In this episode I bring you obesity and bariatric surgery research scientists, Dr. Randy Seeley. If you have been a longtime listener of the podcast then you will likely remember Dr Seeley from Episode 34 where he helped us understand the theory of Set-point for body fat mass and Episode 56 where we did a deeper dive into the biology of body weight. This time I bring Dr Seeley back to help get us get up to speed on what research has learned about bile acid metabolism in general and as it relates to obesity and bariatric surgery specifically. We also talk some about the “bugs” of the gut, also known as the gut microbiome. Additionally, we chat about what his research is revealing about sleep apnea and the gut, as well as iron metabolism after bariatric surgery. And just for fun, there is a cameo appearance of his dog, Ziggy. After all that, as always, I share with you my concluding thoughts about the episode. But before I cut to the episode I want to tell you about the sponsors who make this podcast possible. That would be you, my listeners. You support the podcast every time you tell someone about it, share it, rate it, and if you are able, by becoming a patron. You can become a patron of the podcast at either Patreon or PayPal where you have the option of offering either recurring monthly support or one time support. Click on Patreon or PayPal to be taken to their sites or you can find the links in the upper right-hand corner of my website, WeightLossSurgeryPodcast.com If you are already a supporter of the podcast in any capacity, thank you ever so much. Discussed In This Episode: Randy Seeley, PhD is a Professor of Surgery, Internal Medicine, and Nutritional Science at the University of Michigan. One area his research focuses on is trying to find and understand the molecular signals that come from the gut in general and how bariatric surgery changes those signals to support a reduction in hunger and weight. What is Bile: Made in the liver and stored in the gallbladder. When we eat foods with lipids (fat). Bile is released at the beginning of the small intestines. Unused bile acids are reabsorbed into the blood at the bottom part of the small intestine and are brought back up to the liver to be used again. Roux-en-Y Gastric Bypass (RYGB) patients have higher levels of bile circulating in their blood compared to non-RYGB patients. Interestingly, animal models and humans who undergo Vertical Sleeve Gastrectomy (VSG) also have increased blood levels of bile, even though the intestines are not changed in VSG, only the stomach is changed. The reason is that the liver stops taking up, recycling, as much bile. Somehow the liver knows that part of the stomach has been removed. Figuring out if this matters, led Dr Seeley to dig deeper into the role of bile acids. It turns out that bile acids not only work to break down dietary fats that are eaten. Bile also acts a Hormone (A hormone is a chemical signal that is released in one area of the body and communicates with another part of the body by binding with a receptor.) One of the important receptors that bile binds to is FXR. FXR has been linked to many aspects of metabolism. In order to determine what role FXR plays in the binding of bile, Dr Seeley’s lab created genetically alerted rodents who no longer have the FXR receptor. They then performed VSG on the rodents. The theory was that if elevated plasma bile acids (bile in the blood) mattered to why the surgery works, then you would expect that animals who no longer have the FXR receptor would not respond as well to the surgery. That is exactly what happened. Ultimately, the animals without FXR did not have suppression of food intake even though it has a smaller stomach. Additionally, the FXR-missing animals did not have blood glucose level improvement. Why does this matter? Dr Seeley argues the more we can identify these specific molecular pathways by which bariatric surgery works the better we can understand who might benefit from the surgery and ultimately, perhaps, we can make surgery a thing of the past because we have figured out treatments that are just as beneficial but not as invasive as surgery. Bile acid is not just one thing. There are different types of bile acids, or as Dr Seeley likes to call it, a gemisch (meaning mixture) of bile acids. Most basically there are Primary Bile Acids, which are made by the liver and there are Secondary Bile Acids, which are altered, changed, by the bacteria in the gastrointestinal track. Some of the primary and secondary bile acids turn on and off different receptors including FXR. Studies in humans are more complicated because as Dr Seeley points out, people don't want to line up to have their FXR receptor deleted. However, the biology between rodents and people is translatable. My questions to Dr Seeley: Are the changes in bile acid metabolism independent of weight loss or are they due to lowered body fat stores, or reduced calorie intake, or different calories, or increased physical activity, etc? To answer this question Dr Seeley discusses a study completed at Washington University, by Samuel Klein, MD who compared people who had gastric band, VSG, and RYGB. He compared people who did well with the band (lost similar amounts of weight to VSG and RYGB people) to people who had VSG or RYGB. What he found is that even though the gastric band patients had lost similar amounts of weight, their bile acids had not changed. The change in bile acids are only seen in the VSG and RYGB patients. But how does the liver know to not uptake bile and why? We don't know the answer, yet. Bugs: My Question: What role do the bugs (bacteria) living inside the gut have