mitochondria, inside every one of your cells, is oxidizing glucose and fatty acid and metabolites. And it's using the energy stored in those carbon-carbon bonds to force protons into the inner membrane space. Those protons don't want to stay there. They want to flow back against their electrochemical gradient. And the only way for them to do that is to pass through this water wheel that's in the inner mitochondrial membrane. And that water wheel is called the V1-V0 ATPase, and it phosphorylates ADP into ATP. And so normal mitochondria couple the oxidation of metabolites to this phosphorylation via the ATPase water wheel. UCP1 is, imagine if some jerk drilled a hole into your engine cylinder. If that happened, you'd still burn gasoline, it would still combust. But with an escape route, there's no way for that combustion gas to push up on the piston and you wouldn't go anywhere. Your engine would heat up, but you wouldn't go anywhere. In the same way, UCP1 is a simple channel in the membrane. And those protons that your mitochondria work so hard to pump into the inner membrane space, they just leak back across. And the ATPase sits there without spinning. And so all of the energy just is released as heat. It's the least efficient way to make ATP possible. So UCP1 uncouples oxidation from ADP phosphorylation and makes heat. You burn metabolites, but get heat instead of ATP. So here's my first multiple choice question for you all. Stimulating human brown fat activity can be achieved by A, cold exposure. B, drugs that block the sympathetic nervous system. C, fasting. Or D, sleep deprivation. We'll give you all a second to lock in your final answers. I don't really know. Oh, looks like everybody locked in their final answers. And then both people got it right. Okay, I'm going to make sure I say the trick was that drugs that block the sympathetic nervous system would lower brown fat activity. And also diet, although there's a lot to understand here, eating actually increases brown fat activity. So both of those choices, and I don't know what sleep deprivation was. That was a red herring. But everybody else got cold exposure increases brown adipose tissue activity. Nice job. Give yourselves a round of applause. Okay. So I just want to show you what this looks like. This metabolite uptake looks like in people. So this is PET FDG imaging. So it's radioactive glucose injected into someone. They stand with their hands above their head and the black is where that glucose goes. If you ask them to wear a cold vest running cold water through it, this is what they look like. So you can see this brown adipose tissue underneath the scapula and in between the vertebrae. That's why you need to finish your shower on the back of your neck. When this was first sort of observed in humans in 2009, it was kind of anecdotally noted that the amount of brown fat seemed to decrease with age, obesity, and diabetic status. What we've learned now is that there seem to be two types of people out there. People who can increase their energy expenditure in the cold with nice brown fat detectable on PET CT. And then these other people for whom we can't really see any increase in glucose uptake. And we don't see any change in energy expenditure. The people on the left of your screen with brown fat, it seems to be present in about a third of people. And they seem to be protected from all sorts of bad cardiovascular complications. So how do you, if you are one of the unluckies and you don't have it, can you come join us on the brown fat team? And we think the answer is yes. So here are two quick studies of people where we take a fat biopsy from the thigh and measure the amount of that UCP1 protein. Then we have them put the ice pack on their thigh every day. And look, we've recruited more UCP1 into their thigh fat. Like I said, though, there's a systemic effect. So it actually even increases UCP1 in the thigh that doesn't receive the cold. This actually even works in type 2 diabetic patients. And my all-time favorite study is, it's small, but this group took eight type 2 diabetics and measured their ability to dispose of glucose with hyperinsulinemic euglycemic clamps. So higher glucose infusion rate means better insulin sensitivity. And then they asked them to sit around in their shorts and a t-shirt every day at 57 degrees. Like I said, they didn't like it. But the fact is, every single person's glucose infusion rate increased at the end of this study. So cold exposure does condition brown fat to do its job better. So what about drugs that could increase the sympathetic activity? The problem with these is that we're still trying to figure out which drug to target which receptor. We know in mice that the beta-3 receptor and agonizing the beta-3 receptor increases brown fat activity, but it doesn't work in people. We've used this drug mirabigron. And when I say we, I mean my colleagues, not me. My colleagues have used this drug mirabigron to increase brown fat activity, and it does increase brown fat glucose uptake. The problem is that it causes tachycardia and increases blood pressure. And this is also true for other sympathomimetics like ephedrine. You get this increase in blood pressure and an increase in heart rate, which probably we don't want to be doing to people who have cardiovascular issues. It's worth noting on this slide, though, that cold is the pure, pure stimulus. Because cold, while it does increase blood pressure, it allows the normal