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The Chief Scientific Advisor at Novo Nordisk, Lotte Bjerre Knudsen, was the key force who pushed hard to develop GLP-1 drugs for treating obesity and subsequently for Alzheimer's. She was recently recognized by the 2024 Lasker Medical Research Award, and the 2024 AAAS Bhaumik Breakthrough of the Year Award. That recognition is richly deserved, since it is unclear if the GLP-1 drug path to obesity treatment, and all of the associated benefits, would have been seen at this time without her influence. That's especially true given the mystery for why people with Type 2 diabetes (for which these drugs were used for many years) did not exhibit much in the way of weight loss. We discussed that and the future of these drugs, including their potential to prevent neurodegenerative diseases. And about dressing up in pink!The Ground Truths podcasts are also available on Apple and Spotify.Our entire conversation can also be seen by video at YouTube along with all of the Ground Truths podcasts. If you like the video format, please subscribe to this channel. Even if you prefer video, please take a look at the transcript with graphics and useful links to citations.A Video Clip below on the barriers of a woman scientist to push Novo Nordisk to develop GLP-1 for obesity. “I was always just been a nerdy little scientist who kind of found home here in this company for 35 years.”—Lotte Bjerre Knudsen, 60 MinutesTranscript with Links to audio and external referencesEric Topol (00:06):Well, hello, it's Eric Topol with Ground Truths, and I have with me a special guest. She's the Chief Science Officer of Novo Nordisk and it's Lotte Bjerre Knudsen, and we're delighted to have her. She's a recent recipient of the Lasker Award, which I think is considered like the pre-Nobel Award here in the United States. And I was involved with her in terms of researching who was the principal person who brought the GLP-1 drugs to the forefront for obesity, and it turned out to be Lotte. So welcome, Lotte.Lotte Bjerre Knudsen (00:48):Thank you very much. And also very, very happy to be here. I'm not the Chief Science Officer for Novo Nordisk, I'm the Chief Scientific Advisor of working for the Chief Science Officer of Novo Nordisk, but maybe too many people, not so different, right?From Laundry Detergents to GLP-1 DrugsEric Topol (01:06):Yes. Thank you, I actually meant to say advisor, but yes, I'm glad you cleared that up. I know from speaking to some of your colleagues, I actually spoke to Robin yesterday that you are looked to very highly, the most highly regarded person in science there, so not surprisingly. What I want to do is first talk about the glucagon-like peptide-1 (GLP-1) that got its legs back in, I guess 1984. So we're going way back. And what's also interesting is that you go way back at Novo Nordisk to 35 years in 1989. And so, there had been this work with this extraordinary hormone and neurotransmitter with a very short half-life that you knew about. But when you first started in Novo Nordisk, you weren't working on this. As I understand it, you're working on laundry detergent enzymes. How did you make this pivot from the laundry enzymes to getting into the GLP-1 world?Lotte Bjerre Knudsen (02:16):Yeah, thank you for that question. I'm from the technical University of Denmark, so I'm trained in biotechnology, and we're a small country, so not that many companies to work for. And I always had my mind set on, I wanted to work for Novo as it was called back then, and it just happened to be in the industrial enzyme part that I got my foot in first. And then I had a very interesting boss at the time. Unfortunately, he's not alive anymore, but he was both a medical doctor as well as a chemist. So he was actually put in charge of actually, let's see if we can do something new in diabetes. And then since he hired me and I had not been there that long, I simply tagged along as the youngest scientist on the team, and then suddenly I became a diabetes researcher. Around the same time, I think you remember that all of pharma was interested in obesity in the early 90s, everyone wanted to do diabetes as well as obesity, but they were separate teams and they all wanted to do small molecules, but it just happens to be so that the best idea we could find at that time was actually GLP-1, because we actually had clinical data relatively early that GLP-1 was a really good candidate as a treatment for diabetes because of the glucose sensitivity of the actions.(03:43):So you'd have efficient lowering of glucose through a dual mechanism with increasing insulin, lowering glucagon, and then it was safe because there wasn't this hypoglycemia you get from insulin. But then I had other colleagues who were working on obesity, and I was just kind of listening, right, what's going on there? And then also a colleague that I had, we had, I don't know if you remember the old Hagedorn Research Institute, but Novo actually had kind of like an academic research institute that was affiliated with us. And there was this group that were working on this glucagon tumor model that produced high levels of glucagon, GLP-1 and PYY. And these rats, they starved themselves to death. And I knew about that from 1994. So that actually inspired my thinking. So when Stephen Bloom's paper came out in January of 1996, and he was the first one to call GLP-1 a neurotransmitter, I think, but I was already way into actually screening these kind of molecules that later then became liraglutide.No One Else Thought About This [Obesity](04:54):And then I thought, why on earth should we not actually do both things at the same time? If we have an idea that can both work in diabetes in a much safer way than in insulin, and then also at the same time work in obesity. But the reality is that no one else thought about this, or if they thought about it, they didn't really think that it would a good idea. But I think I had the luxury of being in a biotech company, so everyone was working with peptides and proteins. So I don't think I got the same challenge that the other people in the other pharma's got when they all wanted small molecules.Eric Topol (05:36):Well, also just to set the foundation here, which you alluded to, there had been so many attempts to come up with a drug that would work, not just of course in diabetes where there are many classes of drugs, but moreover, to treat the condition of obesity. Actually, I was involved with one of them, Rimonabant and did the large trial, which as you know, led to having to stop the drug, discontinue it because it was associated with suicidal ideation and actual some suicide. So there had been such a long history of checkered inability to come up with a drug. But what was striking is the challenge, and this is one of the first important questions about, when you had the extended half-life of the first GLP-1 drug, that instead of having to take multiple times a day, you could actually, with liraglutide get to a point where you were starting to get to an extended half-life. This is now going back to 1997 with approval in 2010, still 14 years ago. But when you came up with this drug, because this was certainly one of your great contributions, this drug was just a step along the way in this kind of iterative process, wouldn't you say? It wasn't the long half-life and the potency that eventually got us to where we are today. Is that true?Lotte Bjerre Knudsen (07:15):Yeah, it was a stepwise process. And what's super interesting about this class of medicines is that they're actually so different. If you talk about a class of medicine where small molecules, they can be different, but they're usually more alike than they're different. And when it comes to this class with these medium-sized peptides, people tried a whole bunch of different things. So they're actually really, really different. Some are simple peptides. So the idea that I came up with was to use this fatty acid isolation principle, and that's then a subclass in the class. And then the first, once weekly, for example, was an antibody-based molecule liraglutide. So they're much, much, much larger molecule compared to the small peptides. So they're very different. And neither the simple peptides nor the really big antibody derived molecules, they don't give a lot of weight loss. So we actually get more weight loss with these kinds of molecules, which is also why you can now see that it has actually kind of inspired a whole industry to kind of try and go and make similar kinds of molecules.Eric Topol (08:27):Well, inspired a whole industry is an understatement. It's become the most extraordinary class of drugs, I think in medical history, having been a student of various, I mean obviously statins have been a major contribution, but this seems to have transcended that already. We're going to talk about more about where things are headed, but this fatty acid acetylation was a major step forward in extending the half-life of the drug, whereby today you can give semaglutide once a week. And this, I think, of course, there are many ways that you might've been able to extend the half-life, but you were starting with a hormone, a natural hormone neurotransmitter that had such an exquisitely short half-life of basically second or minutes rather than that you could give for a week. So I know there were many different ways you could have protected or extended the half-life one way or another, but this seemed to be a breakthrough of many along the chain of breakthroughs. But the question I have is when you were giving this to the diabetics, which was the precedent, that was really what these drugs were first intended, they didn't lose that much weight, and they never, still today when it's looked at for obese non-diabetics versus diabetics, there's a gap in weight loss. Why is that at the exact same dose, with the exact same peptide that the weight loss differs for people with type 2 diabetes as compared to those who have pure obesity?The Mystery of Why People With Type 2 Diabetes Don't Lose Weight Like Those With Obesity Lotte Bjerre Knudsen (10:09):Yeah, I can't give you a molecular answer to that, right. But I think the notion, I think it's the same for example with metformin, even though it gives less weight loss because that has also been tried in both people with diabetes and people without diabetes. So I think it's just for somehow people with diabetes are more resistant to weight loss. I think it's a really good question that I'm hoping maybe we could get through, for example, with proteomics and actually comparing people with diabetes and people without diabetes and looking at people who have the similar kind of weight loss. That could be really interesting. But I really don't have a good molecular answer for you, but it's just a really, really strong fact. But it also leads me to wanting to say it's interesting, because if that had been our motivation to actually say, oh, there's weight loss in diabetes, let's pursue it in people with obesity, I don't think we would've done that because the weight loss in people with diabetes wasn't that impressive. So it was very important for our chain of thought and decision early on that we actually knew that GLP-1 had these separate effects and that they could work in the brain and have a separate effect on well-known pathways in the brain. And that was more our motivation to actually continue to invest in obesity.Eric Topol (11:42):Yeah, no, I think this is when we did the research on the committee for the American Association for Advancement of Science (AAAS) award, the Mani L. Bhaumik Award, that you were recognized for the breakthrough of the year, this year. We tried to scour all the work and we actually had to hit Danish translations and all sorts of other papers they reviewed. And we learned through that process working on this committee that you were the one to be the champion of pushing this towards obesity, and it would've easily been missed because as we've been discussing, the weight loss in people with diabetes was small, but you push for it. And this was an extraordinarily important push because what it has resulted in, of course, has been spectacular. And obviously as we're going to get into much more than just obesity and obesity related conditions. But before we get to those other conditions, and as you've been known in the medical community as “the mother of GLP-1”, you were dubbed that term. The GLP-1 receptor is expressed in many parts of the body. Maybe you could just tell us about the distribution because this, I think is tied into these central nervous system effects that are not just related to the gut hormone type of axis.GLP-1 Receptors and the BrainLotte Bjerre Knudsen (13:17):So I spent a lot of time on that together with my amazing colleague, Charles Pyke, who's an histology expert because it turned out to be so very important. In general, when you're trying to make new medicines, understanding the mechanism, sometimes people say, yeah, who cares? But actually, it should matter, I think because where it becomes really important can be an understanding what they do not do. We've had to do a lot of proving the negatives for GLP-1. We went through these issues with thyroid cancer, pancreatitis, pancreas cancer. In all of that work, it was actually really important that we could show where the GLP-1 receptor was not expressed. So in the pancreas, we know that it's primarily on the insulin producing cells, and then we also have them in the intestine where they're probably involved in regulating inflammation and really creating a much healthier gut.(14:15):And then we have a lot of receptors in the brain. They're typically expressed on neurons, but they're also on astrocytes, they're also on smooth muscle cells. We have them on the heart and the sinus node. That's why there's a small increase in heart rate. We have them in the kidney, on again some smooth muscle cells that are renin positive. So there we can start thinking blood pressure and other things. So it turns out that you can go around the body and there are all of these specific GLP-1 receptor population, that you can see how they tie into the pharmacology. But obviously in physiology, they're not as important as they have turned out to be in pharmacology when we suddenly come with 24 hours a day exposure for a day or a week or for as long as the administration interval is. So, but specifically for obesity, I think it's in the vein, it's hard to, you should always be careful.(15:18):That's something I've learned to never say never. Of course, there could be a contribution from the peripheral nervous system as well to the effects in obesity. But I do think there are so many important and well described neuronal populations that have the GLP-1 receptor and which are accessible from the periphery. So just to mention, maybe one of the most, well-known is a POMC/CART neuron in the hypothalamus. They have the GLP-1 receptor, they're activated, but there also is an inhibitory tone on the AgRP and NPY neurons, and it fits very well with that. We know that people report that they feel more sated, they feel less hungry. But then there are also effects in the hindbrain and in some of the reward centers also have GLP-1 receptors. And we know that also now, we have really good actually clinical studies that show that there is a change in food choice and people can control their food intake better. So I think that fits very well with effects on the reward system. So it's a whole myriad, or maybe you could say that GLP-1 orchestrates a number of different neuronal populations to have these overall effects that reduce energy intake.Eric Topol (16:42):Yeah, it's pretty striking. It's almost like we're all walking around with GLP-1 deficiency, that if we had this present at higher levels around the clock, and of course eventually we'll see things that are well beyond obesity, how well this has an impact. Now, there was an extraordinary review in Cell Metabolism on the brain and GLP-1, and not just the brain, but the essential nervous system, the neurovascular, it's called the “GLP-1 programs and neurovascular landscape.”(17:20):And in this review, it got into the brain effects that were well beyond, I think what are generally appreciated. Not only the protection of the integrity of the blood-brain barrier, this whole neuroglial vascular unit, the myelin sheath protection, reducing inflammation within the brain, improving the glymphatic flow, which is of course critical for clearing waste and promoting cerebral vascular remodeling and more, so the brain effects here is what it seems to be. You mentioned the reward circuit, of course, but the brain effects here seem to be diverse, quite a bit of breath and extraordinary. And as we've seen in the clinic now with the work that's been done, we're seeing things about addiction, even gambling, alcohol, drugs, I mean neuropsychiatric impact, it's pretty profound. Maybe you could comment about that.On to Alzheimer's and Parkinson's DiseasesLotte Bjerre Knudsen (18:23):Yeah. I haven't read that paper yet, but I just saw it earlier. And I have been following this for about actually more than 10 years because when I was kind of over the big work of actually getting the approval for diabetes and obesity. I thought I had a little bit of capacity to actually look at Alzheimer's and Parkinson's disease because I just thought there's such an insane unmet need and what if GLP-1 could actually make a difference? And the first big paper that talked about this was actually in Nature Medicine in 2003, and it was originally, I think I should credit Nigel Greig. Greig, he's from NIH or from NIA, I can't remember, right. But he was actually the first one, I think to say if GLP-1 has all of these important effects in the pancreas and to protect cells, and there are all these GLP-1 receptors in the brain, maybe it also protects neurons.(19:25):So that was the first hypothesis. And the paper on Nature Medicine in 2003 describes how the GLP-1 receptor in the hippocampus is involved in cognition. And then we did a couple of studies in different animal models, and I was, to be honest, really confused. But then there was a new paper in Nature Medicine in 2018 that started to focus in on neuroinflammation. And by that time, I knew much more about inflammation and knew GLP-1 actually lower CRP by about 50% in the different trials. So I was really tuned into the potential importance of that in cardiovascular and kidney disease. But I was like, oh, what if that's also something that is important in the brain? Then it made more sense to me to try and build some evidence for that. So that was how we actually started looking at a hypothesis for Alzheimer's and Parkinson's.(20:21):And we now have a really large phase three study ongoing, but of course, it's a hypothesis, right? And no one has yet, I think, proven that GLP-1 has really important effects on these indications, but we are testing it in 4,000 people with Alzheimer's disease. So our hypothesis is around neuroinflammation, but defined in a way where you could say it's both peripheral inflammation and the effect it has on the vasculature, it's the effect on the blood-brain barrier. It's the astrocytes and the microglia, and there are probably also some T cells that have the GLP-1 receptor that could be important. And then couple that up also with some of the new information from neurons, because there are two papers to think in the last year that has highlighted neurons either in the hindbrain or a little bit further on. Both of them are probably hindbrain populations that actually seem to be really important in regulating both peripheral as well as central information.(21:27):So what if neurons are actually also an overlooked mechanism here, and both of these neuronal populations have the GLP-1 receptor and are accessible from the periphery, even though the child super paper in Nature doesn't mention that, but they do have the GLP-1 receptor. So there are all these different mechanisms that GLP-1 can have an impact on the broad definition maybe of neuroinflammation. And maybe the way one should start thinking about it is to say it's not an anti-inflammatory agent, but maybe it induces homeostasis in these systems. I think that could maybe be a good way to think about it, because I think saying that GLP-1 is anti-inflammatory, I think that that's wrong because that's more for agents that have a really strong effect on one particular inflammatory pathway.Eric Topol (22:22):That's a very important point you're making because I think we conceive of these drugs as anti-inflammatory agents from these more diverse actions that we've just been reviewing. But I like this restoring homeostasis. It's an interesting way to put it. This brings us, you mentioned about the Parkinson's, and when I reviewed the three randomized Parkinson's trials, they're all small, but it appears to be the first disease modifying drug ever in Parkinson's. Of course, these were done with different drugs that were older drugs. We haven't seen the ones that yet to be with semaglutide or other agents. And I wondered if you pushed, just like you did for obesity within Novo Nordisk, you pushed to go into obesity. Did you also force to push for Alzheimer's?Lotte Bjerre Knudsen (23:19):Yes. So that is also me who had to argue for that. I'm happy to do these things. I was born brave. I am happy to do these things.Eric Topol (23:31):That's wonderful. Without you, we would be way behind, and it took decades to get to this point. But look where we are now, especially with all the rigorous trials, the large clinical trials. You're into one right now of some 20,000 participants to see whether not just people with prior heart disease, but people without known heart disease to see whether or not this will have an effect. And there's so much data now, of course, already a completed trial with reduction of heart attacks and strokes. But now to extend this to people who are not such high risk, but these large trials, we keep learning more. Like for example, the reduction of inflammatory markers is occurring even before the weight loss that starts to manifest. So we learned a lot from the trials that are just even beyond some of the major primary outcomes. Would you agree about that?Lotte Bjerre Knudsen (24:34):So I'm not sure we can say that it comes before the weight loss because the energy intake reduction happens instantly. The glycemic response happens instantly. And all of these improvements will of course also have an effect to dampen inflammation. We do not have data that supports that it comes before because we haven't sampled that much in the beginning.Eric Topol (25:04):Okay.Lotte Bjerre Knudsen (25:05):I wouldn't be able to say that, and I don't think there are any, well, it's hard to keep up that the entire literature on GLP-1 these days, but I don't think anyone has actually shown that there is a separation because it's super hard to separate when things are occurring at the same time.Eric Topol (25:24):Yeah, I'm just citing the heart disease trial where in the New England Journal that point was made. But I think your point also that there was already a change in energy intake immediately is apropos for sure. Now, when we get into this new paper of yours, the proteomics, can you tell us about that because that's really exciting. We're in a high throughput proteomics era right now that we can analyze thousands of plasma proteins in any given individual. What are you learning about proteomics with the GLP-1 drug?The GLP-1 Drug Impact on ProteomicsLotte Bjerre Knudsen (26:07):Yeah, yeah. So I'm also the super excited about omics, right? Because I have worked in a wonderful organization of people who can do these large scale clinical trials, and we used to not collect a lot of samples for future use, but we've done that for some years now. So now we have this amazing collection of samples we can learn from and actually both inform the patients and the physicians, but also inform future research. So we have been doing that in our semaglutide trials, and we've just published the proteomics data from the step one and step two trials. So the phase 3a trials that supported the approval of semaglutide for the treatment of obesity. So one of them in people with obesity and one in people with obesity and diabetes, and those data are now published in Nature Medicine. [3 January 2025]. And we were learning a lot of things because you can compare the proteome effects to what has been done in the decode cohort.(27:11):So they have all these disease signature. So that's one thing that you can for sure see, and you can see a lot of things there with hints towards addiction. And then also you can take more predefined signatures also to look into what actually might be driving the cardiovascular risk. So I think there are so many things that you can learn from this, and of course it can also inform when you look at what's actually mediating the effect and probably something around inflammation is important. We have already also shown a more standard mediation analysis that shows that actually the most explainable factor for the effect on MACE [major adverse cardiovascular events] in the select trial is inflammation. It doesn't explain everything, but it actually looks like it's more important than BMI and weight loss. So that's really interesting how much we can learn from there. We're making the data are available at the summary statistic level so people can go and play with them ourselves.(28:23):And I think as we have more different kinds of medicines available in obesity, it's also a way to kind of compare how these different medicines work. And as we get more and more better at maybe also characterizing people with obesity, because I think that's a great thing that's going to happen now is there's going to be more funding for obesity research. Because I think that's what the attention that we are seeing right now is also giving. Then we can better start to understand. We always, we've been saying that people probably have different kinds of obesity, but we don't really know. So now we can actually start to understand that much better and maybe also understand how these different classes of medicines will work if we have the proteome data from different trials.Eric Topol (29:10):No, I'm absolutely fascinated about the proteomics. I call it a quiet revolution because many people don't know about it. [My recent post on this topic here.](29:18):The ability to assess thousands of proteins in each individual, and it's giving us new insights about cause and effect as you alluded to, the relationship with as you said, MACE (major adverse cardiovascular events) and the actions of this drug class. I mean, there's just so much we can learn here from the proteomics. Another thing that's fascinating about the GLP-1 is its effect on epigenetic clocks. And recently at one of the meetings it was presented, this is Steven Horvath that we had on Ground Truths not long ago. He talked about at this talk that for the first time to see that you could basically slow the epigenetic clock with a GLP-1. Is there any further information about that?Lotte Bjerre Knudsen (30:16):Yeah, no. We've never had enough of a sample size to actually be able to look at it, so unfortunately, no. But there is something else, right, because there is this group at the Stanford, Tony Wyss-Coray or something.Eric Topol (30:33):Yes, Tony Wyss-Coray.Lotte Bjerre Knudsen (30:35):Now he published a paper, is it two years ago? Where he did it using proteomics. He defined an anti-aging signature for various different organs.Lotte Bjerre Knudsen (30:46):We are in the process of trying to see if we could take those signatures and apply them on to our data.Eric Topol (30:55):Well, what's interesting is we're pretty close friends, and he, not only that paper you mentioned on organ clocks, which is a phenomenal contribution, but he has a paper coming out soon in Nature Medicine, the preprint is up, and what he showed was that the brain and the immune system was the main organ clocks that were associated with longevity. And so, it takes another step further and it's looking at 11,000 plasma proteins. So it's really interesting how this field is evolving because the omics, as you put it, whether it's proteomics, and now we're learning also about the epigenome and what brings us to the potential that this class of drugs would have an impact on health span in all people, not just those who are obese. Would you project that's going to be possible in the years ahead?Lotte Bjerre Knudsen (32:02):I don't know about health span, but because certainly there's been so many studies with metformin and there's been a lot of wonderful data showing an effect on the epigenetic clocks, but not really an effect on lifespan because that metformin is so widely used. If that was the case, it would be easy to dig those data out of different registries. But certainly a healthier aging is the most obvious one because when you have one class of medicine that actually has so many different effects. Right now we are looking at them at a one by one case, but we really should be looking at them so you are getting the benefits on the heart and the vasculature on the brain and the kidneys and the diabetes and the knees. You're getting all of that at the same time, and that certainly should lead to much, much healthier lives. And then of course, we just need to get people to eat healthier. Also, maybe we should talk a little bit about the food industry. I heard you did that in some of your podcast, right?Eric Topol (33:17):Yes. That is the big food, if you will. It's a big problem, a very big problem, and the ultra-processed foods. And so, lifestyle is not good and trying to compensate for that with a drug intervention strategy is like chasing your tail. So you're absolutely right about that. I mean, I guess what I'm getting into here is that whereas today we keep seeing the effects, whether it's the liver, the kidney, the heart, obesity, and people with diabetes. But for example, in the Alzheimer's trial, do you have to be obese to be enrolled in the Alzheimer's trial, or is it just people who are at risk for developingAlzheimer's?Lotte Bjerre Knudsen (34:01):Yeah, no, you do not have to be obese. It's a standard Alzheimer's trial.GLP-1 PillsEric Topol (34:07):So this will be one of the really important trials to get a readout in people who are not having an obesity background. Now, the future, of course, gets us to oral GLP-1 drugs, which obviously you have there at Novo Nordisk. And it seems to me once that happens, if it can simulate the effects we see with the injectables, that would be another big step forward. What do you think about that?Lotte Bjerre Knudsen (34:39):Yeah. Isn't it interesting, what we've learned is that people actually don't mind the injections, right? Also, because I think it's simple, once a week injection and the needles are so small, obviously there are people who really have needle phobia, but take those aside, it's relatively few. I would argue if you close your eyes and somebody else used this needle on you, you would not be able to feel where it was inserted, right? They're so small. So it becomes maybe a personal preference. Would you like to have once a day or maybe twice a day tablets, or are you fine with once a week injection? And I think there probably will be quite a few once they've tried it. And now so many have tried it and they actually, maybe it gives us a simple lifestyle. You don't have to do it every day, right? You can just have a weekly reminder.Eric Topol (35:46):Yeah, no, I think that's really interesting what you're bringing up. I never thought we would evolve to a point where injectables were becoming some common, and I even have some physician colleagues that are taking three different injectable drugs.Lotte Bjerre Knudsen (36:00):That's also just mentioned Richard DiMarchi, who I shared the Breakthrough Prize with, and also Svetlana Mojsov, who I was one of the other two recipients for the Lasker prize because they both been at Rockefeller, and they both have worked a lot with peptides, and they both say the same thing. They were told so many times, this is not medicines, these kinds of molecules just they're not medicines. Forget about it. It turns out people were wrong. And peptides can be medicines, and they can even be produced also in a sustainable manner with fermentation, which is not a bad way of producing medicines. And people actually don't mind. Maybe some people actually even like it because it's once a week and then it's done.Confronting BarriersEric Topol (36:58):Yeah, no, that's a very important point. And the quest for the oral, which have more issues with bioavailability versus the peptides that are having such pronounced impact is really interesting to ponder. Well, before we wrap up, it's very clear the impact you've had has been profound, not just obviously at Novo Nordisk, but for the world of advancing health and medicine. And you've mentioned some of the key other people who have made seminal contributions, but I think you stand out because when we went deep into who took this field forward into obesity and who might also wind up being credited for Alzheimer's, it was you. And as a woman in science, especially in an era that you've been at Novo now for three and a half decades, there weren't many women in science leaders. And for one to be, as you said, you're brave for the good old boys to listen to the woman in science. Tell us about that challenge. Was this ever an issue in your career? Because obviously we want to have this whole landscape change. It is in the midst of change, but it's certainly still a ways to go. So maybe you can give us insight about that.Lotte Bjerre Knudsen (38:27):Yeah. Well, it for sure was a thing. It was a very male dominated world, and in a way, it might have prevented other people from doing it. But then, as I said, I was born brave for some reason. I'm not really sure why. It actually motivated me to kind of like, yeah, I'm going to show them. I'm going to show them. So it never really got to me that people, not everyone was nice to say. There was the first 10 years of my career, I think they were quite lonely, but then I was really inspired. I was so happy to be allowed to work on this. I thought it was super fun. And I did find people who wanted to play with me. And I also have to say that the CSO back then, Mads Krogsgaard Thomsen, he always supported me. So maybe I didn't get everything I wanted, but I always got what I needed in order to progress.(39:29):So on the women's side, and I think that yes, and there's still a change to be made, and I'm actually a little bit on behalf of my generation, maybe not too proud of the change we made because we didn't do a lot of change. It was all the women coming from the arts and the culture. They were the ones who actually make the big change here like 5 or 10 years ago. So I've also started to be more open about sharing my journey and advocating for women in science. So that's why I show up in pink to some of these award sessions just to be a little bit different and to maybe also just show that you don't have to be a certain type in order to fit into a certain job. But there is still a change to be made where people should be better at listening to what a person say and what ideas they say.(40:28):And they should be mindful about not always labeling women as passionate. When people call me passionate, I say like, no, thank you. I'm actually not too happy about the mother of either, because men always are being told. They're being told that they're brave and ambitious and courageous and strategic, whereas we we're, oh, you're so passionate. No, thank you. I'm also brave and strategic and ambitious and all of that. So we simply put different vocabulary on. I don't think people don't do it on purpose. I think we need to be better at actually giving people at work the same kind of vocabulary for their contributions. And I think that would mean that we get listened to in the same way. And that would be important. And then I also have to say that science, whether it comes from men or women, doesn't really matter.