to play in any of this? Dr Seeley points out that there is some controversy around the question of if and how much the microbiome influences weight. Here is what we know after surgery, the bugs in the poop are different after RYGB than before. What we don't know is if the changes in the gut bacteria are a knock-on effect (a consequence) of bariatric or are they something that helps drive (create) some of the biological changes of the surgery (chicken or egg question)? After all, the bugs can change the bile acids and bile acids can change the bugs. Again, we don't know that answers, yet. Dr Seeley’s long-term research goal is to recapitulate (mimic or repeat) the benefits of bariatric surgery without having to actually perform bariatric surgery. He highlights that it is not realistic to expect that all the multiple millions of people who are affected by obesity can or will have bariatric surgery. Therefore, research needs to help us find alternative treatments that are as effective. My question: Are these changes durable? Do they last? For some people the changes are durable but the question is for whom are the changes durable? Dr Seeley talks about type 2 diabetes (T2D), stating that it is well known that bariatric surgery helps treat T2D. However, it is also known that for many people, their T2D will return at some point after bariatric surgery. We agreed that the longer a person had their T2D before bariatric surgery, the greater the chance their T2D will come back after bariatric surgery, but we cannot say exactly when nor how significantly their T2D will return. The fact that there is a high chance of recurrence is not a question of if we should do bariatric surgery, but rather when (the sooner the better?) Sleep Apnea: Another example of how bariatric surgery helps with biology is related to obstructive sleep apnea (OSA). Many people who are affected by obesity also have OSA and are on or should be on CPAP therapy. It is known that OSA improves after bariatric surgery. The question is why? To attempt to answer this question, Dr Seeley started thinking about why do people affected by obesity even get OSA? The notion that fat around the airway causes the airway to collapse when you lay down depending on which way you lay down never made sense to Dr Seeley. So he tested this on rodents by placing the rodents in a special chamber called a plethysmograph (an instrument that measures the change in volume within an organ or whole body). While the animal is in the chamber the researchers can also manipulate the gas mixture (O2 and CO2). When the researchers raised the amount of carbon dioxide in the chamber and the animal responds by breathing harder, AKA the Hypercapnic Ventilator Response (HVR). They then took rodents who had obesity and found that as the CO2 level in the chamber went up, the rodents HVR went down, their drive to breath is lower. They then performed VSG on the rodents and found that the HVR, the drive to breath, normalized again, independent of weight! This led them to conclude that bariatric surgery changes the drive to breath by showing us that there is intimate involvement from our GI tract relating to our HVR and drive to breathe. Iron Metabolism: Dr Seeley’s research is next leading him to study iron and bariatric surgery. It is a well-known fact that after bariatric surgery iron levels decline in both humans and in research rodents. In researching why this may be, it appears that the rodents’s body wants have a lower iron level. However, it is not just because there is lower iron absorption after bariatric surgery. It also appears that the system, the animal’s body, wants to maintain a lower iron level. Why and how does the body know? More research is needed to answer this question. So in summary, there are benefits with bariatric surgery, we know a tiny portion of them, we know the vast majority of people will reap benefits, but exactly how much and why, we’re still figuring out. Concluding Thoughts So there you have it… is it all clear now? Ok, full disclosure, I realize some of you may be thinking there you have what? After all, it could be easily argued that this episode leaves us all with more questions than answers. And it is hard to make decisions, such as should a person have bariatric surgery and which procedure when all you have are more questions, not answers. Honestly my intent in bringing you this episode was not to answer the big questions, to take the 30 thousand foot view; But rather the opposite, to look very close and get really, really specific. My goal was to help show you in one conversation with one fun and wicked smart scientist, a tiny fraction of some of the research that is happening 24/7, 365 days a year, year after year. All of which is occurring to help us understand the How and Why of a question we actually already know the answer to. That answer being that for most people bariatric surgery works really well. When most people have bariatric surgery they lose weight, the majority of that weight being fat mass. We have known this fact for many, many years. But how and why bariatric surgery works, these are the questions that science is constantly attempting to answer. It is true that in many ways we are reverse engineering the problem. Our ability to safely perform the surgeries has out-paced our deep understanding as to how and why the surgeries work. You will often hear the explanation of bariatric surgery works because of restriction when you make the stomach smaller, and malabsorption when you make the intestines shorter. Which is a little like saying a plan flies because you turn the engine on and speed the plane down a runway. True… These