baroreceptor reflex to take over. And we get this decrease in heart rate, maintaining cardiac output. So I want to finish by saying what we're learning now is that it could be more than just burning the calories and the sugar oxidizing metabolites. Brown fat activity is associated with decreased risk for fatty liver disease. And I'm not the one who says brown adipose tissue is a secretory organ. A lot of my colleagues in the field are writing reviews titled exactly that, trying to make catalogs. And this is what my lab works on. We try to study the things that are secreted by active brown adipose tissue and how those things could signal to the rest of the body to reduce inflammation, reactive oxygen species, limit the amount of fat. Limit the molecular signs of aging and improve insulin sensitivity and muscle regeneration. So what I want to conclude with is to remind everybody I'm not a clinician or a physician in any way. So what I tried to say is everything in moderation, including cold. Cold exposure is definitely a good thing for the human body. It is a physiologically natural state. And I think up to the point where shivering occurs, it's probably good for almost everybody to enjoy some cold every once in a while. With the caveat that people who couldn't tolerate the increase in blood pressure or heart rate probably shouldn't be routinely cold exposing themselves and especially should not be shivering. My lab is working on trying to measure brown fat activity using techniques that don't rely on ionizing radiation and PET scans. And I think that, I hope, our work will shed light on new ways to activate brown fat and potentially new pathophysiologies of brown adipose tissue. And this kind of relates to the most cutting edge stuff that's coming out about diet and how specific types of lipids and also carbohydrates could support efficient inefficiency of the UCP1 uncoupling in brown adipose tissue. That's my talk today. I really appreciate you all listening. I'd be happy to answer any questions and thanks for having me. Well, that was really exciting and really interesting. Thank you, both of you, for that. And to everybody, don't forget about these five key takeaway messages that have been put together with our speakers' input to help summarize but also have application towards perhaps your own patients or to those in your communities and how the information here might be able to help. Now before we start the Q&A, I wanted to tell you a little bit about things to expect after the webinar. Later today you'll actually receive an email going over some information about the webinar itself and this can also help you claim your CE credit if needed. So look for today's webinar recording on the ADA's Institute of Learning page in about a few weeks. You can certainly remind any fellow members that they can watch this webinar for one CE credit eligible until December 2025. Now again I'd like to thank our speakers for a wonderful presentation today and if you haven't done so already feel free to use the Q&A box now on Zoom to ask questions that you have. As we'll spend the next few moments going over them. So you know with this one of the first questions we had was centered around infrared light therapy and perhaps Paige this is one a little bit towards yourself but certainly Matt if you have any thoughts on this but that idea of could infrared light therapy have some of the same impact or similar impact as heat therapy? So there isn't a lot of research yet but certainly far infrared saunas which use basically a light approach are available and they utilize a lower temperature to get those some of those same benefits and so for people who maybe don't really feel don't like that heat or are less able to tolerate that heat the infrared saunas are one alternative. There's not a lot of research on those yet and and what we really are trying to figure out in the field is how critical is that increase in core body temperature versus increasing specific tissues. So we don't yet know and some of these sauna approaches don't have as robust effect on whole body temperature but that may not be necessary for certain benefits so it's it's really just too hard to answer right now but I think if you if I think my take-home is whatever approach whatever heat feels good to you is the one you should you should try. Yeah that's really interesting because you know maybe just kind of in in contrast here Matt to yourself you know as we talk about heat therapy, light therapy, ice baths you know kind of going into that realm you know just in general perhaps what do you think of that how often would you really need to do something like that to maybe activate brown fat in the ice bath? Any thoughts? Yeah absolutely and I think I can even take down a couple of these other questions and and remind you that this isn't a point counterpoint with me and Paige. In some ways like I don't I don't think it's I don't think you should be thinking about like how cold should I be or how hot should I be. I think that you should be thinking about avoiding the thermo-neutral zone and so like with with the the ice baths I guess what I think some in some ways is that's probably overkill. You don't need to be spending thousands of dollars at a ski resort getting into a ice bath with you know on TikTok or whatever. Your body goes into non-shivering thermogenesis just below the thermo-neutral point and so really I'm not saying an ice bath is bad but any amount of cold