Understanding the Role Transcription Factors Play in Obesity
Obesity has nearly tripled worldwide since the 1970s. Consequently, a major health concern related to obesity is that excess fat can spill into organs such as the liver, which can lead to fatty liver disease or even liver cancer. Grant Barish, MD, assistant professor in the Division of Endocrinology, Metabolism and Molecular Medicine, explains his latest work examining metabolic switches to understand why metabolic disorders such as obesity occur and how they could be used as potential therapies.
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Learn more about Grant Barish, MD
Grant Barish, MD
Grant Barish, MD is an Assistant Professor of Medicine the Division of Endocrinology.Learn more about Grant Barish, MD
Transcription:
Understanding the Role Transcription Factors Play in Obesity
Melanie Cole, MS (Host): Obesity has nearly tripled worldwide since 1970s. A major health concern related to obesity is that excess fat can spill into organs, such as the liver, which can lead to fatty liver disease or even liver cancer. Joining us today is Dr. Grant Barish. He’s an assistant professor in the division of endocrinology, metabolism, and molecular medicine at Northwestern Medicine, and he’s here to discuss his latest work examining the mechanisms that lead to fat accumulation in the liver. Dr. Barish, it’s a pleasure to have you with us. This is a fascinating topic. I so enjoyed studying your research. Before we begin, tell us a little bit about yourself and your role in the division of endocrinology at Northwestern.
Grant Barish, MD (Guest): Sure. Thank you very much for speaking with me. So as you said, I'm a member of the division. I joined Northwestern about seven years ago. I have both clinical training and pretty extensive training in molecular biology and animal physiology. So my post-doctoral work predated my recruitment and arrival here at Northwestern Medicine. In terms of my role here, I'm primarily research focused although I do see patients as well. My time split would probably be about 80 or 90% in the lab and the other 10 to 15% seeing patients. I have a weekly clinic actually at one of our affiliates, at the Jesse Brown VA Medical Center where I see patients, veterans, with some of our endocrine fellows and help in their training. I also serve on the inpatient consult service at Northwestern Memorial Hospital for hospitalized patients with endocrine issues usually for a few weeks a year.
Host: Well, you certainly are involved in so many areas of endocrinology. Let’s talk about your research. Give us a broad overview, Dr. Barish, and explain a little bit about these mechanisms of accumulation of fat in the liver.
Dr. Barish: My training and background is really in focusing on proteins that operate in the nucleus. Some of these can be turned on directly by endocrine hormones like thyroid hormone or glucocorticoids that combine to receptors that act directly on DNA, or other transcription factors that may be turned on or turned off that initiate at the cell surface and then culminate by effecting these proteins that control whether genes are turned on or turned off. So in broad terms, I focus on transcriptional regulation by these DNA binding transcription factors and their actions in the nucleus to control whether genes are turned on or turned off.
It turns out that in a lot of endocrine pathologies in the context of obesity, a lot of changes occur at the level of which genes are turned on or turned off. Some of this may be compensatory because cells and tissues are storing too much energy or too much lipid. Some of these signals or changes can become pathological. So we’re interested in trying to identify and understand these pathways which may be part of the disease, part of the pathogenesis of these disorders that can give rise to insulin resistance or fat accumulation. Some of the pathological changes that you described which can be inflammation of the liver which can lead to cirrhosis or even to liver cancer. As well as pathways that might be therapeutic in effecting the sort of balance of metabolic regulation in a favorable way to hopefully restore or improve changes that can occur with obesity and particularly in the liver to sort of shift this balance towards removing or burning lipid rather than storing it excessively.
Host: In one of your recent studies, Dr. Barish, your team discovered a new function for transcription factor called BCL6. Tell us a little bit about these studies and the results and help us understand those mechanisms that lead to this accumulation so that it’s possible to develop these new treatments. Tell us about the BCL6 inhibition.