two things are necessary to make a plan fly, but they are not sufficient. You need more than power and a runway to make a plan fly. The same way restriction and malabsorption are necessary parts of bariatric surgery, but we now know because of scientists like Randy Seeley, those two things are not sufficient. There is more going on that makes bariatric surgery work as effectively as it does. But exactly how and why is still being answered, study-by-study. Which brings me to another deeper question, when we get really honest about how much we do and do not know about how and why bariatric surgery works, should we even be performing bariatric surgery? What if in all the research we discover a negative consequence of bariatric surgery that tips the scales towards a much lower efficacy? Should we just put a moratorium on bariatric surgery until we understand more about the how and why it works and the risks and benefits therein? Well, as you might have guessed, I am not in favor of this. Although our bariatric medical and surgical knowledge only spans back to the 1950’s, our understanding the potential health consequences of obesity goes back much farther. To date, bariatric surgery is the most effective treatment we have, even when you factor in what we do not yet know about bariatric surgery. But, having said that, I am continually encouraged by the research scientists like Dr Seeley who are seeking to understand how bariatric surgery works in hopes that broadly an alternative to surgery can be identified and more specifically, we can better determine for whom bariatric surgery will have the most benefit and which surgery. Will have these answers in the next few years? I do not think so. But, when you look at the radical advances science has made just in the last 100 years compared to all scientific advances over human existence, well, I don't think we are doing too badly. And as one final word, here in the United States we just had our national Thanksgiving holiday. I want to take this opportunity to express my gratitude, my thanksgiving, to all of you for listening, for sharing the podcast with others, for writing me at reeger@weightlosssurgerypodcast and for becoming a patron. I do not keep this podcast alive for fame or fortune. I keep it alive because you tell me it makes a difference for you. In this seemingly ever more complicated world, my reasons for keep-on, keeping on, truly against all odds, is simple because of you. You are the reason and I am grateful for you. Never forget, I believe in you. Connecting with Dr Seeley on Twitter Connecting with Reeger Email: reeger@weightlosssurgerypodcast.com Facebook Instagram Twitter
In this episode I welcome back research scientists, Dr. Randy Seeley. Dr Seeley is a Professor of Surgery, Internal Medicine, and Nutritional Science at the University of Michigan. In this episode we discuss bile acid metabolism, the gut microbiome, sleep apnea and the gut, and iron metabolism.
In this episode I bring you obesity and bariatric surgery research scientists, Dr. Randy Seeley. If you have been a longtime listener of the podcast then you will likely remember Dr Seeley from Episode 34 where he helped us understand the theory of Set-point for body fat mass and Episode 56 where we did a deeper dive into the biology of body weight.
This time I bring Dr Seeley back to help get us get up to speed on what research has learned about bile acid metabolism in general and as it relates to obesity and bariatric surgery specifically. We also talk some about the “bugs” of the gut, also known as the gut microbiome. Additionally, we chat about what his research is revealing about sleep apnea and the gut, as well as iron metabolism after bariatric surgery. And just for fun, there is a cameo appearance of his dog, Ziggy.
After all that, as always, I share with you my concluding thoughts about the episode.
But before I cut to the episode I want to tell you about the sponsors who make this podcast possible. That would be you, my listeners. You support the podcast every time you tell someone about it, share it, rate it, and if you are able, by becoming a patron. You can become a patron of the podcast at either Patreon or PayPal where you have the option of offering either recurring monthly support or one time support. Click on Patreon or PayPal to be taken to their sites or you can find the links in the upper right-hand corner of my website, WeightLossSurgeryPodcast.com If you are already a supporter of the podcast in any capacity, thank you ever so much.
Discussed In This Episode:
Randy Seeley, PhD is a Professor of Surgery, Internal Medicine, and Nutritional Science at the University of Michigan.
One area his research focuses on is trying to find and understand the molecular signals that come from the gut in general and how bariatric surgery changes those signals to support a reduction in hunger and weight.
What is Bile: Made in the liver and stored in the gallbladder. When we eat foods with lipids (fat). Bile is released at the beginning of the small intestines. Unused bile acids are reabsorbed into the blood at the bottom part of the small intestine and are brought back up to the liver to be used again.
Roux-en-Y Gastric Bypass (RYGB) patients have higher levels of bile circulating in their blood compared to non-RYGB patients.
Interestingly, animal models and humans who undergo Vertical Sleeve Gastrectomy (VSG) also have increased blood levels of bile, even though the intestines are not changed in VSG, only the stomach is changed. The reason is that the liver stops taking up, recycling, as much bile. Somehow the liver knows that part of the stomach has been removed.