exposure is actually good and so it might be overkill and so I want to answer that also these questions about you know what about hot to cold hot to cold. Yeah definitely I think that in all of those cases you're sort of stretching the rubber band of your body's homeostatic mechanisms and you know stretching a rubber band using that too much is of course not good but keeping it nice and stretched is great and so I think ice baths are great and I think you know that I live in Maine so the more often I'm cold the better but I just want the audience to realize here that you don't need to go that far at least with cold exposure just sit my office is 64 degrees so I'm getting it right now. Yeah that's what I would say. Yeah no it's an interesting point you know because you know yes as a couple of members have asked so I'm gonna combine some people's questions just for sake of time. I can think of an exercise though to say there's low intensity suggestions and high intensity suggestions so when you when you say that Matt I couldn't help but think of that as is that somewhat comparable you know perhaps to both of you in that thought of this idea of you know as one member here had raised this idea of skiing and then you know you jump into a sauna or a hot jacuzzi and then you you do snow angels and you bounce back and forth as a lot of people have done. Is there something though to be said about doing more the extreme to get more benefit or more adaptation compared to the lower temperatures or you know more neutral if that makes sense. Is there something about that like is it you know embedded within that? I think that's to me I don't think we know yet and so I think that for I don't think we know and I think again if I was talking to a person about cold exposure I'd literally say anything that you do is better than sitting at thermoneutrality. You know I hope that my own research is used to try to answer some of the questions that you just posed Steve like but I just don't think we can know that right now. We're sort of limited a bit in our field because we have to inject radioactive glucose into people to know if they have brown fat and that that carries a bunch of problems with it and so we're sort of waiting for great biomarkers that's what I do to be discovered so that we can answer the questions that you're talking about but in the meantime I would say don't let perfect be the enemy of good. Don't sit around at thermoneutral. Get any kind of cold exposure you can. So maybe this way Paige you know thinking not everybody has a sauna or necessarily a hot tub so do heating pads have similar effects as heat therapy as you've described? Any differences across men and women, young old, different body status, any insight to that? So there haven't been a lot of studies looking at heating pads but like that diathermy is something that could be similar to that right where you're just heating the tissue or the muscle and that has shown some benefits so similar to Matt's perspective I think a little heat can go a long way. We don't you know in the research realm we're studying this very system systematically you know we're applying a certain dose of heat and trying to see what those effects are and we don't know what how to work backwards from there yet and say even just a little bit of heat is good in terms of say a warm bath versus you know a hot tub but I will say that's one of the things we're trying to figure out and so in our clinical trial that we're doing right now with 60 individuals half of them are going to be in a hot bath a hot tub and the other half are in a thermo-neutral bath so their body temperature is not changed but they're submerged in the water and actually if you think about thermo-neutral that's 98 degrees that is actually a warm bath so if there are benefits to that warm bath on in terms of some of these metabolic aspects that we're interested in and some of these brain cognitive aspects then we will find that out at the end of our study so I think that that information is coming and in the meantime if it feels good sit in the hot bath. Wow that's really interesting and that's a great point with just typical baths they actually are quite warm that way so on some levels going back to that kind of dose response as well as you know I think what these questions are getting out on some levels again from an exercise view is specificity you know localized effect on the tissue that of exposure just as Matt it seemed your studies were showing a little bit within a cold pack potentially having some influence as well so you know another question kind of in line with this and perhaps you know both but if you drink a cold beverage is there any evidence or thought that actually could work and maybe even on the other side if you drink really warm beverages are there is there anything going on there something as simple as that maybe yes I would say that the the canonical way that your body senses cold is with with receptors in your skin but there are studies that you know that find the same receptors that sense cold in your skin expressed in cells and tissues that are inside your guts it's also true coming to the person who asked about infrared light the opsin proteins that allow your eyes to detect light are also expressed on tissues that are in your guts and so we're still learning is that because the the cells inside my body can sense temperature or light and it seems like they they actually can which is a little