Selected Podcast
Examining the Molecular and Metabolic Underpinnings of Appetite Regulation
Lisa Beutler, MD, PhD takes a neuroscience and genetic-based approach to understand how neurons, hormones and metabolites in the gastrointestinal tract communicate both hunger and satiation with the brain. Tune in to hear more about her work and its potential impact on treating diseases such as obesity, diabetes and inflammatory bowel disease.
Featured Speaker:
Learn more about Lisa Beutler, MD, PhD
Lisa Beutler, MD, PhD
Lisa Beutler, MD, PhD is a Assistant Professor of Medicine (Endocrinology).Learn more about Lisa Beutler, MD, PhD
Transcription:
Examining the Molecular and Metabolic Underpinnings of Appetite Regulation
Melanie Cole, MS (Host): Today we’re investigating the dynamics of gut brain communication underlying hunger. Joining me today is Dr. Lisa Beutler. She’s an assistant professor of medicine in the division of endocrinology at Northwestern Medicine. Her work focuses on understanding those dynamics of the gut brain communication and hunger. She’s joining me today to talk about her latest work. Dr. Beutler, I'm so glad to have you joining us. You're relatively new to Northwestern Medicine. Can you start by telling us about yourself and your role in the division of endocrinology?
Lisa Beutler MD, PhD (Guest): I'm a new physician scientist in the division of endocrinology. I started here in July. Prior to that, I completed my MD PhD at the University of Washington and then both a medicine residency and endocrinology fellowship at UCSF. While I was at UCSF, I did post-doctoral research in Zach Knight’s lab there, which is where I started my current line of work. In terms of my role in the division here specifically, I'm currently devoting my time to setting up my lab. But starting next year, I’ll also be seeing patients about once per week in the endocrinology clinic.
Host: What a fascinating topic we are talking about today. Communication between the gut and brain is critical for homeostasis. So how does your communication represented in the dynamics of feeding circuits, give us a little broad overview of your research.
Dr. Beutler: At the broadest level, what I want to understand is how the brain integrates peripheral signals that tell us when we’re hungry and should eat and how it integrates the peripheral signals that conversely tell us when we’re full and when we should stop eating. Really central to understanding how the brain integrates this information is to understand communication between the gastrointestinal tract and the brain following food intake. So immediately after a meal. My post-doctoral work helped to clarify some of this communication, but there's a ton we don’t understand yet. I'm taking a neuroscience and genetics based approach to answering some of these questions. The specific questions that I'm interested in asking right now are what specific nutritional signals in the gut are sensed to tell us we’re full and we should stop eating. How not just the nutrient signals themselves but the gut hormones released in response to nutrients in the gut are involved in driving this satiation and that includes insulin, amylin, glucagon, GLP1, CCK. There's just a very long and growing list of these hormones that may be involved in the gut’s communication with the brain to tell us we’re full. I'm interested in what metabolites are required to communicate satiation versus hunger. Then beyond this kind of basic questions about how we sense hunger and how we sense satiation, fueled in large part by my work as a clinician I'm also really interested in how disease states effect appetite and energy homeostasis and how they effect this communication. So as we begin to figure out some of the basic answers, I'm also interested in determining how the signaling goes awry in disease states. This includes probably most obviously obesity and type II diabetes, but I'm also interested in diseases like inflammatory bowel disease and cancer which may also effect gut brain communication and appetite.
Host: Wow. That is absolutely so interesting. What have you found? Tell us about some of the results.
Dr. Beutler: My main post-doctoral work focused on AGRP neurons, which are a small population of hunger activated neurons in the hypothalamus. This small population of neurons has been studied for decades and they were kind of viewed as passive sensors of an animals nutritional state. So these are hunger detecting neurons. So they're activity turned on when it sensed metabolites or hormones indicative of starvation. These neurons were thought to kind of tune down when they sensed glucose, insulin, and other satiation factors.