Figuring out if this matters, led Dr Seeley to dig deeper into the role of bile acids. It turns out that bile acids not only work to break down dietary fats that are eaten. Bile also acts a Hormone (A hormone is a chemical signal that is released in one area of the body and communicates with another part of the body by binding with a receptor.) One of the important receptors that bile binds to is FXR. FXR has been linked to many aspects of metabolism.
In order to determine what role FXR plays in the binding of bile, Dr Seeley’s lab created genetically alerted rodents who no longer have the FXR receptor. They then performed VSG on the rodents. The theory was that if elevated plasma bile acids (bile in the blood) mattered to why the surgery works, then you would expect that animals who no longer have the FXR receptor would not respond as well to the surgery. That is exactly what happened. Ultimately, the animals without FXR did not have suppression of food intake even though it has a smaller stomach. Additionally, the FXR-missing animals did not have blood glucose level improvement.
Why does this matter? Dr Seeley argues the more we can identify these specific molecular pathways by which bariatric surgery works the better we can understand who might benefit from the surgery and ultimately, perhaps, we can make surgery a thing of the past because we have figured out treatments that are just as beneficial but not as invasive as surgery.
Bile acid is not just one thing. There are different types of bile acids, or as Dr Seeley likes to call it, a gemisch (meaning mixture) of bile acids. Most basically there are Primary Bile Acids, which are made by the liver and there are Secondary Bile Acids, which are altered, changed, by the bacteria in the gastrointestinal track. Some of the primary and secondary bile acids turn on and off different receptors including FXR.
Studies in humans are more complicated because as Dr Seeley points out, people don't want to line up to have their FXR receptor deleted. However, the biology between rodents and people is translatable.
My questions to Dr Seeley: Are the changes in bile acid metabolism independent of weight loss or are they due to lowered body fat stores, or reduced calorie intake, or different calories, or increased physical activity, etc?
To answer this question Dr Seeley discusses a study completed at Washington University, by Samuel Klein, MD who compared people who had gastric band, VSG, and RYGB. He compared people who did well with the band (lost similar amounts of weight to VSG and RYGB people) to people who had VSG or RYGB. What he found is that even though the gastric band patients had lost similar amounts of weight, their bile acids had not changed. The change in bile acids are only seen in the VSG and RYGB patients. But how does the liver know to not uptake bile and why? We don't know the answer, yet.
Bugs:
My Question: What role do the bugs (bacteria) living inside the gut have to play in any of this? Dr Seeley points out that there is some controversy around the question of if and how much the microbiome influences weight. Here is what we know after surgery, the bugs in the poop are different after RYGB than before. What we don't know is if the changes in the gut bacteria are a knock-on effect (a consequence) of bariatric or are they something that helps drive (create) some of the biological changes of the surgery (chicken or egg question)? After all, the bugs can change the bile acids and bile acids can change the bugs. Again, we don't know that answers, yet.
Dr Seeley’s long-term research goal is to recapitulate (mimic or repeat) the benefits of bariatric surgery without having to actually perform bariatric surgery. He highlights that it is not realistic to expect that all the multiple millions of people who are affected by obesity can or will have bariatric surgery. Therefore, research needs to help us find alternative treatments that are as effective.
My question: Are these changes durable? Do they last?
For some people the changes are durable but the question is for whom are the changes durable? Dr Seeley talks about type 2 diabetes (T2D), stating that it is well known that bariatric surgery helps treat T2D. However, it is also known that for many people, their T2D will return at some point after bariatric surgery. We agreed that the longer a person had their T2D before bariatric surgery, the greater the chance their T2D will come back after bariatric surgery, but we cannot say exactly when nor how significantly their T2D will return. The fact that there is a high chance of recurrence is not a question of if we should do bariatric surgery, but rather when (the sooner the better?)