(41:32):Successful science is always the work of many. And I hope that some of you will actually listen to my last speech because that's what I speak about, how it's always the work of the many. And also, how if you want to do something novel, then you actually have to do it at a time when no one else is doing it, and you should believe in your ideas. So believe in it, listen to the critique, but believe in it, and then come back with new arguments or give up if you can't come up with any new arguments, right?Eric Topol (42:05):Well, we'll definitely put a link to the Lasker Awards speech that you gave. And I just want to say that the parallels here, for example, with Kati Karikó , my friend who had the Nobel Award for mRNA, she spent three decades trying to get people to listen to her and never got a grant from the NIH or other places [our conversation here]. And it was a really tough battle. And as you already touched on Svetlana Mojsov, who did some of the seminal work at Rockefeller to isolate the portion of GLP-1, that really was the key part peptide, and it was overlooked for years. And so, it's a tough fight, but you're paving the way here. And I think the contributions you've made are just so extraordinary. And I hope that over the years we will continue to see this momentum because people like what you've done, deserve this extraordinary recognition. I'm glad to see. And the Lasker Award is really capping off some of that great recognition that is so well deserved. We've covered a lot of ground today, and I want to make sure if I missed anything that you wanted to get into before we wrap up.Lotte Bjerre Knudsen (43:30):I think we've been around all the exciting biology of GLP-1, both in diabetes, obesity, cardiovascular, kidney, potential in Alzheimer's and addiction. We'll see, we need the clinical data and we've put out a message to inspire people to do new science. There's still a lot of unmet need out there. There's a lot of diseases that don't have good treatments. Even in the diseases we've talked about there's a lot of money for diabetes. There are no disease modifying therapies for diabetes. It's not really changing the course of the disease. So there's a lot of things that needs great scientists.Eric Topol (44:17):And I guess just in finishing the discovery of this class of drugs and what it's led to, tells us something about that, there's so much more to learn that is, this has taken on perhaps the greatest obstacle in medicine, which was could you safely treat obesity and have a marked effect. Which decades, many decades were devoted to that and gotten nowhere. It's like a breakthrough in another way is that here you have an ability to triumph over such a frustrating target, just like we've seen with Alzheimer's, of course, which may actually intersect with Alzheimer's, with a graveyard of failed drugs. And the ones that it were approved so far in certain countries, like the US are so questionable as to the safety and efficacy. But it gives us an inspiration about what is natural that can be built on the basic science that can lead to with people like you who push within the right direction, give the right nudges and get the support you need, who knows what else is out there that we're going to be discovering in the years ahead. It's a broad type of lesson for us.Lotte Bjerre Knudsen (45:38):Yeah, there is another hormone that's also in phase three clinical development, right? The amylin hormone. We've had pramlintide on the market for years, but we have this long-acting version that is in phase three clinical development. That could be the same kind of story because there's also additional biology on that one.Eric Topol (45:58):Yeah, this is what grabs me Lotte, because these gut hormone, we've known about them, and there's several more out there, of course. And look what they're having. They're not just gut hormones, like you said, they're neurotransmitters and they're body-wide receptors waiting to be activated, so it's wild. It's just wild. And I'm so glad to have had this conversation with you. Now, congratulations on all that you've done, and I know the Nature Medicine paper that just came out is going to be just one of many more to come in your career. So what a joy to have the chance to visit with you, and we'll be following the work that you and your colleagues are doing with great interest.Lotte Bjerre Knudsen (46:45):And thank you very much, and thank you for your wonderful podcast. They're really great to listen to on the go. 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Note: This podcast is a companion to the Ground Truths newsletter “A Big Week for GLP-1 Drugs”Eric Topol (00:06):It is Eric Topol with Ground Truths, and with me today is Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) as we get to know these family of drugs and he's a true pioneer. He's been working on this for decades. So welcome, Daniel.Daniel Drucker (00:43):Thank you.Eric Topol (00:45):Yeah, it's great to have you and to get the perspective, one of the true pioneers in this field, because to say it's blossom would be an understatement, don't you think?Daniel Drucker (00:57):Yeah, it's been a bit of a hectic three years. We had a good quiet 30 plus years of solid science and then it's just exploded over the last few years.Eric Topol (01:06):Yeah, back in 30 years ago, did you have any sense that this was coming?Daniel Drucker (01:14):Not what we're experiencing today, I think there was a vision for the diabetes story. The first experiments were demonstrating insulin secretion and patents were followed around the use for the treatment of GLP-1 for diabetes. The food intake story was much more gradual and the weight loss story was quite slow. And in fact, as you know, we've had a GLP-1 drug approved for people with obesity since 2014, so it's 10 years since liraglutide was approved, but it didn't really catch the public's attention. The weight loss was good, but it wasn't as spectacular as what we're seeing today. So this really has taken off just over the last three, four years.Eric Topol (01:58):Yeah, no, it's actually, I've never seen a drug class like this in my life, Daniel. I mean, I've obviously witnessed the statins, but this one in terms of pleiotropy of having diverse effects, and I want to get to the brain here in just a minute because that seems to be quite a big factor. But one thing just before we get too deep into this, I think you have been great to recognize one of your colleagues who you work with at Harvard, Svetlana Mojsov. And the question I guess is over the years, as you said, there was a real kind of incremental path and I guess was in 1996 when you said, well, this drug likely will inhibit food intake, but then there were gaps of many years since then, as you mentioned about getting into the obesity side. Was that because there wasn't much weight loss in the people with diabetes or was it related to the dose of the drugs that were being tested?Why Did It Take So Long to Get to Obesity?Daniel Drucker (03:11):Well, really both. So the initial doses we tested for type 2 diabetes did not produce a lot of weight loss, maybe 2-3%. And then when we got semaglutide for type 2 diabetes, maybe we were getting 4-5% mean weight loss. And so that was really good and that was much better than we achieved before with any glucose lowering drug. But a lot of credit goes to Novo Nordisk because they looked at the dose for liraglutide and diabetes, which was 1.8 milligrams once daily for people with type 2 diabetes. And they asked a simple question, what if we increase the dose for weight loss? And the answer was, we get better weight loss with 3 milligrams once a day. So they learn that. And when they introduced semaglutide for type 2 diabetes, the doses were 0.5 and 1 milligrams. But in the back of their minds was the same question, what if we increased the dose and they landed on 2.4 milligrams once a week. And that's when we really started to see that the unexpected spectacular weight loss that we're now quite familiar with.Eric Topol (04:16):Was there also something too that diabetics don't lose as much weight if you were to have match dose?Daniel Drucker (04:22):Yeah, that's a general phenomenon. If one goes from either diet to bariatric surgery, and certainly with weight loss medicines, we tend to see maybe two thirds to three quarters of the amount of weight loss in people with type 2 diabetes. We don't really understand it. The brain pathways are probably resistant to some of the pathways that are activated that lead to weight loss, and it's really an interesting observation that needs further study.The Brain EffectEric Topol (04:50):Yeah, it's fascinating really. And it might've at least in part, held up this progress that has been truly remarkable. Now, recently you published a paper among many, you're a very prolific scientist, of course, physician scientist, but back in December in Cell Metabolism was a very important paper that explored the brain gut axis, the ability to inhibit inflammation and the mechanism through Toll-like receptors that you were seeing that. So maybe you could summarize the fact that you saw this, you were quoted in this Atlantic piece by Sarah Zhang, the science behind Ozempic was wrong. The weight loss effects of GLP-1 drugs have little to do with the gut and basically claiming that it's related to the effects on the brain, which of course could be reduced inflammation, reduced or inhibiting centers of addiction craving, that sort of thing. So how do you interpret your recent results and ongoing studies regarding GLP-1's effect on the brain?Daniel Drucker (06:02):Sure, so to be clear, I don't think that was a quote. I never would've said the science behind Ozempic was wrong. I think that was a headline writer doing what they do best, which is catching people's attention. I think what I was trying to say is that where this field started with insulin secretion first and then weight loss second, those are clearly very important pharmacological attributes of GLP-1. But physiologically, if we take GLP-1 away or we take the receptor away, you don't really develop diabetes without GLP-1. You don't really gain a lot of weight without GLP-1. So physiologically it's not that important. Why do we have GLP-1 in the distal gut? I think physiologically it's there to defend against infection and reduce gut inflammation. But we noticed that GLP-1 reduces inflammation in many different places in the heart and blood vessels and in the liver and many organs where you don't see a lot of GLP-1 receptors and you don't see a lot of GLP-1 receptors on immune cells.Daniel Drucker (07:04):So that really led us to the question, well, how does it work and affect all these organs where we don't see a lot of the receptors? And that's where we landed on the brain. Obviously the nervous system can communicate with many different cell types in almost every organ. And we identified neurons that expressed the GLP-1 receptor, which when blocked abrogated or completely eliminated the ability of GLP-1 to reduce inflammation in the periphery in white cells or in lungs. So it's been known for some time that the brain can control the immune system. So this is just the latest piece in the puzzle of how GLP-1 might reduce inflammation.Eric Topol (07:49):And just to be clear, I was quoting the Atlantic headline, not you that you were quoted within that article, but this is something that's really interesting because obviously GLP-1 is made in the brain in certain parts of the brain, it's transient in terms of its half-life made from the gut. But when we give these drugs, these agonists, how does it get in the brain? Because isn't there a problem with the blood brain barrier?Daniel Drucker (08:22):So I don't think the drugs get into the brain very well. We have a lot of data on this, so people have done the classic experiments, they either make radioactive ligands or fluorescent ligands, and they look how much gets in it and not very much gets in beyond the blood-brain barrier. And we also have big drugs that are immunoglobulin based and they work really well, so they don't get into the brain very much at all. And so, the way I describe this is that GLP-1 talks to the brain, but it doesn't directly get into the brain to meaningful extent, it does communicate somewhat there are areas obviously that are accessible in the area of the stream and circumventricular organs, but most of the time we have this communication that's not well understood that results in the magic that we see. And there are some discussions around for the neurodegenerative disease story where GLP-1 is being looked at in Parkinson's disease and in people with Alzheimer's disease. Would you be able to get more benefit if you could get the drugs into the brain to a greater extent, or would you simply increase the adverse event profile and the adverse response? So really important area for study as we begin to go beyond diabetes and obesity.Eric Topol (09:41):Yeah, I mean as you're pointing out, there's two ongoing trials, pretty large trials in Alzheimer's, early Alzheimer's, which may be a little bit too late, but at any rate, testing GLP-1 to see whether or not it could help prevent progression of the disease. And as you also mentioned, diseases and Parkinson's. But I guess, so the magic as you referred to it, the gut -brain axis so that when you give the GLP-1 family of drugs, we'll talk more about the double and triple receptor in a moment, but when you give these drugs, how does the message you get from the gut to the brain would you say?Daniel Drucker (10:27):So pharmacologically, we can give someone or an animal the drug, it does reach some of the accessible neurons that have GLP-1 receptors, and they probably transmit signals deeper into the brain and then activate signal transduction. So one way to look at it, if you use c-fos, the protein, which is an immediate early gene, which is increased when we activate neurons, we see rapid activation of c-fos in many regions that are deep within the brain within minutes. And we know that GLP-1 is not getting directly to those neurons, but it's activating pathways that turn on those neurons. And so, there's probably a very intricate set of pathways that sense the GLP-1 and the accessible neurons and then transmit those signals deeper into the brain.Double and Triple Receptor AgonistsEric Topol (11:18):Okay, well that makes sense. Now, as this has been moving along in obesity from semaglutide to tirzepatide and beyond, we're seeing even more potency it appears, and we have now double and triple receptors adding into glucagon itself and the gastric inhibitory polypeptide, and there's mixed data. So for example, the Amgen drug has the opposite effect on GIP as does the dual receptor, but comes out with the same weight loss I guess. How do we understand, I mean you know these gut hormones inside and out, how do we get such disparate results when you're either blocking or revving up a peptide effect?Daniel Drucker (12:13):Yeah, it's a mystery. I always sort of joke that you've invited the wrong person because I don't fully understand how to reconcile this honestly. There are some theories you could say that tirzepatide may possibly desensitize the GIP receptor, and that would align with what the GIP receptor blocking component is. And so, I think we need a lot of research, we may actually never know in humans how to reconcile these observations. I think we can do the experiments in animals, we're doing them, other people are doing them to look at the gain and loss of function and use best genetics. But in humans, you'd have to block or activate these receptors in very specific populations for a long period of time with tools that we probably don't have. So we may not reconstruct. We may end up with Maritide from Amgen that's producing 15-20% plus weight loss and tirzepatide from Lilly, that's spectacular, that's producing more than 20% weight loss. And yet as you mentioned at the GIP level, they have opposite effect. So I don't think we fully understand. Maybe your next guest will explain it to you and invite me on. I'd be happy to listen.Eric Topol (13:27):Well, I don't know. I don't think anybody can explain it. You've done it as well as I think as possible right now. But then we have the triple receptor, which it seems like if you take that drug, you could just go kind of skeletal. It seems like there's no plateau and its effect, that is I guess is it retatrutide, is that the name of it?Daniel Drucker (13:47):Retatrutide, yeah.Eric Topol (13:48):Retatrutide, okay. And then of course we're going on with potentially oral drugs or drugs that last for a year. And where do you see all that headed?Daniel Drucker (14:00):So I think the way I describe innovation in this field is there are two buckets that we've talked about today. So one bucket is the new molecule, so we're going to have all kinds of different combinations that will be peptides, that will be small molecule orals, the NIH is funding innovative programs to see if we can develop cell-based factories that produce GLP-1. There are gene editing and gene therapy approaches. So there are going to be multiple different molecular approaches to delivering molecules that are better and hopefully easier to take maybe once monthly, maybe every six months. So that's really exciting. And the other obvious bucket is the disease that we're targeting, so we started off with type 2 diabetes. We're now firmly established in the obesity field. In your field, we've seen consistently positive cardiovascular outcome trials. We had a press release a few months ago in October - November saying that semaglutide reduces chronic kidney disease. We have trials underway with peripheral artery disease with Parkinson's disease, with Alzheimer's and a number of neuropsychiatric conditions. So I think we're going to see both innovation on the molecule side as well as expanding if the trials are positive, expanding clinical indication. So it's going to be a pretty exciting next couple of years.Eric Topol (15:21):Right, no question. And as you well know, just in the past week, the FDA gave the green light for using these drugs for heart failure with preserved ejection fraction, which was an important randomized trial that showed that. Now there's got to be some downsides of course there's no drug that's perfect. And I wanted to get your comments about muscle loss, potentially bone density reduction. What are the downsides that we should be thinking about with these drugs?Side EffectsDaniel Drucker (15:54):Sure, so the known side effects are predominantly gastrointestinal. So we have nausea, diarrhea, constipation and vomiting. And very importantly, if those side effects are severe enough that someone can't eat and drink for 24 hours, we need to tell them you have to seek medical attention because some people will get dehydrated and rarely get acute kidney injury. This is rare, but it's described in many of the outcome trials, and we definitely want to avoid that. Gallbladder events are probably one in several hundred to one in a thousand, and that can be anywhere from gallbladder inflammation to gallbladder stones to biliary obstruction. Don't fully understand that although GLP-1 does reduce gallbladder motility, so that may contribute. And then very rarely we're seeing reports of small bowel obstruction in some people difficult to sort out. We don't really see that in the large clinical trials, but we have to take people at there were, we haven't seen an imbalance in pancreatitis, we haven't seen an imbalance of cancer.Daniel Drucker (17:01):There is no evidence for clinically significant bone disease either at the level of reduced bone densities or more importantly at the level of fractures. And we have a lot of real world data that's looked at that. Now muscle losses is really interesting. So when the initial drugs were approved, they didn't produce much weight loss. We didn't think about it. Now that we're getting the 15 20% plus, the question is, will we see clinically significant sarcopenia? And I use the word clinically significant carefully. So we definitely see muscle lean mass loss on a DEXA scan, for example. But what we're not seeing so far are people who are saying, you know what my grip strength is weak. I can't get up off the chair. I have trouble reaching up into the cupboard. My exercise or walking capacity is limited. We're not seeing that. In fact, we're seeing the opposite.Daniel Drucker (17:53):As you might expect, people are losing weight, they're less achy, they can move more, they can exercise more. So the question is buried within that data, are there some individuals with real clinical sarcopenia? And as we get to 25% weight loss, it's very reasonable to expect that maybe we will see some individuals with clinical sarcopenia. So you're very familiar. There are half a dozen companies developing medicines to promote fat mass loss and spare muscle with or without semaglutide or tirzepatide. And this is a really interesting area to follow, and I don't know how it's going to turn out. We really have to see if we are going to see enough clinically significant muscle loss and sarcopenia to merit a new drug category emerge, so fascinating to follow us.Eric Topol (18:46):No, I'm so glad you reviewed that because the muscle loss, it could be heterogeneous and there could be some people that really have some substantial sarcopenia. We'll learn more about that. Now that gets me to what do we do with lifelong therapy here, Daniel, where are we going? Because it seems as though when you stop these drugs, much of the benefit can be not potentially all, but a substantial amount could be lost over time. Is this something that you would view as an insulin and other hormonal treatments or how do you see it?The Question of ReboundDaniel Drucker (19:26):Yeah, so it's fascinating. I think that traditional view is the one that you just espoused. That is you stop the drug, you regain the weight, and people are concerned about the rebound weight and maybe gaining more fat and having less favorable body composition. But if you look at the data, and it's coming very fast and furious. A few months ago, we saw data for a tirzepatide trial, one of the surmount obesity trials, the first author was Louis Aronne in New York and they gave people tirzepatide or placebo for 38 weeks. And then they either continue the tirzepatide or stop the tirzepatide. One year later, so no tirzepatide for one year, more than 40% of the people still managed to keep at least 10% of their weight off, which is more than enough in many people to bestow considerable metabolic health. So I think there are going to be people that don't need to take the medicines all the time for weight loss, but we must remember that when we're excited about heart attacks and strokes and chronic kidney disease, there's no evidence that you can stop the medicines and still get the benefits to reduce those chronic complications.Daniel Drucker (20:46):So we're going to have to get much more sophisticated in terms of a personalized and precision medicine approach and ask what are the goals? And if the goals are to reduce heart attack strokes and death, you probably need to stay on the medicine if the goals are to achieve weight loss so that you can be metabolically healthy, there may be a lot of people who can come off the medicine for considerable amounts of time. So we're just learning about this. It's very new and it's really exciting.Suppressing Inflammation as the Common ThreadEric Topol (21:11):Yeah, no question. And just going back to the inflammation story in heart disease, it was notable that there were biomarkers of reduced inflammation in the intervention trial before there was any evidence of weight loss. So the anti-inflammatory effects here seem to be quite important, especially with various end organ benefits. Would you say that's true?Daniel Drucker (21:35):Yeah, I think that's one of my favorite sort of unifying theories. If we step back for a minute and we come into this and we say, well, here's a drug that improves heart disease and improves liver inflammation and reduces chronic kidney disease and may have some effect on atherosclerosis and is being studied with promising results and neurodegenerative disease, how do we unify all that? And one way is to say all of these chronic disorders are characterized by a component of chronic inflammation. And Eric, it's fascinating. I get reports from random strangers, people who've been on tirzepatide or people who have been on semaglutide, and they tell me, and you'll be fascinated with this, they tell me, my post Covid brain fog is better since I started the drug. They send me pictures of their hands. These are people with chronic arthritis. And they say, my hands have never looked better since I started the drug. And they tell me they've had ulcerative colitis for years on biologics and all of a sudden it's in remission on these drugs. So these are case reports, they're anecdotes, but they're fascinating and quite consistent with the fact that some people may be experiencing an anti-inflammatory effect of these medicines.Eric Topol (22:55):And I think it's notable that this is a much more potent anti-inflammatory effect than we saw from statins. I mean, as you know, well they have an effect, but it's not in the same league, I don't think. And also the point you made regarding this is a very good candidate drug class for Long Covid and for a variety of conditions characterized by chronic inflammation. In fact, so many of our chronic diseases fit into that category. Well, this is fascinating, and by the way, I don't know if you know this, but we were both at Johns Hopkins at the same time when you were there in the early eighties. I was there as a cardiology fellow, but we never had a chance to meet back then.Daniel Drucker (23:41):So were you just ahead of Cricket Seidman and the whole team there, or what year was that?Eric Topol (23:46):Just before them, that's right. You were there doing, was it your internship?Daniel Drucker (23:50):I was doing an Osler internship. I think Victor McKusick loved to have a Canadian every year to recognize Osler, one of the great Canadians, and I was just lucky to get the slot that year.Eric Topol (24:04):Yeah, it's wild to have watched your efforts, your career and your colleagues and how much of a profound impact. If you were to look back though, and you were to put this into perspective because there were obviously many other hormones along the way, like leptin and so many others that were candidates to achieve what this has. Do you think there's serendipity that play out here or how do you kind of factor it all together?Daniel Drucker (24:38):Well, there there's always serendipity. I mean, for decades when people would write review articles on the neuropeptides that were important for control of hunger and satiety and appetite circuits, I would open the article, read it, and I'd say, darn, there's no GLP-1 on the figure. There's no GLP-1 or receptor on the figure, but there's leptin and agouti and the POMC peptides and all the melanocortin and so on and so forth, because physiologically, these systems are not important. As I mentioned, you don't see childhood obesity or genetic forms of obesity in people with loss of function mutations in the GLP-1 sequence or in the GLP-1 receptor. You just don't see a physiologically important effect for having low GLP-1 or having no GLP-1. And that's of course not the case for mutations in NPY or the melanocortin or leptin, et cetera.Other EffectsDaniel Drucker (25:36):But pharmacologically, it's been extraordinarily difficult to make drugs out of these other peptides and pathways that we talked about. But fortuitously or serendipitously, as you point out, these drugs seem to work and amazingly GPCRs are notoriously prone to desensitization. We use that in clinical medicine to turn off entire circuits. And thankfully what goes away with GLP-1 are the adverse effects. So nausea, vomiting, diarrhea, constipation, we see those during the first few weeks and then there's tachyphylaxis, and they generally go away in most people, but what doesn't go away through good fortune are the ability of GLP-1 to talk to those brain circuits and say, you know what? You're not hungry. You don't need to eat. You don't need to think about food. And that's just good luck. Obviously pharmacologically that's benefited all of us working in this area.Eric Topol (26:31):It's extraordinary to be able to get desensitized on the adverse effects and not lose the power of the benefit. What about addiction that is, whether it's alcohol, cigarettes, gambling, addictive behavior, do you see that that's ultimately going to be one of the principal uses of these drugs over time?Daniel Drucker (26:55):The liver docs, when I give a talk at a metabolic liver disease meeting, they say we love GLP-1 because not only might it take care of liver disease, but there are still some people that we see that are having problems with alcohol use disorders and it might also reduce that. And obviously there are tons of anecdotes that we see. If you go on social media, and you'll see lots of discussion about this, and there's a hundred or so animal paper showing that addiction related dependence behaviors are improved in the context of these medicines. But we don't have the clinical data. So we have a couple of randomized clinical trials, small ones in people with alcohol use disorder, very unimpressive data. We had a trial in people with smoking, didn't really see much, although interestingly, they noted that people drank less alcohol than they did the smoking trial. So there are dozens and dozens of trials underway now, many investigator initiated trials looking at whether it's nicotine or cocaine or cannabinoids or all kinds of compulsive behaviors. I think in the next 12 to 24 months, we're going to start to learn are these real bonafide effects that are seen in large numbers of people or are these just the anecdotes that we won't get a very good complete response. So it's really exciting neuroscience and we're going to learn a lot over the next couple of years.Eric Topol (28:20):Yeah, no, it's a fascinating area which just extends the things that we've been discussing. Now, let's say over time, over the years ahead that these drugs become because of the competition and various factors, perhaps in pill form or infrequent dosing, they become very inexpensive, not like they are today.Daniel Drucker (28:44):That'd be great speaking as a non-pharmaceutical physician.Eric Topol (28:48):Yeah, yeah, no, these companies, which of course as you well know, it accounts for the number one economy in Denmark and is having a big impact in Europe. And obviously Eli Lilly is now the most valued biopharma company in the world from all these effects are coming from this drug class, but let's just say eventually it's not expensive and the drug companies are not gouging and pleasing their investors, and we're in a different world. With all these things that we've been discussing, do you foresee a future where most people will be taking one form or another of this family of drugs to prevent all these chronic conditions that we've just been discussing independent of obesity, type 2 diabetes, the initial frontier? Do you think that's possible?Daniel Drucker (29:42):Yeah, I'm a very conservative data-driven person. So today we don't have the data. So if I was in charge of the drinking water supply in your neighborhood and I had unlimited free cheap GLP-1, I wouldn't dump it in there just yet. I don't think we have the data, but we have trials underway, as you noted for Alzheimer's disease, a challenging condition for our society with a huge unmet need if like fingers crossed, if semaglutide does show a benefit for people living with early Alzheimer's disease, if it helps for Parkinson's, if it helps for metabolic liver disease, there are also studies looking at aging, et cetera. So it's possible one day if we have a lot more data that we will begin to think, okay, maybe this is actually a useful medicine that should deserve much more exposure, but today we just don't have the data.Eric Topol (30:38):Absolutely. I couldn't agree more, but just wanted to get you kind of speculate on that a bit off script if you will, but what your thoughts were, because this will take a long time, get to that point, but you just kind of wonder when you have an absence of chronic significant side effects overall with these diverse and relatively potent benefits that cut across many organ systems and as you just mentioned, might even influence the aging process, the biologic process.Worsening InequitiesDaniel Drucker (31:10):There's another related sort of angle to this, which is that the accessibility of these medicines is very challenging even in well-developed countries, the United States, Europe, et cetera, and we have hundreds of millions of people in the global south and less well-developed economies that are also challenged by heart disease and diabetes and obesity and chronic kidney disease and liver disease. And I think we need to start having conversations and I think they are happening just like we did for HIV and just like we did for hepatitis and certainly we did very quickly for the Covid vaccines. We need to think out of the box and say we need to help people in other parts of the world who may not have access to the medicines in their current form and at their current pricing. And I think these are really important moral and ethical discussions that need to be happening now because soon we will have small molecules and the price will come down and we need to make sure it's not just people in well-developed countries that can afford access to these medicines. I think this is a great opportunity for pharmaceutical companies and the World Health Organization and other foundations to really think broadly about how we can benefit many more people.Eric Topol (32:29):I couldn't agree with you more and I'm so glad you emphasize that because we can't wait for these prices to come down and we need creative ways to bridge, to reduce inequities in a vital drug class that's emerged to have far more applicability and benefit than it was initially envisioned, certainly even 5, 10 years ago, no less 30 years ago when you got on it. So Daniel, I can't thank you enough for this discussion. Really a candid discussion reviewing a lot of the things we do know, don't know will know someday perhaps. I just want to note, I know so many people are cheering for you and your colleagues to get recognized further like by the Nobel folks in the years ahead. I think it's pretty darn likely and hopefully when we get a chance to visit again in the years ahead, we'll unravel some of the things that we discussed today that we didn't know the answers and that you as a really an authority and pioneer in the field. Also, I could admit that there's a ways to go to really understand the boundaries if there are boundaries here for how these drugs are going to be used in the years ahead.Daniel Drucker (33:51):Yeah, it's another great story for basic science and bench to bedside, and it's just another story where none of us could have predicted the outcomes that we're talking about today to their full extent. And so to the extent that we can convince our governments and our funding agencies to really fund discovery science, the benefits are never apparent immediately. But boy, do they ever come in spades later on in an unpredictable manner. And this is just a great example.Eric Topol (34:20):Yeah, I also would say that this work cracking the case of obesity, which has been a stumbling block, I ran a big trial with Rimonabant, which was a failure with the neuropsychiatric side effects and suicidal ideation that had to get dropped. And there's many others like that as you know, very well Fen-Phen, and a long list. And the fact that this could do what it's doing and well beyond just obesity is just spectacular. And what I think it does, what you just mentioned, Daniel, is the basic science work that led to this is I think an exemplar of why we should put in these efforts and not expect immediate benefits, dividends of those efforts. Because look what's happened here. If you can break through with obesity, imagine what lies ahead. So thanks so much for joining and we'll look forward to continuing to follow your work. I know you're publishing the same pace, exceptional prolific pace over many, many years, and I'm sure that's going to continue.Daniel Drucker (35:34):Well, I have a great team and so it's a pleasure me to go into work and talk to them every day.********************Thanks for listening to/reading Ground Truths.Please share if your found this podcast informative Get full access to Ground Truths at erictopol.substack.com/subscribe

In episode 6 of the Public Sector Unearthed podcast, we dive into the Empowered Communities program with Kristina Musial-Aderer, adviser, Empowered Communities at the National Indigenous Australians Agency, Reshaune Singer, engagement officer for NPY Empowered Communities and Jason Quin, executive manager of NPY Empowered Communities. They share how the program runs from the ground up, how they connect with community, and what motivates them to keep going every day.Kristina, shines a light on what the makes the Empowered Communities program stand out and how the government acts not as the primary driver but as an enabling partner. She also highlights how the program varies significantly across different communities and regions to accommodate the unique needs and circumstances of each area.Joining the conversation from Alice Springs, Reshaune, and Jason provide insights into how the program is running in the NPY region. Located in a tri-state area, Jason and Reshaune talk about the need for strong community ties and innovative communication and decision-making strategies are important for success. The conversation also explores their personal journeys, revealing the deep connections and motivations that drive their commitment to working closely with First Nations communities.This episode's unearthed wisdom: Empowering First Nations communities requires genuine partnership, respect for indigenous knowledge, and a commitment to community-led solutions. Hosted on Acast. See acast.com/privacy for more information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.24.550381v1?rss=1 Authors: Kumari, R., Pascalau, R., Wang, H., Bajpayi, S., Yurgel, M., Quansah, K., Hattar, S., Tampakakis, E., Kuruvilla, R. Abstract: Neuropeptide Y (NPY) is best known for its effects in the brain as an orexigenic and anxiolytic agent and in reducing energy expenditure. NPY is also co-expressed with Norepinephrine (NE) in sympathetic neurons. Although NPY is generally considered to modulate noradrenergic responses, its specific roles in autonomic physiology remain under-appreciated. Here, we show that sympathetic-derived NPY is essential for metabolic and cardiovascular regulation in mice. NPY and NE are co-expressed in 90% of prevertebral sympathetic neurons and only 43% of paravertebral neurons. NPY-expressing neurons primarily innervate blood vessels in peripheral organs. Sympathetic-specific deletion of NPY elicits pronounced metabolic and cardiovascular defects in mice, including reductions in insulin secretion, glucose tolerance, cold tolerance, pupil size, and an elevation in heart rate, while notably, however, basal blood pressure was unchanged. These findings provide new knowledge about target tissue-specific functions of NPY derived from sympathetic neurons and imply its potential involvement in metabolic and cardiovascular diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.11.548551v1?rss=1 Authors: Zhang, S. X., Kim, A., Madara, J. C., Zhu, P. K., Christenson, L. F., Lutas, A., Kalugin, P. N., Jin, Y., Paul, A., Tian, L., Lowell, B. B., Andermann, M. L. Abstract: We investigated how transmission of hunger- and satiety-promoting neuropeptides, NPY and alpha MSH, is integrated at the level of intracellular signaling to control feeding. Receptors for these peptides use the second messenger cAMP, but the messenger's spatiotemporal dynamics and role in energy balance are controversial. We show that AgRP axon stimulation in the paraventricular hypothalamus evokes probabilistic and spatially restricted NPY release that triggers stochastic cAMP decrements in downstream MC4R-expressing neurons (PVHMC4R). Meanwhile, POMC axon stimulation triggers stochastic, alpha MSH-dependent cAMP increments. NPY and alpha MSH competitively control cAMP, as reflected by hunger-state-dependent differences in the amplitude and persistence of cAMP transients evoked by each peptide. During feeding bouts, elevated alpha MSH release and suppressed NPY release cooperatively sustain elevated cAMP in PVH MC4R neurons, thereby potentiating feeding-related excitatory inputs and promoting satiation across minutes. Our findings highlight how state-dependent integration of opposing, quantal peptidergic events by a common biochemical target calibrates energy intake. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this podcast episode, we hear from ISSA's own team members and bootcamp co-hosts Jenny Scott and John Bauer for our first edition of Lighting Fitness Facts and Trainer REAL talk. In this episode Jenny and John shed light on the latest scientific research and evidence-based information in the world of health and fitness, exploring fascinating studies and discoveries that can revolutionize the way we approach our well-being.In our first round of questions, Jenny and John dive into intriguing findings that uncover the mysteries behind our appetite, exercise motivation, cell metabolism, resistance training, and more. They then move into the Training Real Talk segment where they discuss strategies for making health cool and promoting scientific literacy in the fitness world. Discover how to prioritize your health, access reliable sources of information, understand basic science concepts, and seek guidance from experts!References from this episode: References for show notes:Yue Qi, Nicola J. Lee, Chi Kin Ip, Ronaldo Enriquez, Ramon Tasan, Lei Zhang, Herbert Herzog. Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons. Cell Metabolism, 2023; DOI: 10.1016/j.cmet.2023.04.020Leandro Garcia, Matthew Pearce, Ali Abbas, Alexander Mok, Tessa Strain, Sara Ali, Alessio Crippa, Paddy C Dempsey, Rajna Golubic, Paul Kelly, Yvonne Laird, Eoin McNamara, Samuel Moore, Thiago Herick de Sa, Andrea D Smith, Katrien Wijndaele, James Woodcock, Soren Brage. Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes: a dose–response meta-analysis of large prospective studies. British Journal of Sports Medicine, 2023; bjsports-2022-105669 DOI: 10.1136/bjsports-2022-105669Dohnalová, L., Lundgren, P., Carty, J.R.E. et al. A microbiome-dependent gut–brain pathway regulates motivation for exercise. Nature, 2022 DOI: 10.1038/s41586-022-05525-zWeakley, J., Schoenfeld, B.J., Ljungberg, J. et al. Physiological Responses and Adaptations to Lower Load Resistance Training: Implications for Health and Performance. Sports Med - Open 9, 28 (2023). https://doi.org/10.1186/s40798-023-00578-4

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.26.525731v1?rss=1 Authors: Crosson, T., Bhat, S., Wang, J.-C., Salaün, C., Roversi, K., Herzog, H., Rafei, M., Blunck, R., Talbot, S. Abstract: Nociceptor neurons play a crucial role in maintaining the body's equilibrium by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. Using an ovalbumin mouse model of airway inflammation, we found that these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r, along with Il6. A screening of asthma-driving cytokines revealed that IL-13 drives part of this reprogramming, including Npy1r overexpression via the JAK/STAT6 pathway, while IL-1{beta} induces IL-6 expression and release. Additionally, we observed that sympathetic neurons release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, characterized by the release of IL-6, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.14.516867v1?rss=1 Authors: Barde, S., Aguila, J., Zhong, W., Solarz, A., Mei, I., Prud'homme, J., Palkovits, M., Turecki, G., Mulder, J., Uhlen, M., Nagy, C., Mechawar, N., Hedlund, E., Hokfelt, T. Abstract: BACKGROUND: Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems, including substance P(SP)/tachykinin, neuropeptide Y(NPY) and their G protein-coupled receptors are involved in mood regulation.METHODS: We assessed the transcript levels (qPCR) of SP/tachykinin and NPY systems in five regions from postmortem brains of male and female depressed subjects who committed suicide (DSS) and controls: dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), the dorsal raphe nucleus (DRN), locus coeruleus (LC) and medullary raphe nuclei (MRN). We also analysed human LC neurons isolated using LCM with Smart-seq2 RNA sequencing. RESULTS: Transcripts for all nine members were detected in male and female controls with marked regional variations of the raw CT values and with the highest levels for several tachykinin and tachykinin receptor transcripts in the DRN and for NPY and NPYR transcripts in the PFC regions. Significant sex differences for controls were recorded only in the DRN (NPYR2 greater than in females) and LC (TAC3 and NPY greater than in females). Elevated expression in DSS was recorded in (i) DLPFC for SP, TAC and TAC3 in females, SP in males, and NPYR1 in both sexes; and (ii) LC for all tachykinin family transcripts in females, SP, TACR1 and TACR3 in males, NPY in both sexes, and NPYR1 in males. CONCLUSIONS: The selective perturbation of neuropeptide systems in MDD patients may assist in the search for novel treatment strategies for subjects afflicted by this grave disorder. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.18.516150v1?rss=1 Authors: Ursem, S. R., Diepenbroek, C., Kool, T., Eggels, L., Heijboer, A. C., la Fleur, S. E. Abstract: Fibroblast growth factor 23 (FGF23) is a key regulator of systemic phosphate homeostasis, but also an interplay with glucose metabolism has been suggested. Several studies implicate a function of FGF23 in the brain, and indeed we have recently identified FGF23 protein in several brain areas in rats, such as the hypothalamus, third ventricle and choroid plexus. In the current study, we aimed to determine the effect of an intracerebroventricular (icv) injection of FGF23 in the third ventricle of rats on hypothalamic genes involved in glucose regulation. In addition, we assessed whether glycerol can be used safely for icv injections as glycerol is used as a stabilizing compound for FGF23 protein. Adult Wistar rats received an icv injection of recombinant rat FGF23 or vehicle. Dose dependent behavioral changes, suggestive of stress, were observed directly after infusion of FGF23. After 60 min animals were sacrificed and the arcuate nucleus, lateral hypothalamus and choroid plexus were isolated. In these brain regions gene expression was determined of the FGF23 receptor complex (FGFR1, Klotho), NPY, POMC, phosphate transporters (SLC20 and SLC34 families) and markers of cellular ER stress (ATF4 and the ratio of spliced/unspliced XBP1). We showed that glycerol is well tolerated as stabilizer for icv injections. In FGF23-treated animals, cellular ER stress markers were increased in the arcuate nucleus. FGF23 injection did not affect expression of its receptor complex, NPY, POMC, or phosphate transporters. Future studies are warranted to investigate the effect of FGF23 in the brain on the protein level and on neuronal activation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Sisters in Law LIVE : Interview with Chloe Fragos and Tasmin Erlandson from NPY Women's Council - 14.9.2022 Sister's In Law host Sarah Edwards along with CAWLS' intern Sarah Hellyer welcome NPY's Chloe Fragos and Yasmin Erlandson into the studio to discuss community development and legal education projects at the Domestic and Family Violence Service run by NPY Women's Council.  Hosted by lawyers from the Central Australian Women's Legal Service (CAWLS) in Mparntwe/ Alice Springs, Sisters in Law provides information about the law, women's rights and access to justice. Broadcast Live on 8CCC 102.1FM + listen On Demand and subscribe to our podcast!    See omnystudio.com/listener for privacy information.

In this episode, CAWLS host Sally Krutsch interviews Rachel Neary and Mel Bakewell from the Ngaanyatjarra Pitjantjatjara Yankunytjatjara Women’s Council. NPY Women’s Council operates a Domestic and Family Violence service providing case work, legal education, support and training. Tune in to learn more about NPY Women’s Council, the long standing relationship NPY has with Anangu women, the work they do and how to contact them. Website: NPY Women's Council (npywc.org.au) Phone Number: 1800 180 840 Email: enquiries@npywc.org.au This episode features music from local artists: 'Lottery' by Sally Balfour and 'The Ending' by Kirra Voller. Please note, Sisters in Law is designed and intended to provide general information current at the time of publication, for informational purposes only. The contents do not constitute legal advice. You should seek legal advice or other professional advice in relation to any particular matters you may have. Reach us at cawls.org.au/contact/ Produced in partnership with 8CCC Community Radio. Sisters In Law Season Two has been made possible through the support of the Community Broadcasting Foundation. Find out more at www.cbf.org.auSee omnystudio.com/listener for privacy information.

Fear-conditioning learning is a low-threshold enduring psychiatric process that prepares a defense against dangerous phenomena and reduces the need to iteratively relearn the signal. It is a pattern recognition response that can be modulated by experience and the severity of the stress signal and it is a response that deteriorates in the elderly and in certain neuropsycoses and anxiety disorders throughout life. Fear conditioning must be fluid to readjust according to reverse learning. Persistent fear and avoidance of the potential for fear-associated events are common presentations of social anxiety disorder (SAD) and avoidant behavior maintains SAD, thus it prevents the reversal of fear in social situations. The best treatment outcomes are CBT including exposure therapy, which leads to fear extinction. Pharmacotherapy including antidepressants, benzodiazepines, beta-blockers, anticonvulsants, or neuroleptics, are commonly administered with low efficacy. Neuropeptide Y (NPY), a 36-amino acid peptide, is the most abundant and widely distributed neuropeptide in the mammalian brain and it may be involved in social behavior and the fear circuitry, including activities in the amygdala, hippocampus, septum, periaqueductal gray, locus coeruleus, cerebral cortex, basal ganglia, hypothalamus, and thalamus. NPY is also a feeding simulant, regulator of blood pressure, bioenergetics , neuroendocrine hormone responses, neuronal excitability, and neuroplasticity including epigenetic mechanisms. Not surprisingly, exogenous NPY causes a variety of behavioral effects when administered into the brain of rodents including stimulation of food intake when administered into the hypothalamic paraventricular nucleus, and it promotes social interaction when administered into the dorsolateral septum and basolateral amygdala and has anxiolytic and antidepressant-like effects when administered intracerebroventricularly (i.c.v.).NPY also affects different aspects of fear-related behaviors, as shown in fear conditioning studies in rodents. Next time we will link Acid Sphingomyelinase to NPY and the anxiety disorders of the elderly.. Int J Mol Sci. 2020 Nov; 21(21): 8220. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.23.352187v1?rss=1 Authors: Lee, Y., Song, H. Y., Kim, Y. B., Kim, K. S., Ha, D.-S., Jang, M., Lee, J., Kim, S. J., Choi, H. J. Abstract: Agouti-related protein (AgRP) has been believed to be the main driver of feeding behaviors ever since its discovery. However, recent studies using fiber photometry and optogenetics proved that feeding behaviors are not directly driven by AgRP neurons (temporal discrepancy between neuronal activity and behavior). To resolve this paradox, we conducted novel multi-phase feeding experiments to scrutinize the dynamics of AgRP. Fiber photometry study showed that AgRP neurons start to deactivate even before the initiation of the food search phase. Using optogenetics, we could prove that the feeding behavior induced by AgRP neuron activation had substantial temporal delay and the feeding behavior was sustained for substantial time even after cessation of optogenetic activation. These results indicate that AgRP neurons are not the direct driver of feeding behavior and another downstream neuron is the driver of feeding behavior. Leptin receptor (LepR) neurons in the lateral hypothalamus (LH). LH LepR neurons were activated before voluntary food search behavior initiation and showed robust increase after food approach behavior. Artificial activation of LH LepR neurons drives food search and food approach behavior. In accordance, chemogenetic activation of LepR neurons increased food search and food approach behaviors. Lastly, slice calcium imaging results showed the possibility that NPY from the AgRP neurons could be the downstream neuromodulator of AgRP neuron, driving LH LepR neuron activation. Overall, our study shows that AgRP neurons are not the direct drivers of feeding behavior, whereas LH LepR neurons directly drive sustained food seeking behavior. Copy rights belong to original authors. Visit the link for more info

Conscious leadership in the yoga industry!Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, shares about what is needed in 2020 and beyond to move our industry forward. Links:  Align and Elevate, build your business for $22/monthMoney Course for yoga teachers: Open to receive Teacher Training 2021 www.norwaypoweryoga.com/tt-spring-2021NPY Online www.norwaypoweryoga.com/npy-online Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Conscious leadership in the yoga industry!Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, shares about what is needed in 2020 and beyond to move our industry forward. Links:  Align and Elevate, build your business for $22/month  Teacher Training 2021 www.norwaypoweryoga.com/tt-spring-2021NPY Online www.norwaypoweryoga.com/npy-online Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

2020 is all about stepping into quality over quantity. In this episode Caroline introduces you to the concept of niching your yoga classes, and why this is so important.  Conscious leadership in the yoga industry!Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, shares about what is needed in 2020 and beyond to move our industry forward. Links:  Align and Elevate, build your business for $22/monthThe Money Course: Open to Receive  Teacher Training 2021 www.norwaypoweryoga.com/tt-spring-2021NPY Online www.norwaypoweryoga.com/npy-online Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

In this episode, Caroline dives into the reason many yoga teachers "feel icky" charging money for their medicine. Check it out.Conscious leadership in the yoga industry!Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, shares about what is needed in 2020 and beyond to move our industry forward. Links: Money Course for yoga teachers Align and Elevate, build your business for $22/month  Teacher Training 2021 www.norwaypoweryoga.com/tt-spring-2021NPY Online www.norwaypoweryoga.com/npy-online Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

This mini episode is a Monday morning motivational episode from Caroline Herring. Few people can fire you up and make you feel as grounded in one moment, the way Caroline can. Enjoy! Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, stays connected to you. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.carolineherring.netNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Are you distracted? Overwhelmed? A little reminder to take a break.Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, stays connected to you. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.carolineherring.netNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Your body is always trying to communicate with you. Through sensations, signals, or feelings. Are you listening?Do you know what that sensation means?Do you know why you are "tight" in that muscle?Listen to this episode and get a glimpse at what our most recent TTers have experienced this weekend. Ready to grow your practice and dive deeper into the science of movement and technology of yoga and how the two merge? Then you should consider signing up for the next round of TT with Norway Power Yoga. Dates will be annouced in September, but if you want to reserve your spot already for spring 2021, email caroline@norwaypoweryoga.com and we'll get you settled. Are you a yoga teacher who's had your business struck by corona? Caroline has launched an affordable place to grow your business as a yoga teacher. No, you don't need more followers. No, you don't need to invest 1000s of $$ into a business program. In this platform you pick and choose what you want to implement, and you can watch your business and classes grow. Step by step. It's a long-term game, honey. And I'm with you for the ride. To join Align & Elevate go to www. carolineherring.mykajabi.com Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, stays connected to you. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.ineedtoexhale.comNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Change is constant.Change is inevitable.Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, shares how we live, breathe, and practice mind-body fitness. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

A simulcast from Instagram. We decided to also make it into a podcast.Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, stays connected to you. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.ineedtoexhale.comNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Things discussed:-why can´t I get out of the house?-where is really going on?-how to I fix it? This episode is really about taking your power back and getting back on that mat, figuratively and literally.Enjoy!Awake by NPY is the channel where NPY founder and mind-body fitness entrepreneur, Caroline Herring, stays connected to you. Links:  NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.ineedtoexhale.comNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

In this episode NPY founder Caroline Herring shares her deepest fear, and how she's going to commit to facing that fear here on AWAKE by NPY because life as we know it, is changing. Per Caroline's request there's no editing, no fuss on this episode, read below for a personal letter from her. Dear AWAKE by NPY listener,For a while having a yoga podcast has felt limiting to me, there's so much else going on, so many things I'd like to talk about. So many things WE need to talk about. So I'm writing this to let you know that the podcast is going to change. Who knew AWAKE by NPY would be so descriptive, huh?We're waking up in a new world. We're waking up to uncomfortable truths. We are waking up to ourselves. This is happening off the mat. I hope you have a mat, a safe space, to step on to practice showing up, to practice just being. If you don't, I invite you to let AWAKE by NPY be that space for you.I love you, I promise we are in this together, and by gosh, I do hope you misunderstand something I say in this episode, because opening up for people to misunderstand you, opens you up to PEOPLE.And ps. I named it TRUST.Love you, always-C"TRUST" wouldn't it be nice to knowthat knowing isn't about informationbut about trust trusting isn't about believingit's about knowing,and the only way to knowis to trust  CONNECT WITH US::NPY Online www.norwaypoweryoga.com/npy-onlineEXHALE www.ineedtoexhale.comNorway Power Yoga www.norwaypoweryoga.com Caroline’s Instagram: @lineherring www.instagram.com/lineherringNPY Instagram: @norwaypoweryoga www.instagram.com/norwaypoweryoga 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.31.126805v1?rss=1 Authors: Wang, Z., Jiang, C., Yao, H., Chen, O., Rahman, S., Gu, Y., Huh, Y., Ji, R.-R. Abstract: Opioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between mu opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone. Copy rights belong to original authors. Visit the link for more info

What a week it has been, my friend. None of us could have predicted this. In this episode I share a little bit about how yoga has helped me navigate what is happening in the world right now, and how to move forward with my business. NPY has full operations online, we are updating the library of classes every day. You can access NPY yoga at awakebynpy.teachable.comCoupon code: corona50 will get you half off your first month of ALL ACCESS

We apologize for the delay in podcasting this week. THIS IS WHY:In this episode Caroline shares one of the most important things in an NPY class and why that is. She also shares about what she realized over the weekend and why she had to re-record this episode. Connect with us:www.instagram.com/norwaypoweryogawww.instagram.com/lineherring

IN THIS SECOND INSTALLMENT OF OUR 3-PART SERIES ON CAROLINE'S TEACHING PHILOSOPHY SHE SHARES HOW SHE FACILITATES FOR HER STUDENTS AND HELPS THEM WITH ONE OF THE MOST IMPORTANT THING ABOUT YOUR YOGA PRACTICE, THE SHOWING UP PART.As humans we won't do stuff unless we find value in it. Entertainment, education, numbing..it's all value. Caroline noticed early on in her PT/yoga career that there was one thing that separated the people who would have clients and students showing up every week for YEARS.She talks about:-how she translated that into the yoga room-how she "let herself be human"-how consistency is the key-how she facilitates at NPY through challenges, events, and so on-how you might find yourself surprised when you attend a SMWYP at NPYAs always, Caroline encourages you to TAKE WHAT YOU NEED, and if you don't get what you need where you are she encourages you to go look for it elsewhere.Thank you so much for listening, please leave us a review so we can guide the content in the future and give you more of what you want. Connect with us:Caroline's InstagramInstagramFacebookWebsite

IN THIS FIRST OF A 3-PART SERIES ABOUT CAROLINE'S TEACHING PHILOSOPHY, SHE SHARES A VERY PERSONAL JOURNEY OF INCORPORATING HER BIGGEST LESSON OF 2019 INTO HOW SHE TEACHES YOGA CLASSES AND TEACHER TRAININGS.Get to know the girl behind the speaker in this episode. In a very personal approach Caroline shares her biggest lesson of 2019 and how this lesson is seeping into every single part of how she now teaches yoga.She talks about how to finally nail THAT pose. How to break it down to elements. She discusses the format of her signature class AWAKE by NPY where students are invited to stay, prep, or fly. And how to choose which level you are at.We appreciate you so much, please leave us a review, tell us what you liked about this episode. Connect with us:InstagramFacebookWebsite

Happy Monday! Time to set that intention for this week. In this episode Caroline shares a simple practice to reframe your inner dialogue, to one that is uplifting and nourishing, rather than one that "kicks you in the face."Thank you so much for listening to AWAKE by NPY and if you feel inclined to, share this on your social media, with a friend, or someone you know can find some value here.Connect with us:www.norwaypoweryoga.comFB: facebook.com/norwaypoweryogaIG: instagram.com/norwaypoweryoga.IG instagram.com/strengthtopause

BONUSPAUSE by NPY are mini episodes intended to help you live more mindfully during your day, or to grow your practice off the mat. Ideas, concepts, tools and ways to de-stress will all be found right here. Enjoy! *Some of these episodes are not recommended to listen to while you are operating a machinery, or a vehicle. We ask that you use these responsibly, and we are not responsible for any accidents cause by you listening to this.

BONUSPAUSE by NPY are mini episodes intended to help you live more mindfully during your day, or to grow your practice off the mat. Ideas, concepts, tools and ways to de-stress will all be found right here. Enjoy! *Some of these episodes are not recommended to listen to while you are operating a machinery, or a vehicle. We ask that you use these responsibly, and we are not responsible for any accidents cause by you listening to this.

How to build a foundation for a life-long yoga practice?-take right vs. wrong out of your yoga vocabulary and what to replace it with instead-how can I look at this pose and get what I need from the pose-1 constant thing that happens in your body every day-Caroline's journey "physical practice vs spiritual practice"-take what you need from the practice, so it becomes YOUR practice-what is the right pose for me?-how is movement expressed in yoga-everything we see in yoga is "made up" by someone (like everything we can perceive)-how we start TTers off with identifying the body-how to create a fluid yoga practice-demands vs what we are prepared for-ASSESS BODY workshop in AWAKE by NPY, to see where your foundation is-body responds to INPUT, i.e. demands and information you are giving your body-comparing yourself to seasons of different INPUT-being honest about where we are-what are you prepared for right now?-how to make the process of assessing it easier-you are inherently worth no matter what your practice looks like-treat your practice as a mirror-self-judgement-choice of grace-understanding the seasons of your practice-understanding that you are the one judging you, it's a season, it will pass-consistency in your practice-what matters in the end-AWAKE by NPY, ASSESS PRACTICE workshop, to assess how and where your practice is serving you and where you can make it serve you more-cultivate a sustainable practice that offers you transformation-this was really a way to build the foundation before building the foundation

In this episode:-hello and welcome-Caroline talks about AWAKE by NPY the class and how it came to be-Caroline introduces ways to take responsibility for your practice through the three part format; pause, prep, flyMake sure you take a screenshot and tag us while you listen to this episode, we are forever grateful for all the shares and love you give us! @norwaypoweryoga on IG@strengthtopause (Caroline's personal IG)Want to cultivate a deeper practice, get on our email list to get exclusive pre-launch deets on the online platform AWAKE by NPY.Want to be a guest on the podcast? Have an inspiring yoga story/journey? We'd love to chat, email us at hello@norwaypoweryoga.com and subject line "podcast" and we'll start the conversation to see if we're the right fit for each other.

Are you an optimist or a pessimist? Scientists from the University of Michigan say the answer may be in your genes. They've discovered optimism is directly related to levels of a molecule in your brain called neuropeptide Y or (NPY). So if you have low levels of NPY, you may be more likely to have depression than someone with high NPY levels. You may also be more prone to being negative and less likely to cope well with stress. The study published in the journal Archives of General Psychiatry the study describes tests carried out by the scientists. After having their NPY levels measured, a group of volunteers had their brains scanned while being shown neutral, negative and positive words. Those with low levels of NPY showed increased activity in part of their brains called the prefrontal cortex - which processes emotion - while viewing the negative words. Those with higher NPY levels showed less brain activity in response to the negative words. A second test involved inducing mild pain in the volunteers, and again those with NPY rated their feelings as more negative than those with higher NPY levels. The findings expand scientists' understanding of the physiology of depression, and may ultimately lead to a new treatment. In the meantime, unfortunately, the study doesn

In this episode, we look into the process of hunger, satiety, and the role of Leptin, CCK and NPY hormones in these processes . In addition, we talk about different diets (low-carb, fruit diet, low-fat) and their potential harms to human body. **Since this show is being recorded for CFMU 93.3 radio station, all the music has been removed.**

R.I.P. NIPSEY HU$$LE. ▶ Discover: @staycoolfam | @bobbyskang @fevra @eyukaliptus @rhymingstanzah @kulv-reyatt @ukimusik ▶ Check out “Sanity” the debut in Stay Cool's single series courtesy of Gino Holroyd & Axel Logan https://soundcloud.com/staycoolfam/gino-holroyd-sanity-prod-axel-logan ▶ Stay Cool on Spotify: http://bit.ly/staycoolspotify ▶ Support by copping merch: https://staycoolfam.bandcamp.com/merch We're back in London after an incredible trip to New York, and while out there we did two new episodes of the show. Here's the first, a three-hour blowout show featuring mixes from my London fam that travelled with me Bobby Kang, Kulv Reyatt and Stanzah as well as Eyukaliptus, Fevra and Uki, three friends of mine from across the pond representing NYC and Toronto. This episode aired on https://waxxworldwide.com, thanks for having us on! Look out for the next episode in just over a weeks time. - seangran PS: London rapper Lord Apex just dropped a sick new San Andreas tribute EP on @radiojuicy1 and they've given us some codes to get it free. Enter one of the below codes at https://radiojuicy.bandcamp.com/yum to get your free copy. 3ryq-3nbv dmu6-cjl9 pg5k-wg5t 82rt-h3nb xml8-y5kx hgpy-3fgq 4ufn-hmfz qlal-vte6 9s9j-6bfy Tracklist (seangran mix) 1. Kyle Dion - Brown 2. Frankliin - Lie (interlude) 3. Ama Lou - Tried Up 4. KOKIO - New World 5. monte booker - interstellar w- bari 6. [radiochamploo] - NPY.HLE [SKXN.E MIX] 7. Ryan Hemsworth - One of One 8. Lophiile - Common Sense (Instrumental) 9. Mozaic - Eastside Johnny 10. B-Side - Sorry feat. The Breed 11. Little Simz - Flowers 12. The Cool Kids - Simple Things (feat. Syd & QUIÑ) 13. flavors - le pensuer feat. chester watson 14. cay caleb. - so good rmx 15. B. Cool-Aid - howigotover f. klevah 16. idntrmmbr. - two. 17. Lord Apex - Snoop SNL 18. Tyler, The Creator x Toro y Moi - Hey You 19. frankclear - Musaca 20. Amp Fiddler - Through Your Soul (feat. Bubz Fiddler, J Dilla) 21. Feiertag - Feathers (feat. Pip Millett) 22. Lucky Daye - Extra 23. Guru Griff - Leaving Bobby Kang Mix Fevra Mix Eyukaliptus Mix Stanzah! Mix Kulv Reyatt Mix Uki Mix

-----> Click here to support the podcast and keep it free! Support us via Patreon!Acute: stimulates SNS, raise your defenses Chronic: Increase in cortisol stimulates neuropeptide (NPY) - hunger pathway (discuss) Increases insulin  and leptin resistance Shifts white fat into visceral abdominal region Decreases brown fat activation Brown fat is the fat on babies and decreases throughout life Metabolically active (converts chemical energy to heat) Lots of mitochondria (why its fat) Fasting makes white fat behave more like brown fat The more fat the more cortisol (having fat is a stressor to itself) ANOTHER vicious cycle. Half of patients with obesity have hypercortisolism and have are normal. If high cortisol higher risk for heart disease DECREASE STRESS BY Reasonable exercise SLEEP Screen time Just say no - JOMO (Joy of missing out) meditation

In this podcast we talk with Professor Chen and Dr Steyn on their recent work 'Actions of NPY, and Its Y1 and Y2 Receptors on Pulsatile Growth Hormone Secretion during the Fed and Fasted State' recently published in the Journal of Neuroscience.

Die LQYLWUR Selektion ermöglicht es aus kombinatorischen Nukleinsäurebibliotheken Oligonukleotidsequenzen zu identifizieren, die verschiedenste Zielmoleküle mit hoher Affinität und Spezifität binden können. Dadurch haben sich Aptamere zu einer potenten Alternative zu den in der Diagnose, Therapie und als Forschungsreagentien etablierten Antikörper entwickelt. Mit Hilfe der SELEX-Technologie (6ystematic (volution of /igands by (;ponential Enrichment) ist es in dieser Arbeit gelungen, 2' amino-stabilisierte RNA-Aptamere gegen das Neuropeptid Y und ein ausgewähltes, funktionell relevantes Prionproteinepitop zu generieren. Die Anreicherung funktioneller Sequenzen erfolgte durch einen affinitätschromatographischen Prozess. Zudem sollten bereits vorliegende RNA-Aptamere, die gegen das rekombinante Prionprotein in früheren Arbeiten selektiert wurden, charakterisiert werden. Das Neuropeptid Y (NPY), bestehend aus 36 Aminosäuren, gehört zur Familie der pankreatischen Polypeptide und ist bei der Steuerung einer Vielzahl physiologischer und pathophysiologischer Prozesse von Bedeutung. Es wird angenommen, daß durch selektive Bindung unterschiedlicher NPY-Konformationen an die einzelnen GProtein gekoppelten NPY-Rezeptorsubtypen (Y1, Y2, Y3, Y4, Y5 und Y6) unterschiedliche Signale vermittelt werden können. Dieses differentielle Bindungsverhalten von NPY an seine Rezeptorsubtypen ist bisher unvollständig verstanden. Die in dieser Arbeit generierten Anti-NPY-Aptamere binden ihr Zielmolekül -NPY- mit einer Affinität von 370 nM und sind durch eine hohe Spezifität innerhalb der pankreatischen Polypeptidfamilie charakterisiert. Die Bindungsregion des Aptamers an den C-Terminus des Neuropeptid Y wurde durch Kartierungs-Experimente mit NPY-Analoga LQ YLWUR bestimmt. Die NPY-Analoga stellen sowohl verschiedene Untereinheiten von NPY, als auch Modifikationen des Peptides, die zu Rezeptorsubtypspezifitäten führen, dar. Durch Punktmutationen im C-terminalem NPY-Bereich konnte u.a. gezeigt werden, daß die Aminosäure Arginin an Position 33 für die Komplexbildung von NPY und Aptamer essentiell ist. In den Bindungsstudien in Gegenwart selektiver Agonisten zeigte sich, daß die Bindungseigenschaften von NPY am Y2 Rezeptor weitgehend mit denen an das Aptamer übereinstimmen. Die Kompetition des Aptamers mit den Rezeptoren um 3H-NPY wurde an Zellen, die die Rezeptoren NPY-Y1, NPY-Y2, bzw. NPY-Y5 exprimieren, untersucht. Das Aptamer verdrängte NPY mit besonders hoher Affinität am Y2 Rezeptor im Vergleich zur Verdrängung am Y1- bzw. Y5-Rezeptor. Die Anti-NPY-Aptamere weisen ein Bindungsverhalten am NPY vergleichbar zum Y2-Rezeptor auf und stellen damit ein wertvolles Werkzeug zur selektiven Charakterisierung der Interaktion zwischen NPY und seinen Rezeptoren dar. Von entscheidender Bedeutung für die Pathogenese der übertragbaren spongiformen Enzephalopathien ist die infektiöse Form des Prionproteins (PrPSc). Es wird angenommen, daß PrPC durch einen posttranslationalen Prozeß in PrPSc konvertiert werden kann. Trotz identischer Primärstruktur unterscheiden sich die beiden Prionproteinisoformen (PrPC und PrPSc) grundlegend in ihren biochemischen und biophysikalischen Eigenschaften. Die in früheren Arbeiten selektierten Prionprotein-Aptamere sollten im Hinblick auf ihr diagnostisches Potential charakterisiert werden. Erste strukturelle Untersuchungen führten zu der Annahme, daß die RNA-Aptamere ein G-Quartett als stabilisierendes Sekundärstrukturmotiv ausbilden können. Sowohl Kartierungsstudien mit unterschiedlichen Prionproteinpetiden als auch Bindungsstudien mit N-terminal trunkiertem PrPSc zeigten, daß der N-Terminus für die Bindung der Aptamere essentiell ist. In Gelshiftexperimenten mit verschiedenen Hirnhomogenaten konnte die spezifische Bindung der Aptamere an authentisches PrP gezeigt werden. Aufgrund der fehlenden PrPSc-Isoformspezifität der untersuchten Aptamere ist eine diagnostische Anwendung kaum denkbar. Die Bindung der Aptamere in der pKsensitiven, N-terminalen Prionproteindomäne läßt eine Anwendung in Kombination mit Proteinase K-Verdau in Analogie zu den derzeit benutzten BSE-Testverfahren nicht zu. Im letzten Teil der Arbeit sollten RNA-Aptamere gegen einen für die Konversion wichtigen Bereich des Prionproteins (AS 90-129) generiert werden. Es konnte gezeigt werden, daß die in einer vorgeschalteten Prionpeptidselektion (AS 90-129) identifizierten Aptamere in der Lage sind, ihr Zielmolekül im Gesamtkontext des Prionproteins zu erkennen. In funktionellen Studien in persistent Prion-infizierten Neuroblastomzellen wurde eine statistisch signifikante und spezifische Reduktion der Akkumulation von GHQRYR synthetisiertem PrPSc zu hochmolekularen Aggregaten in Gegenwart einer ausgewählten Aptamersequenz beobachtet. Im Verlauf der Pathogenese von spongiformen Enzephalopathien korreliert die PrPSc- Aggregatbildung mit Infektiosität und Neurodegeneration. Damit bieten die selektierten Aptamere möglicherweise eine Ausgangsbasis um Therapeutika zu entwickeln, die den Verlauf der Prionerkrankungen beeinflussen.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.20.051649v1?rss=1 Authors: Popovitz, J. M. B., Mysore, S. P., Adwanikar, H. Abstract: Anxiety outcomes following traumatic brain injury (TBI) are complex, and the underlying neural mechanisms are poorly understood. Here, we developed a multidimensional behavioral profiling approach to investigate anxiety-like outcomes in mice that takes into account individual variability. Departing from the tradition of comparing outcomes in TBI versus sham groups, we identified animals within the TBI group that are vulnerable to anxiety dysfunction by applying dimensionality reduction, clustering and post-hoc validation to behavioral data obtained from multiple assays for anxiety at several post-injury timepoints. These vulnerable animals expressed distinct molecular profiles in the corticolimbic network, with downregulation in GABA and glutamate, and upregulation in NPY markers. Indeed, among vulnerable animals, not resilient or sham controls, severity of anxiety outcomes correlated strongly with expression of molecular markers. Our results establish a foundational approach, with predictive power, for reliably identifying maladaptive anxiety outcomes following TBI and uncovering neural signatures of vulnerability to anxiety. Copy rights belong to original authors. Visit the link for more info

*In this show, on the heels of the 21 insights around the clock, you’ll learn just how destructive excess artificial light is to your health and your overnight restoration, and you’ll also gain a better understanding of the complex interplay between your hormones and the habits that are at the core of your lifestyle.* Before we begin, if you happened to miss part 1 or just want to refresh what we covered last week, click here ( https://www.bradkearns.com/2020/10/23/a-circadian-rhythm-24-hour-tour-inspired-by-dr-jack-kruse-insights-part-1/ ) to listen to that episode first. Now, onto part 2! Here are some key points we’ll go over during this episode: Most postmenopausal women find exercise training extremely frustrating as hormone response is altered as they age. In contrast, men usually don’t lose their GH levels until they’ve reached 50-55 years of age, and are also protected by their testosterone levels, which persist throughout life (if they’re not suffering from inflammation that is, because that will directly lower their testosterone levels). GH and testosterone are the key players that work to keep a man’s heart and muscles in shape. *What happens when step 20 (the surge of prolactin) is broken in modern humans?* -------------------------------------------------------------------------------- This used to be more frequent among diabetics, but, because of our excessive technology use post-sunset, it’s becoming more common in all humans. Artificial lights tend to be super bright and completely interfere with the usual circadian signals from the hormone response, so it’s no wonder that light after sunset reduces the prolactin surge humans are supposed to experience. This is linked to sleep, as *chronic lowered prolactin surges are associated with lower growth hormone secretion during the anabolic phases of sleep.* One thing that really affects your cardiac and skeletal muscle function is lowered chronic GH secretion, because it directly affects the process of autophagy. This is why heart failure is strongly associated with low IGF-1 and sex steroid hormone levels. When growth hormone is not released in normal amounts, it also decreases our lean muscle mass and increases our fat percentage in all our organs and in our body. This leads to slowly declining organ dysfunction and poor body composition. We can measure this process clinically by looking for falling DHEA and GH/dopamine levels as we age. *What happens in normal aging in step 21?* ------------------------------------------ Aging is among the most common features found in studies on modern humans when DHEA and GH craters on hormone panels. The loss of the prolactin surge is especially prominent in postmenopausal women. Most women begin to suffer from falling DHEA and GH levels around age 35-40 while they are still in peri-menopause. The higher their HS-CRP levels, the faster they enter peri-menopause and the quicker they enter menopause. They also age faster on a cellular level because their circadian chemical clocks are sped up. As a consequence, their telomeres shorten faster as well. Women have higher levels of leptin for childbearing, so they are more prone to leptin resistant issues than men. This helps explain why older women struggle with cognitive haze, loss of body composition, poor sleep, and increased levels of heart disease after menopause. Many physicians think the losses they suffer are due to the loss of estrogen from ovarian failure, but the loss of growth hormone and progesterone production are far more significant in their physiology. Progesterone is the off switch to anything that is pro-growth. Modern women are usually estrogen dominant even after menopause because of mismatches in circadian biology. Cognitive loss is especially common in post-menopausal women. They also lose on average 1% of their bone mineral density per year from menopause in large part due to the loss of progesterone, not estrogen. Loss of progesterone also corresponds to poor sleep in these women too. Replacing progesterone in women has a major effect on their sleep and bone stock. It also dramatically improves their memories and cognitive function as well. *The cost of snacking after dinner and how it affects the circadian cycle:* --------------------------------------------------------------------------- If you choose to eat within 4 hours of sleep, you will never see the prolactin surge you need, because any spike in insulin turns off this critical sleep time release that corresponds to the cellular maximums of the autophagic process for humans. Agouti, the incretin gut hormone, also rises in the blood to higher than normal levels to block leptin from entering the brain. * It appears 12-3 AM are the critical hours at night where the remnants of mammalian hibernation lie for our species. These are the anabolic times for sleep when we are rebuilding our proteins and recycling our cellular contents. They are three of the most important hours in all human biology. If you miss them, you can bet you have several neolithic diseases for sure. Why do you ask? If these three hours are not reached enough during our sleep cycle, autophagy is never optimized and cellular repair does not occur in our cells. This means we are using old broken down parts in our cells as the next day arrives at 6 AM and cortisol rises again to wake us up. We can measure the efficiency of this process by checking DHEA and IL-6 levels. I also like to measure hormone panels to see if the inflammation has destroyed any other hormone cascades in aging men or women. This is vital in taking care of older people and treating their longevity. IL-6 levels correspond to Leptin resistant states as well. This makes sleep and metabolic coupling tightly controlled by circadian biology at all times of our life. It is magnified because sleep gets worse as we age and our DHEA, HDL, and HS CRP rise. This is where, during a bio-hack, we can see why circadian mismatches can cause neolithic diseases in humans. Often times, we can find the same issues develop much earlier in a young paleo person who has a lot of mismatches in their circadian biology. I test them the same way I would an older person. * Growth Hormone is released in a pulsatile fashion from 12-3 AM during restorative sleep cycles 3 & 4, and this hormone facilitates autophagy and recycling of proteins. In essence, GH keeps us younger and in great shape when we sleep like a rock star. The problem is a modern man does not sleep well because of his brain’s technology and screen creations. * *More about Prolactin* You must be asking, why is this prolactin hormone so important in a warm adapted human? Prolactin is not just a hormone that secretes human milk. That is the best-known action of prolactin, but not the most important. Immediately after prolactin is released during sleep, another signal is sent to the anterior pituitary to release the largest amount of Growth Hormone as we sleep (GH). GH is stimulated only during autophagic sleep cycles in stage 3 and 4 to increase protein synthesis for muscle growth while you’re dissipating heat via the uncoupling proteins. This is where the major release of GH occurs in humans post-puberty when they are warm adapted. 99.9% reading this blog are warm adapted. If you chose to become cold adapted the GH story radically changes, as laid out in CT-6.  GH and dopamine are analog proteins. The implications here are huge for the warm adapted human if this prolactin surge is not adequate to allow us to enter the anabolic stages of sleep. Prolactin surge is diminished by both artificial lights at night and by foods that stimulate NPY, (namely carbs and protein) when they are eaten in fall and winter when biology says they should not be available. * If you are leptin resistant for any reason, have sleep apnea, you will always have an altered body composition because of a low GH level and an altered sex steroid profiles on testing. The reason is that DHEA is the immediate precursor for those hormones and is always low in people with bad sleep efficiency. Most VLCers who are warm adapted face this very problem today. VLC diet is best used in the cold-adapted mammal and not the modern warm adapted lifestyle. In essence, this diet is a mismatch for our modern lifestyle. This is why so many bloggers think ketosis is a dirty word for performance and body composition. This all implies that as you age you will have higher body fat percentage, lower muscle mass, if autophagy is not optimized by great sleep. This is precisely what we see today in most modern humans as they age. Invariably, their sleep cycles and sleep durations are poor and decreased from their childhood levels. As they age, there is a chronic insidious erosion of circadian biology by decisions made by modern humans over and over again. In addition to using blue-light blocking glasses at night (check out Raoptics.com for some amazing, high-quality frames and don’t forget to add my discount code!), I also really enjoy Himalayan salt lamps for the mellow, orange hue they give off. So, tonight, instead of blasting your eyeballs with screen technology for hours, try reading a book, playing a board game or puzzle, taking a walk, or doing some stretching/light yoga movements….just try to find activities that you enjoy doing as a way of winding down and aligning yourself with your circadian rhythm. *TIMESTAMPS:* Brad reviews the first 21 insights from the first show. He looks at what is happening with your circadian rhythm throughout the day. [01:39] Melatonin is of great importance. [06:52] Post-menopausal women often have problems with sleeping and gaining weight. [09:20] Cold therapy for post-menopausal women is of great benefit. [10:01] Men are protected by their testosterone levels which persist throughout life provided they are not suffering from inflammation. Dysfunctional relationship dynamics can destroy your testosterone. [11:25] Men do not lose their growth hormone levels until 50 to 55 years of age. [13:47] There is no reason for men to slow down on their athlete goals as they age. [14:31] In Dr. Kruse’s practice he sees many young males whose inflammation has damaged their sex hormone levels. [17:10] Most women begin to suffer from falling D H E A and growth hormone levels around age 35 to 40. Replacing progesterone is very helpful for women. [20:13] How does snacking after dinner affect your circadian cycles? [24:15] It appears that 12 to 3:00 AM are the critical hours at night are where the remnants of mammalian hibernation lie for our species. Dr. Kruse says they are the most important three hours in all of human biology. [26:39] The implications for the growth hormone are huge for the warm adapted human. [29:14] If you’re going to go keto or do cycles throughout the year, the winter time is a great time to completely avoid carbs for a 30-day restriction or experimental period. [31:10] As you age, you will have a higher body fat percentage, lower muscle mass if autophagy is not optimized by great sleep. [33:60] It is highly recommended that your nighttime activities include softer lights and less technology. [36:19] *LINKS:* * Brad’s Shopping Page ( http://www.bradkearns.com/shop/ ) * Dr. Jack Kruse ( https://jackkruse.com/ ) * 1st Dr. Kruse Show ( https://www.bradkearns.com/2020/10/23/a-circadian-rhythm-24-hour-tour-inspired-by-dr-jack-kruse-insights-part-1/ ) * Brad’s Cold Therapy Video ( https://www.youtube.com/watch?t=2s&v=AF6d9ngxnDo ) * Brad’s Cold therapy Podcast ( https://www.bradkearns.com/2018/08/27/brad-kearns-everything-you-need-to-know-about-cold-water-therapy/ ) * BradKearns.com/MOFO ( http://bradkearns.com/MOFO ) * John Gray Podcast ( https://www.bradkearns.com/2020/07/28/healing-strained-relationships-with-increased-self-awareness-hopeful-new-strategies-and-fake-it-till-you-make-it/ ) * Mark Sisson Instagram ( https://www.instagram.com/marksissonprimal/?hl=en ) * Charles Allie ( https://www.nytimes.com/2019/07/10/sports/the-worlds-fastest-old-man.html ) * Dr. Michael Platt Podcast ( https://blog.primalblueprint.com/dr-michael-platt-on-adrenalin-dominance/ ) * Meatrx.com ( https://meatrx.com/ ) * Carnivoremd.com ( https://carnivoremd.com/ ) * RAOptics.com ( https://raoptics.com/ ) * Prolactin information ( https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/prolactin ) *Follow me on social media for more great content!* Instagram: @bradkearns1 ( https://www.instagram.com/bradkearns1/ ) Facebook: @bradkearnsjumphigh ( https://www.facebook.com/bradkearnsjumphigh ) Twitter: @bradleykearns ( https://twitter.com/bradleykearns ) *Sponsors* Check out each of these companies because they are absolutely awesome or they wouldn’t occupy this revered space. Seriously, Brad won’t sell out to anyone if he doesn’t love the product. Ask anyone. * Almost Heaven Sauna ( http://almostheaven.com/ ) : Affordable at-home sauna kits for the ultimate relaxation and hormonal boost on demand * Brad’s Macadamia Masterpiece: ( http://bradventures.com/ ) Mind-blowing, life-changing nut butter blend * CAR.O.L bike: ( http://carolfitai.com/ ) Cardiovascular optimized logic stationary bike for a highly effective eight-minute workout * Male Optimization Formula with Organs (MOFO): ( http://bradkearns.com/mofo ) Optimize testosterone naturally with 100% grassfed animal organ supplement * Perfect Keto: ( http://perfectketo.com/ ) The cleanest, purest, most potent ketone supplements and snacks * LetsGetChecked ( http://lgc.com/brad ) : At-home medical testing with great prices, quick results, and no hassles * Vuori Activewear: ( http://vuori.com/ ) The most comfortable, functional, and fashionable gear, evoking the chill SoCal coastal lifestyle *Donations* ! 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