Dr. Barish: Sure. So one of the transcription factors that we’ve been interested in for a number of years, even predating my arrival at Northwestern is a particular transcription factor, as you said, called BCL6. It stands for b-cell lymphoma 6. It was first identified in work that was focused on cancer, but it turns out that this transcription factor is expressed broadly throughout many tissues of the body. Not only in immune cells, but also in tissues such as the liver or in the fat. It’s functions outside of immunity were really poorly defined. We had some lines of evidence that pointed to potential metabolic functions for b-cell 6. So we’ve been interested in pursing that and how it might relate to obesity and some of the changes that occur there. Using sort of a genetic approaches, we’ve been able to identify new and powerful regulatory functions for b-cell 6 and it’s impact in both the adipose tissue as well as in the liver.
Although it’s tough to summarize all of the data, what I can say is that genetically deleting or ablating this factor in either the liver or in the adipose tissue rendered a very favorable effect on metabolism and particularly type 2 diabetes. One of the really most striking effects when we deleted this gene either in the fat or in the liver was that there was a strong protection from the development of excessive fat accumulation in the liver, which is an exciting finding. The mechanisms by which this occurs and it’s actions in fat and in liver are different, but in either tissue the sort of overarching impact is to reduce the amount of fat accumulation in the liver.
Host: Fascinating. This is such an interesting study. As I said at the beginning, I really enjoyed reading it. It makes the BCL6 inhibition such an interesting target for boosting that liver’s ability to burn excess fat and to better characterize these exact mechanisms by which the fat burning operates. I'm an exercise physiologist. Obesity is one of my passions. So how do you take this study? How do you envision your research translating to patient care with a study that has so many far reaching aspects as this possibly does?
Dr. Barish: Yeah, no. That’s a great question. I mean one of the challenges which is true for this factor is with many genes that researchers are studying. Obviously this gene subserves important functions under normal circumstances, but we’ve found in our studies that actually eliminating or reducing this gene, at least in some tissues, may hold potential benefit for metabolic pathologies. So the question which still is not totally clear yet is whether we could in a manner that was safe and not deleterious reduce or inhibit this particular factor for therapeutic benefit in obesity related diseases.
Interestingly with advances in drug development in the last several years, there are now ways—10 years ago, this would not have been possible—but there are now ways to very selectively target particular proteins like BCL6, which exist in the nucleus of cells with small molecules. Such compounds have been developed. Some of these are being developed for treatments in diseases like lymphoma, which is obviously a blood cell type cancer, and there the idea is that BCL6 is essential for some lymphomas. By reducing its levels, that may suppress the development of these malignancies. Whether you could leverage such compounds for metabolic benefit is not yet known and we’re interested in trying to test that. One of the other features which is attractive from our studies is that there appears to be an effect from BCL6 on the liver specifically. There can be ways therapeutically to target drugs to particularly home to the liver. So that can be potentially a way to more limit the effects of such drugs so that you're not hitting this transcription factor across all tissues of the body.
All of this remains a future challenge. BLC6 is very important for normal immune cell development. So I think it’s going to have to be carefully looked at and sorted out whether there’s a window of therapeutic opportunity for reducing BCL6 and improving metabolism without having adverse consequences for deleting or suppressing this protein in other tissues. This is always a challenge that many of us working in metabolism face is trying to find windows of opportunity to therapeutically intervene on genes.
Host: Well, as I said before, it could have such far reaching effects. As we wrap up, Dr. Barish is there anything else you would like providers to know about this really interesting work that you're doing and when you feel that it’s important that they refer to the specialists in endocrinology at Northwestern Medicine.
Dr. Barish: Sure. I would say that a lot of our work is focused on basic mechanisms. Our hope is that some of these will translate, but it’s always a challenge. I think as we and others advance in our understanding of these pathways, it really paves the way to new opportunities whether intervening on the particular target or other factors or components that are elucidated through more basic approaches to understanding the biology that is related to and underlies metabolic disease and obesity related pathologies.
In terms of the clinical activity—and diabetes has some major clinical challenges. I'm sure you're aware with a huge percentage of our population afflicted by this. Generally speaking, specialists like myself and others here at Northwestern, we see both type 1 and type 2 and diabetes. Particularly with the patients with type 2 diabetes, which is the more common form, that become more complicated because they are not successful with a single drug or even a couple of drugs as therapies and really progressed to needing combinations of therapies or have other comorbidities such as associated fatty liver disease or other concerns, cardiovascular disease. These patients can become quite complicated. I think that’s where having specialists that are very focused on diabetes and obesity related disease can be very helpful for these complex patients. Sometimes it just gets beyond the expertise of generalists for tough cases.