Early work from my post-doctoral lab from before I joined the lab showed that this is really not the case at all. Rather, when you give a hungry animal food, AGRP neurons instead of gradually declining in activity as the animal got full, their activity shut off almost instantly before an animal even took a single bite of food. That’s kind of a whole other story onto itself, but it basically left open the entire question on what the role of nutrients are in actually regulating these neurons which have been presumed for decades to be regulated pretty directly by nutrients.
So then what my post-doctoral work showed for the first time is that AGRP neurons are indeed inhibited within minutes of nutrient delivery directly into the stomach. So you take away all the sensory stimuli normally associated with feeding—the sight of food and the smell of food—and the raw nutrients itself in the gut are perfectly sufficient to inhibit AGRP neurons. I found that it doesn’t matter what nutrient is being delivered to the gut. It’s inhibited pretty equally. So to an AGRP neuron, glucose or lipids or protein are kind of the same on a per calorie basis. Furthermore as you would predict, infusing nutrients into an animal’s belly inhibits subsequent food intake. It turns that the changes that we see in AGRP neuron activity with nutrient infusion is really, really good at predicting how much the animal is about to eat. Taken together, these results really move the field from thinking of these neurons as passive detectors of nutritional state as I described them initially to understanding that these neurons are really special active integrators of multiple streams of data, including environmental cues about food the animal’s about to eat, including sensory data from the gut about nutrients, and data from the gut about hormones. That these neurons integrate these multiple streams of data to appropriately drive feeding in a way that in the vast majority of animals maintains good energy homeostasis.
Host: Wow. Isn’t that interesting that the nutrients are pretty much the same with inhibition of the AGRP neurons because I was going to ask you if they require changes in blood glucose.
Dr. Beutler: So that’s a really good question. I think the best way to answer that question is that we think that there's really something special about the gut. Could blood glucose be involved in this? Possibly to some small extent. Wondering whether glucose could directly be regulating these neurons, we did an experiment where we gave an animal glucose directly into its stomach, as I described. We saw this nice prolonged inhibition of AGRP neurons that lasted at least 30 minutes after the glucose was done infusing. Then we did a second experiment where instead of putting the glucose directly into the stomach, we gave the animal just a shot of glucose basically directly into it’s blood stream. Rather than causing that same nice long inhibition of AGRP neurons, this caused only a very transient inhibition of AGRP neurons even though those two manipulations raised blood glucose directly the same amount. So it’s not blood glucose per se that’s causing this prolonger inhibition, but some interaction of glucose with the gut and hormones that are subsequently released that appears to be important.
Host: Well, it certainly is. So how do you envision this research translating to patient care?
Dr. Beutler: I think that’s the million dollar question. So first to be clear, what I'm doing is pretty basic science research that’s on a clinically important problem I would say. I think that anytime you're doing basic science research of clinical import, it’s pretty hard to predict exactly how it will translate. My kind of dream goal would be that in studying the molecular and metabolic underpinnings of appetite we’ll discover novel targets and potentially novel modalities for treatment of obesity and it’s metabolic complications.
Host: Wow. It has such amazing implications for what it could do. What project are you working on next? Is there anything that you’d like providers to know about your work?
Dr. Beutler: So you led really well into this because what I'm working on next is kind of trying to figure out exactly what’s so special about the gut in terms of glucose infusion. What makes glucose in the gut so different from glucose in the periphery. We know a lot about this from the peripheral angle. We know that glucose in the gut releases hormones that glucose in the blood doesn’t. We know that glucose in the gut ends up releasing more insulin because these incretin hormones—GLP1 and GIP—help potentiate insulin release in response to glucose specifically in the gut. The fact is we don’t know how any of that relates to communication of all this to the brain. So one of my immediate goals is to kind of follow that up and see what we find. In terms of anything else I want providers to know, it’s just that I'm always happy to talk about my research. If you have questions, please feel free to get in touch.