Sleep Apnea:
Another example of how bariatric surgery helps with biology is related to obstructive sleep apnea (OSA). Many people who are affected by obesity also have OSA and are on or should be on CPAP therapy. It is known that OSA improves after bariatric surgery. The question is why? To attempt to answer this question, Dr Seeley started thinking about why do people affected by obesity even get OSA? The notion that fat around the airway causes the airway to collapse when you lay down depending on which way you lay down never made sense to Dr Seeley. So he tested this on rodents by placing the rodents in a special chamber called a plethysmograph (an instrument that measures the change in volume within an organ or whole body). While the animal is in the chamber the researchers can also manipulate the gas mixture (O2 and CO2). When the researchers raised the amount of carbon dioxide in the chamber and the animal responds by breathing harder, AKA the Hypercapnic Ventilator Response (HVR). They then took rodents who had obesity and found that as the CO2 level in the chamber went up, the rodents HVR went down, their drive to breath is lower. They then performed VSG on the rodents and found that the HVR, the drive to breath, normalized again, independent of weight! This led them to conclude that bariatric surgery changes the drive to breath by showing us that there is intimate involvement from our GI tract relating to our HVR and drive to breathe.
Iron Metabolism:
Dr Seeley’s research is next leading him to study iron and bariatric surgery. It is a well-known fact that after bariatric surgery iron levels decline in both humans and in research rodents. In researching why this may be, it appears that the rodents’s body wants have a lower iron level. However, it is not just because there is lower iron absorption after bariatric surgery. It also appears that the system, the animal’s body, wants to maintain a lower iron level. Why and how does the body know? More research is needed to answer this question.
So in summary, there are benefits with bariatric surgery, we know a tiny portion of them, we know the vast majority of people will reap benefits, but exactly how much and why, we’re still figuring out.
Concluding Thoughts
So there you have it… is it all clear now? Ok, full disclosure, I realize some of you may be thinking there you have what? After all, it could be easily argued that this episode leaves us all with more questions than answers. And it is hard to make decisions, such as should a person have bariatric surgery and which procedure when all you have are more questions, not answers.
Honestly my intent in bringing you this episode was not to answer the big questions, to take the 30 thousand foot view; But rather the opposite, to look very close and get really, really specific. My goal was to help show you in one conversation with one fun and wicked smart scientist, a tiny fraction of some of the research that is happening 24/7, 365 days a year, year after year. All of which is occurring to help us understand the How and Why of a question we actually already know the answer to. That answer being that for most people bariatric surgery works really well. When most people have bariatric surgery they lose weight, the majority of that weight being fat mass. We have known this fact for many, many years.
But how and why bariatric surgery works, these are the questions that science is constantly attempting to answer. It is true that in many ways we are reverse engineering the problem. Our ability to safely perform the surgeries has out-paced our deep understanding as to how and why the surgeries work.
You will often hear the explanation of bariatric surgery works because of restriction when you make the stomach smaller, and malabsorption when you make the intestines shorter. Which is a little like saying a plan flies because you turn the engine on and speed the plane down a runway. True… These two things are necessary to make a plan fly, but they are not sufficient. You need more than power and a runway to make a plan fly. The same way restriction and malabsorption are necessary parts of bariatric surgery, but we now know because of scientists like Randy Seeley, those two things are not sufficient. There is more going on that makes bariatric surgery work as effectively as it does. But exactly how and why is still being answered, study-by-study.
Which brings me to another deeper question, when we get really honest about how much we do and do not know about how and why bariatric surgery works, should we even be performing bariatric surgery? What if in all the research we discover a negative consequence of bariatric surgery that tips the scales towards a much lower efficacy? Should we just put a moratorium on bariatric surgery until we understand more about the how and why it works and the risks and benefits therein?
Well, as you might have guessed, I am not in favor of this. Although our bariatric medical and surgical knowledge only spans back to the 1950’s, our understanding the potential health consequences of obesity goes back much farther. To date, bariatric surgery is the most effective treatment we have, even when you factor in what we do not yet know about bariatric surgery.
But, having said that, I am continually encouraged by the research scientists like Dr Seeley who are seeking to understand how bariatric surgery works in hopes that broadly an alternative to surgery can be identified and more specifically, we can better determine for whom bariatric surgery will have the most benefit and which surgery.
Will have these answers in the next few years? I do not think so. But, when you look at the radical advances science has made just in the last 100 years compared to all scientific advances over human existence, well, I don't think we are doing too badly.
And as one final word, here in the United States we just had our national Thanksgiving holiday. I want to take this opportunity to express my gratitude, my thanksgiving, to all of you for listening, for sharing the podcast with others, for writing me at reeger@weightlosssurgerypodcast and for becoming a patron. I do not keep this podcast alive for fame or fortune. I keep it alive because you tell me it makes a difference for you. In this seemingly ever more complicated world, my reasons for keep-on, keeping on, truly against all odds, is simple because of you. You are the reason and I am grateful for you.
Never forget, I believe in you.
Connecting with Dr Seeley on Twitter
Connecting with Reeger