Host: Well absolutely it does. Thank you so much for joining us today. 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. Please remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. For more health tips and updates, please follow us on your social channels. I'm Melanie Cole.
Understanding the Role Transcription Factors Play in Obesity
Melanie Cole, MS (Host): Obesity has nearly tripled worldwide since 1970s. A major health concern related to obesity is that excess fat can spill into organs, such as the liver, which can lead to fatty liver disease or even liver cancer. Joining us today is Dr. Grant Barish. He’s an assistant professor in the division of endocrinology, metabolism, and molecular medicine at Northwestern Medicine, and he’s here to discuss his latest work examining the mechanisms that lead to fat accumulation in the liver. Dr. Barish, it’s a pleasure to have you with us. This is a fascinating topic. I so enjoyed studying your research. Before we begin, tell us a little bit about yourself and your role in the division of endocrinology at Northwestern.
Grant Barish, MD (Guest): Sure. Thank you very much for speaking with me. So as you said, I'm a member of the division. I joined Northwestern about seven years ago. I have both clinical training and pretty extensive training in molecular biology and animal physiology. So my post-doctoral work predated my recruitment and arrival here at Northwestern Medicine. In terms of my role here, I'm primarily research focused although I do see patients as well. My time split would probably be about 80 or 90% in the lab and the other 10 to 15% seeing patients. I have a weekly clinic actually at one of our affiliates, at the Jesse Brown VA Medical Center where I see patients, veterans, with some of our endocrine fellows and help in their training. I also serve on the inpatient consult service at Northwestern Memorial Hospital for hospitalized patients with endocrine issues usually for a few weeks a year.
Host: Well, you certainly are involved in so many areas of endocrinology. Let’s talk about your research. Give us a broad overview, Dr. Barish, and explain a little bit about these mechanisms of accumulation of fat in the liver.
Dr. Barish: My training and background is really in focusing on proteins that operate in the nucleus. Some of these can be turned on directly by endocrine hormones like thyroid hormone or glucocorticoids that combine to receptors that act directly on DNA, or other transcription factors that may be turned on or turned off that initiate at the cell surface and then culminate by effecting these proteins that control whether genes are turned on or turned off. So in broad terms, I focus on transcriptional regulation by these DNA binding transcription factors and their actions in the nucleus to control whether genes are turned on or turned off.
It turns out that in a lot of endocrine pathologies in the context of obesity, a lot of changes occur at the level of which genes are turned on or turned off. Some of this may be compensatory because cells and tissues are storing too much energy or too much lipid. Some of these signals or changes can become pathological. So we’re interested in trying to identify and understand these pathways which may be part of the disease, part of the pathogenesis of these disorders that can give rise to insulin resistance or fat accumulation. Some of the pathological changes that you described which can be inflammation of the liver which can lead to cirrhosis or even to liver cancer. As well as pathways that might be therapeutic in effecting the sort of balance of metabolic regulation in a favorable way to hopefully restore or improve changes that can occur with obesity and particularly in the liver to sort of shift this balance towards removing or burning lipid rather than storing it excessively.
Host: In one of your recent studies, Dr. Barish, your team discovered a new function for transcription factor called BCL6. Tell us a little bit about these studies and the results and help us understand those mechanisms that lead to this accumulation so that it’s possible to develop these new treatments. Tell us about the BCL6 inhibition.
Dr. Barish: Sure. So one of the transcription factors that we’ve been interested in for a number of years, even predating my arrival at Northwestern is a particular transcription factor, as you said, called BCL6. It stands for b-cell lymphoma 6. It was first identified in work that was focused on cancer, but it turns out that this transcription factor is expressed broadly throughout many tissues of the body. Not only in immune cells, but also in tissues such as the liver or in the fat. It’s functions outside of immunity were really poorly defined. We had some lines of evidence that pointed to potential metabolic functions for b-cell 6. So we’ve been interested in pursing that and how it might relate to obesity and some of the changes that occur there. Using sort of a genetic approaches, we’ve been able to identify new and powerful regulatory functions for b-cell 6 and it’s impact in both the adipose tissue as well as in the liver.