counterintuitive but I would say that that yes the cells inside your body can detect cold they do not require sending that signal up into your brain to know what to do they merely respond to that signal themselves in what we call a cell autonomous manner so there is research that supports that concept to what extent that response compares to the response you and I experience when we go outside into the snow we're still trying to sort of gauge you know how much cell autonomous temperature sensing contributes to to physiology compared to the regular version of it let's say where it's systemic physiology but yes I guess the answer that took me a while sorry the answer is yes you would probably gain the benefit from drinking cold substances but you pay anything on the on the hot side of things you know I really don't know I would I mean that matt sensor was really very um helpful I think I was just second what he says sure well you know on this maybe you know we are running out of time but there is um two other questions hopefully this first one will be fairly short if you could but the idea of like optimal exposure time so you know page I think you got at this a little bit with your talk but but from the heat perspective is there sort of a thought of how much time you need in warmth and then matt after page could you follow with cold like you know maybe with the ice pack idea or ice bath or something but what's that optimal time or duration I don't think we know yet I like to think that we're going to get there um we're kind of going you know to make sure we see these beneficial effects in our in our trials and then we'll hopefully work backwards but I would say 15 minutes is probably plenty if you're talking sauna or hot water immersion um I'm I'm guess you know speculating at this point that I don't think we're going to need that whole body core temperature raise every time like matt said just get out of thermo-neutral and I think that 15 minutes was probably enough um so I would say that's kind of the low dose but but in terms of is that effective for all these different um metabolic parameters we don't know yet yes same exact same sorry same exact answer um we have a little bit measured and you can see the black stuff show up in people injected with 18 ftg 15 minutes after they put the cold vest on what one thing that that sort of unites page and I is that we're both talking about sympathetic nervous system and activated stuff and your sympathetic nervous system is there for instantaneous response and so it's activated right away how long it takes for you to gain a physiological benefit I think we're still trying to similar to page like work backwards uh to that target from from our you know systematic experimentation to say it's on immediately page this one's for you and this is going to be our last question for time but this one is a big clinical so it'd be interesting your thoughts there's some understanding that skin cancer risk can be increased due to use of heating pads do you have any thoughts of potential implications for this using heat therapy any linkages with cancer that way yeah so there is some literature that some of these heat shock protein pathways are activated in in some cancer pathways um I think the difference in mechanistically is whether it's you know in a pathological contents versus a activation we can see some of the same pathways activated with exercise and disease so just because they're turned on doesn't mean that it's necessarily leading to that pathology I don't know a lot about that direct heat pad effect on the skin in that way but I do think you know too much of anything can be harmful and and you know proceed with caution I do think that you know the most that we know now right now in the literature has to deal with sort of the whole body heating this the water submersion or the sauna type effects um so so uh I think that there's probably still the jury's still out perhaps on on some of that and you know if you're heating every day with the with the heating pad over time that's that could potentially be you know too much and and I could see where that would be dangerous but um a little bit goes a long way so not sure I can exactly answer that in terms of the heating pad intervention but no appreciate that but but that you know again another great exercise principle right overtraining overuse could lead to something I think that really sums up nicely in many ways both your talks about how challenging this is and just finding that right amount and oscillating between both just collectively here goes into the toolbox of behavior change and behavior modifications to treat disease whether it's exercise diet sleep heat cold all these are tools and no one of them is probably superior overall in doing everything we need combinations of of kind of everything um so both of you thank you again for brilliant talks appreciate you staying long but I I hope you you know uh consents by the number of questions and the interest uh this was really a success so thank you to both you for that and to everybody in the audience thank you for your time your attention we hope to see you at another ADA webinar take care everybody thank you again to both of you Paige and Matt bye thanks Paige

Diabetes Care

Heat Therapy

Cold Therapy

Mitochondrial Function

Glucose Regulation

Insulin Sensitivity

Brown Adipose Tissue

Non-shivering Thermogenesis

Exercise Alternative

Infrared Light Therapy

Holistic Health