Host: Well, we certainly will look forward to more results. Please join us again because I would really like to hear about the connection between the microbiome and brain health and how all of this ties together. Thank you so much doctor for joining us today and telling us about your research. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine, please visit our website at nm.org to get connected with one of our providers. If you found this podcast informative, please share on your social channels. Be sure and subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole.
Examining the Molecular and Metabolic Underpinnings of Appetite Regulation
Melanie Cole, MS (Host): Today we’re investigating the dynamics of gut brain communication underlying hunger. Joining me today is Dr. Lisa Beutler. She’s an assistant professor of medicine in the division of endocrinology at Northwestern Medicine. Her work focuses on understanding those dynamics of the gut brain communication and hunger. She’s joining me today to talk about her latest work. Dr. Beutler, I'm so glad to have you joining us. You're relatively new to Northwestern Medicine. Can you start by telling us about yourself and your role in the division of endocrinology?
Lisa Beutler MD, PhD (Guest): I'm a new physician scientist in the division of endocrinology. I started here in July. Prior to that, I completed my MD PhD at the University of Washington and then both a medicine residency and endocrinology fellowship at UCSF. While I was at UCSF, I did post-doctoral research in Zach Knight’s lab there, which is where I started my current line of work. In terms of my role in the division here specifically, I'm currently devoting my time to setting up my lab. But starting next year, I’ll also be seeing patients about once per week in the endocrinology clinic.
Host: What a fascinating topic we are talking about today. Communication between the gut and brain is critical for homeostasis. So how does your communication represented in the dynamics of feeding circuits, give us a little broad overview of your research.
Dr. Beutler: At the broadest level, what I want to understand is how the brain integrates peripheral signals that tell us when we’re hungry and should eat and how it integrates the peripheral signals that conversely tell us when we’re full and when we should stop eating. Really central to understanding how the brain integrates this information is to understand communication between the gastrointestinal tract and the brain following food intake. So immediately after a meal. My post-doctoral work helped to clarify some of this communication, but there's a ton we don’t understand yet. I'm taking a neuroscience and genetics based approach to answering some of these questions. The specific questions that I'm interested in asking right now are what specific nutritional signals in the gut are sensed to tell us we’re full and we should stop eating. How not just the nutrient signals themselves but the gut hormones released in response to nutrients in the gut are involved in driving this satiation and that includes insulin, amylin, glucagon, GLP1, CCK. There's just a very long and growing list of these hormones that may be involved in the gut’s communication with the brain to tell us we’re full. I'm interested in what metabolites are required to communicate satiation versus hunger. Then beyond this kind of basic questions about how we sense hunger and how we sense satiation, fueled in large part by my work as a clinician I'm also really interested in how disease states effect appetite and energy homeostasis and how they effect this communication. So as we begin to figure out some of the basic answers, I'm also interested in determining how the signaling goes awry in disease states. This includes probably most obviously obesity and type II diabetes, but I'm also interested in diseases like inflammatory bowel disease and cancer which may also effect gut brain communication and appetite.
Host: Wow. That is absolutely so interesting. What have you found? Tell us about some of the results.
Dr. Beutler: My main post-doctoral work focused on AGRP neurons, which are a small population of hunger activated neurons in the hypothalamus. This small population of neurons has been studied for decades and they were kind of viewed as passive sensors of an animals nutritional state. So these are hunger detecting neurons. So they're activity turned on when it sensed metabolites or hormones indicative of starvation. These neurons were thought to kind of tune down when they sensed glucose, insulin, and other satiation factors.
Early work from my post-doctoral lab from before I joined the lab showed that this is really not the case at all. Rather, when you give a hungry animal food, AGRP neurons instead of gradually declining in activity as the animal got full, their activity shut off almost instantly before an animal even took a single bite of food. That’s kind of a whole other story onto itself, but it basically left open the entire question on what the role of nutrients are in actually regulating these neurons which have been presumed for decades to be regulated pretty directly by nutrients.