Although it’s tough to summarize all of the data, what I can say is that genetically deleting or ablating this factor in either the liver or in the adipose tissue rendered a very favorable effect on metabolism and particularly type 2 diabetes. One of the really most striking effects when we deleted this gene either in the fat or in the liver was that there was a strong protection from the development of excessive fat accumulation in the liver, which is an exciting finding. The mechanisms by which this occurs and it’s actions in fat and in liver are different, but in either tissue the sort of overarching impact is to reduce the amount of fat accumulation in the liver.
Host: Fascinating. This is such an interesting study. As I said at the beginning, I really enjoyed reading it. It makes the BCL6 inhibition such an interesting target for boosting that liver’s ability to burn excess fat and to better characterize these exact mechanisms by which the fat burning operates. I'm an exercise physiologist. Obesity is one of my passions. So how do you take this study? How do you envision your research translating to patient care with a study that has so many far reaching aspects as this possibly does?
Dr. Barish: Yeah, no. That’s a great question. I mean one of the challenges which is true for this factor is with many genes that researchers are studying. Obviously this gene subserves important functions under normal circumstances, but we’ve found in our studies that actually eliminating or reducing this gene, at least in some tissues, may hold potential benefit for metabolic pathologies. So the question which still is not totally clear yet is whether we could in a manner that was safe and not deleterious reduce or inhibit this particular factor for therapeutic benefit in obesity related diseases.
Interestingly with advances in drug development in the last several years, there are now ways—10 years ago, this would not have been possible—but there are now ways to very selectively target particular proteins like BCL6, which exist in the nucleus of cells with small molecules. Such compounds have been developed. Some of these are being developed for treatments in diseases like lymphoma, which is obviously a blood cell type cancer, and there the idea is that BCL6 is essential for some lymphomas. By reducing its levels, that may suppress the development of these malignancies. Whether you could leverage such compounds for metabolic benefit is not yet known and we’re interested in trying to test that. One of the other features which is attractive from our studies is that there appears to be an effect from BCL6 on the liver specifically. There can be ways therapeutically to target drugs to particularly home to the liver. So that can be potentially a way to more limit the effects of such drugs so that you're not hitting this transcription factor across all tissues of the body.
All of this remains a future challenge. BLC6 is very important for normal immune cell development. So I think it’s going to have to be carefully looked at and sorted out whether there’s a window of therapeutic opportunity for reducing BCL6 and improving metabolism without having adverse consequences for deleting or suppressing this protein in other tissues. This is always a challenge that many of us working in metabolism face is trying to find windows of opportunity to therapeutically intervene on genes.
Host: Well, as I said before, it could have such far reaching effects. As we wrap up, Dr. Barish is there anything else you would like providers to know about this really interesting work that you're doing and when you feel that it’s important that they refer to the specialists in endocrinology at Northwestern Medicine.
Dr. Barish: Sure. I would say that a lot of our work is focused on basic mechanisms. Our hope is that some of these will translate, but it’s always a challenge. I think as we and others advance in our understanding of these pathways, it really paves the way to new opportunities whether intervening on the particular target or other factors or components that are elucidated through more basic approaches to understanding the biology that is related to and underlies metabolic disease and obesity related pathologies.
In terms of the clinical activity—and diabetes has some major clinical challenges. I'm sure you're aware with a huge percentage of our population afflicted by this. Generally speaking, specialists like myself and others here at Northwestern, we see both type 1 and type 2 and diabetes. Particularly with the patients with type 2 diabetes, which is the more common form, that become more complicated because they are not successful with a single drug or even a couple of drugs as therapies and really progressed to needing combinations of therapies or have other comorbidities such as associated fatty liver disease or other concerns, cardiovascular disease. These patients can become quite complicated. I think that’s where having specialists that are very focused on diabetes and obesity related disease can be very helpful for these complex patients. Sometimes it just gets beyond the expertise of generalists for tough cases.
Host: Well absolutely it does. Thank you so much for joining us today. 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. Please remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. For more health tips and updates, please follow us on your social channels. I'm Melanie Cole.