So then what my post-doctoral work showed for the first time is that AGRP neurons are indeed inhibited within minutes of nutrient delivery directly into the stomach. So you take away all the sensory stimuli normally associated with feeding—the sight of food and the smell of food—and the raw nutrients itself in the gut are perfectly sufficient to inhibit AGRP neurons. I found that it doesn’t matter what nutrient is being delivered to the gut. It’s inhibited pretty equally. So to an AGRP neuron, glucose or lipids or protein are kind of the same on a per calorie basis. Furthermore as you would predict, infusing nutrients into an animal’s belly inhibits subsequent food intake. It turns that the changes that we see in AGRP neuron activity with nutrient infusion is really, really good at predicting how much the animal is about to eat. Taken together, these results really move the field from thinking of these neurons as passive detectors of nutritional state as I described them initially to understanding that these neurons are really special active integrators of multiple streams of data, including environmental cues about food the animal’s about to eat, including sensory data from the gut about nutrients, and data from the gut about hormones. That these neurons integrate these multiple streams of data to appropriately drive feeding in a way that in the vast majority of animals maintains good energy homeostasis.
Host: Wow. Isn’t that interesting that the nutrients are pretty much the same with inhibition of the AGRP neurons because I was going to ask you if they require changes in blood glucose.
Dr. Beutler: So that’s a really good question. I think the best way to answer that question is that we think that there's really something special about the gut. Could blood glucose be involved in this? Possibly to some small extent. Wondering whether glucose could directly be regulating these neurons, we did an experiment where we gave an animal glucose directly into its stomach, as I described. We saw this nice prolonged inhibition of AGRP neurons that lasted at least 30 minutes after the glucose was done infusing. Then we did a second experiment where instead of putting the glucose directly into the stomach, we gave the animal just a shot of glucose basically directly into it’s blood stream. Rather than causing that same nice long inhibition of AGRP neurons, this caused only a very transient inhibition of AGRP neurons even though those two manipulations raised blood glucose directly the same amount. So it’s not blood glucose per se that’s causing this prolonger inhibition, but some interaction of glucose with the gut and hormones that are subsequently released that appears to be important.
Host: Well, it certainly is. So how do you envision this research translating to patient care?
Dr. Beutler: I think that’s the million dollar question. So first to be clear, what I'm doing is pretty basic science research that’s on a clinically important problem I would say. I think that anytime you're doing basic science research of clinical import, it’s pretty hard to predict exactly how it will translate. My kind of dream goal would be that in studying the molecular and metabolic underpinnings of appetite we’ll discover novel targets and potentially novel modalities for treatment of obesity and it’s metabolic complications.
Host: Wow. It has such amazing implications for what it could do. What project are you working on next? Is there anything that you’d like providers to know about your work?
Dr. Beutler: So you led really well into this because what I'm working on next is kind of trying to figure out exactly what’s so special about the gut in terms of glucose infusion. What makes glucose in the gut so different from glucose in the periphery. We know a lot about this from the peripheral angle. We know that glucose in the gut releases hormones that glucose in the blood doesn’t. We know that glucose in the gut ends up releasing more insulin because these incretin hormones—GLP1 and GIP—help potentiate insulin release in response to glucose specifically in the gut. The fact is we don’t know how any of that relates to communication of all this to the brain. So one of my immediate goals is to kind of follow that up and see what we find. In terms of anything else I want providers to know, it’s just that I'm always happy to talk about my research. If you have questions, please feel free to get in touch.
Host: Well, we certainly will look forward to more results. Please join us again because I would really like to hear about the connection between the microbiome and brain health and how all of this ties together. Thank you so much doctor for joining us today and telling us about your research. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine, please visit our website at nm.org to get connected with one of our providers. If you found this podcast informative, please share on your social channels. Be sure and subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole.