The Man Who Couldn’t Stop Gaining Weight | A Medical Mystery

24:29Austin Baraki:So that's kind of where I am at right now. The pressure impacts that we are seeing are, may well now be due to a combination of the size of the mass in the brain, as well as that third ventricle enlargement with the enlargement of the chambers. That's called hydrocephalus. And that is a situation where you can have, you know, maybe he has two reasons for the elevated pressure and the papilledema and things like that but that's kind of besides the point right now so right now i'm most suspicious that this patient has a craniofringioma and may secondarily have a syndrome of hypothalamic obesity and so the next steps for this patient would be consulting with people with more expertise in this type of tumor and in particular in how it should be treated and mainly resected mostly surgically is going to be the way that this gets addressed.

25:15Austin Baraki:And so that is well beyond my knowledge base and skill set. I do not have the dexterity to remove a tumor from the very middle of somebody's brain. I'm going to be calling with some other experts to help handle that.

25:26Jordan Feigenbaum:Yeah, no, this is good. This is the one I was curious if you would get the specific diagnosis and I'm going to give you full credit. It is a craniofaryngioma. A quick note on the name because this is some pretty good trivia. The full name is adamantinomatous craniopharyngioma. Adamant means hard, unbreakable, has the same root as adamantium. Here's why that's in the name. Under the microscope, this tumor looks like the tissue that builds the hard enamel on a developing tooth. So it's not really a germ cell tumor and it has nothing to do with the reproductive line, but it is a tooth forming tissue that ended up at the base of the brain and grew into a mass.

25:59Jordan Feigenbaum:Adamantium strikes again. So he's got this diagnosis of a mass, which is doing two things at once. It's pushing on his optic nerves and it's threatening his pituitary gland and you really can't leave that in so as you predicted he did go to the operating room neurosurgery took it out they did a transphenoidal approach basically there's a bone in your skull called the sphenoid bone so they went through that transphenoidal um to reach the cella that little saddle spot um and take this out now pathology comes back and it gives us this actual diagnosis which unfortunately it's benign but it is in sort of the worst possible real estate.

26:35Jordan Feigenbaum:And, you know, you're operating millimeters away from the pituitary stock between what the tumor already did and what the surgery has to do to remove it, that region can take a hit. So right after surgery, this pituitary story shows up on cue. Can't hold on to water. He's putting out liters of dilute urine. So post-op diabetes insipidus and his other pituitary hormones are off too. He ends up on thyroid hormone, cortisol hormone replacement, testosterone, and desmopressin. He's got basically what we call pan-hypopituitarism acquired, and that's the result of the surgery. So the tumor's gone. His vision problem's been addressed and gets better.

27:13Jordan Feigenbaum:His hormones are being replaced. He should be fixed, but he's not. Over the next three months, he gains another 33 pounds. His appetite is way up, as far as he reports, way up from where it was before surgery, and he says he's never full. He describes eating and just not registering any sort of feelings of fullness. But his replacement hormones are dialed in. His thyroid is replaced to Target, for example. The tumor that was pressed on everything is gone. So, Dr. Baraki, do you have any thoughts on what's going on? You know, tumor's gone. He's gaining weight faster than ever. What's up with this patient?

27:49Jordan Feigenbaum:Again, if you're playing along at home, pause now and see if you can come up with a diagnosis.

27:54Austin Baraki:Yeah, super interesting. And, you know, I know that you said this is a longer episode with a lot of twists and turns. you skipped over a lot of the fun part there when you brought up the post-op panhypopituitarism situation and managing his diabetes insipidus and things like that. That is something that I find very interesting and would have been happy to manage for this patient the use of various hormones to kind of restore normal physiology and homeostasis when the patient's pituitary is unable to do it. You hope that in some situations maybe there's some post-operative sort of stunning and things might wake back up over time, but a lot of the time that's not necessarily the case.

28:33Austin Baraki:And I've had plenty of patients over the years with very isolated types of hormonal deficiencies of their pituitary hormones or a handful of folks with pan-hypopituitarism, pan meaning like all of the pituitary hormones that are just not working due to trauma, due to surgery, resection, injury, radiation, all sorts of things affecting the pituitary gland, the pituitary stalk and the hypothalamus. And it can be really challenging. And the reason I'm spending a little bit of time talking about it is just because again, These things, when I see them and have to manage them, where it's like, oh, now I have to, or you have to take over your own physiology, it really helps you recognize how much we take for granted all of the things that our bodies do for us and make it so that we do not have to worry about these things.

29:14Austin Baraki:The most difficult of these has to do with that water regulation, the diabetes insipidus and the use of desmopressin in that patient, because there can be much more rapid and significant complications if your water balance and your blood sodium levels are thrown way off because you take too much or you take too little or you drink too much or you drink too little. And most of the time our bodies handle this for ourselves, but this is a situation where now, if this is a permanent state for the patient, they're gonna have to be closely regulating this basically for the rest of their life, which is quite challenging.

29:44Austin Baraki:So I wanted to mention that as a very interesting element of this case. Now, my prior suspicion had to do with the craniopharyngioma being associated with a syndrome of hypothalamic obesity in this patient. and it seems like his weight gain has continued to accelerate. And so there is this growing and I would say persistent and growing concern for hypothalamic obesity in this patient that despite resection of the tumor, despite cutting it out, the total function of the hypothalamus and its kind of relevant appetite and satiety modulating circuits is not normalized. Maybe they were both down in parallel.

30:22Austin Baraki:maybe there was some kind of irreversible complication that that affected that and led it to not necessarily wake up i would still be thinking and wanting to pay extra close attention again to all of those hormonal axes to make sure that you know he's not getting too much of his hydrocortisone and and things like that as as one example you know is is there some concern around the the growth hormone igf1 axis is there been some form of you know i don't know recurrence of the tumor you know serial imaging was it actually completely resected things like that so that would be kind of the first step is making sure that all of the things that we had proven and established to date have been sufficiently, you know, addressed.

30:58Austin Baraki:The remaining sort of strategies, step one, you could tell them to eat less and move more. And I say that mostly in jest because we know that that is, you know, a generally not super effective strategy in general for most folks and is definitively not going to work in this patient who has a clear, you know, secondary underlying driver of their, you know, seemingly insatiable appetite, lack of satiety, and as a result perpetual weight gain in this situation. So the remaining steps are going to be medical treatment directed at the obesity itself at this point. And so we have a few different strategies as well as, you know, consideration.

31:34Austin Baraki:If it gets to that point, I wouldn't jump to something like metabolic bariatric surgery just yet because I think that there is still likely some, you know, potentially medically treatable neurological issue here that we can address. And so those options include are some of our favorites that we talk about a lot things like glp1 receptor agonists like trisepatide being our favorite at the moment until more effective ones become more available but more specific and more unique to the syndrome of hypothalamic obesity there are sometimes more targeted agents some of these are specific to certain types of congenital syndrome so you've actually talked about some of these things on prior episodes for example when people has like congenital leptin deficiency for example there are things that can be done to address that hormonal deficiency to restore you know healthy physiologic levels and that can go a long way to addressing you know the obesity in that context i don't think that that is the underlying driver here instead the other option that i would consider is a medication called setmelanotide which is something that is used in hypothalamic obesity it is something that i did not have a great deal of experience with prior to you know getting way down further into the weeds in you know obesity care and obesity treatment i've had you know a couple patients at this point for whom it has either been deemed appropriate or for whom we are actually using it and so there are some you know trial data that medicine is called an mc4 receptor agonist and it has it is thought to have much more specificity to the management of hypothalamic obesity in general oftentimes when it is related to these types of situations when there's hypopituitarism at the same time that raises the suspicion as well there are a few other more niche treatments that i have less and less experience with and will kind of reserve comment on but i think that you know my big picture take at this point would be i want to make sure his hormones are all actually you know legitimately well managed and in a healthy spot make sure there's no recurrence of a mass or anything like that probably get him on to his appetite and then start working down the process of, hey, is this patient appropriate for the use of setmelanotide?

33:41Jordan Feigenbaum:Yeah, no, it's great. Very, very well explained. It does have acquired hypothalamic obesity. They did investigate virtually all of the hormones, again, just to verify. They did do repeat imaging. There was no recurrence. And so, yeah, at this point, you're like, okay, this does appear to be acquired hypothalamic obesity. This podcast is brought to you by ButcherBox. One thing I try to stay consistent with is keeping enough protein in the house so I don't end up ordering takeout a few times a week. That sounds simple, but between work and everything else, the grocery store trip is usually the first thing that gets cut.

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38:47Jordan Feigenbaum:And honestly, I just stopped waking up annoyed and a little sweaty. Visit www.sleep.me to get up to$255 off your ChiliPad 2.0 with code BBM. Again, that's www.sleep.me. This is available for Barbell Medicine podcast listeners for a limited time. order today and get free shipping and a 30-day sleep trial and so generally speaking we are going to get into the weeds on this a little bit later on like why this neurological circuit is so important but just briefly inside of this the hypothalamus this specialized area in the brain there are circuits of nerves some that drive hunger others that suppress that we call fullness or satiety.

39:35Jordan Feigenbaum:And so based on which one is sort of higher or lower, that's going to drive food related behaviors, either seeking food or stopping to eat, for example. Now, this tumor, this craniofaryngioma sat right on those nerve cells, right, right on that circuit and the surgery to remove it, you know, damaged that area too. So now the break was gone. Effectively, this individual was persistently hungry, persistently seeking food and yeah, unable to willpower himself out of this. So hunger was just on the whole time. Fullness never registered. And removing the tumor kind of made it worse, which is why he had additional weight gain.

40:12Jordan Feigenbaum:So what happened? They put this patient on terzepatide. At the time, setmelanotide was not approved. And unfortunately, they only followed this patient for four months afterwards. That's when the case report kind of stopped. And he was not on maximal dosage. So during this four-month interlude, he lost nine kilograms. So what is that? 19 pounds or something yeah something like that um of the 60 or so he had gained total and so you know before we move on to some of the pearls some of the takeaways here just in your opinion would you agree that although this is very complicated and you weren't you know we're not there we're not saying anything bad about these these these individuals this is just suboptimal management of uh acquired obesity uh in this case assuming he never lost any more weight he did not get back to his baseline weight, right?

41:02Jordan Feigenbaum:He only lost 20 of the 60 pounds. And so you would say, well, look, do we need to bump the terzepatide dose up? Do we need to add additional, is he a candidate for a metabolic bariatric surgery? You know, effectively to me, this is a case of, while complicated initially to diagnose and manage and whatever, the problem still kind of is there, the unmanaged obesity or insufficiently managed. I don't know, is that kind of how you feel about this? Yeah, you're right.

41:27Austin Baraki:Hard to say without being there. I think, you know, this patient took a while to show up. The first question is like taking seven months before showing up, but maybe that's speaking more to the fact that they're 21 years old than anything else and maybe had other things that they were attributing their headaches to and not worried about it until it became something that they kind of couldn't ignore because it could have been identified and addressed probably earlier along the way with some earlier presentation. And then once it was identified and addressed, on one hand, I can see maybe the clinician's perspective of, oh, the tumor was resected.

41:56Austin Baraki:This should all just melt right away on the back end. maybe but also there's also the question of should anti-obesity therapy have been initiated a bit sooner i can also see a situation where it's like hey this patient went from being 21 and previously healthy to undergoing a relatively invasive brain surgery going through his nose to take this thing out of the middle of his brain and then ending up on numerous new medicines mainly in the form of hormones afterwards he's going to be on hydrocortisone twice a day he's going to be on testosterone every week he's going to be on thyroid hormone every day he's going to be on a bunch of other you know hormone replacements and things like that you could have initiated terzepatide at that point in time but there's also the question of like you know it is an enormous amount of work to be a patient in general and it is an especially enormous amount of work to be a patient with panhypopituitarism and so maybe they said let's like let him you know get acclimated to like this new life that he has to live with all this hormone replacement see what happens with the weight maybe it will improve a little bit more spontaneously on its own before addressing it and then it's a question of like well what was the follow-up like how close of attention were they were they paying to him ultimately over the course of i think you said it was like a few months between the surgery when he gained a bit more weight and came back you know i don't think that there's going to be any like permanent lifelong consequences of him not having been put on something like trisepatide or set melanotide a little bit earlier versus a little bit later in the situation given that he's so young in the situation and with appropriate treatment could probably get back down to healthy body weight and body composition i might have gone about it slightly differently, but there's also patient related factors to consider.

43:23Austin Baraki:I would have had a conversation with him about like, look, man, this sucks. How much are you willing to do at this stage of the game? You know, or do you want us to take it step by step? And then I might've just been like, let's follow you a little bit more closely instead of coming back every few months, maybe come back or chat with me or we'll check in like every, you know, couple of weeks or something like that.

43:38Jordan Feigenbaum:Yeah. Yeah. I think it just speaks to ultimately the importance of these neurological circuits. Right. And that if those become faulty for whatever reason, you know, big trouble and little china we it's very very challenging to manage and so yeah when i read this case i was like oh twists and turns and i was waiting for the big payoff at the end it's like and we put them on terzepatide or set melanotype you know and then ultimately ended up fine unfortunately not the happy ending but i presume if this patient was followed for a long enough period of time um i suppose you know getting this kind of treatment and management is a sign that he has access to great medical care yes i agree expect a pretty good pretty good outcome yeah um but yeah Yeah.

44:17Jordan Feigenbaum:So I wanted to start off some of these takeaways with this hypothalamic sort of circuit, this neurological circuit, because we've talked about it a number of times, but I don't think we've ever kind of gone into the weeds on like, yo, what is happening in the brain? Sure. So we make this case all the time that your body weight primarily is managed at the level of the hypothalamus. You, your genes kind of decide these guardrails, a lower and upper bound, right? And your environment moves you around inside them. But what's regulating this is your hypothalamus. It sits at the base of the brain and there's a small cluster of cells in that area called the arcuate nucleus.

44:52Jordan Feigenbaum:This is positioned right where the blood brain barrier is leaky. So it sort of samples what's floating around in your blood. And there are two populations of neurons that live there and they're wired in opposition to one of another. The first makes a large protein called propiomelanocortin, POMC for short, which basically the cell chops into smaller pieces. AlphaMSH is this signal that's one of those pieces it got chopped into. It is released when these POMC neurons fire, and it travels to a neighboring region of the hypothalamus where it plugs into a receptor called MC4R. Activating MC4R reduces food-seeking behavior, food intake, so on and so forth.

45:36Jordan Feigenbaum:Now, in opposition to that, there's a second group of neurons that makes agouti-related peptide, AGRP, named after a strain of fat yellow mice that led to its discovery. So this travels to that same MC4R receptor, but instead of switching it on, it jams the lock so alpha MSH can't. Now, these neurons also silence those POMC neurons sitting next to them. So AGRP basically wins two different ways. One, they block the signal downstream by blocking that receptor and they shut up the upstream sort of neurons, ultimately increasing food intake.

46:12Austin Baraki:Yeah, it's a super interesting sets of pathways, very complex and probably not that easy to absorb through, you know, purely audio format without like a graphical image representation. And it's something that when I was kind of getting my feet wet in this space and really trying to learn it, get it down, be able to explain it, answer even test questions on it, things like that. It's like, man, how am I going to remember these things? And so I did some trial and error trying to figure out, I've never been much of a mnemonic person, but basically the neuropeptide Y, NPY, and agouti-related peptide, which is like one of my favorite named peptides in the body, just an interesting, cool name, that's one pathway.

46:46Austin Baraki:And then you said the POMC and like CART-related as the other pathway. And so I think I might've even used like Google or like an AI tool or something. I was like, help me come up with some kind of mnemonic for this. And it said, hey, NPY, neuropeptide Y, can stand for, I need pizza yesterday. And so that is the pathway that I remember as being what we call orexigenic, meaning it promotes, you know, appetite, food-seeking behavior. And then you just remember that the other one's the other one. And so that made it much easier for me to keep these straight in my mind.

47:15Jordan Feigenbaum:Yeah, I like that. It's important to note that these aren't subtle effects. If you switch on these agouti-related peptide neurons in a mouse that just finished a meal, it starts eating again almost immediately. If you switch them off in a starving mouse, it'll walk past the food. In humans, loss of function mutations in the MC4R, that receptor, as the most common single gene cause of obesity we know of. You know, somebody listening in the audience might say, well, what about leptin? I hear about leptin all the time. What the heck? We've talked about this a number of times on the podcast, but this is also one of the hormones that the arcuate nucleus is sampling in that leaky blood brain barrier.

47:56Jordan Feigenbaum:As you know, fat tissue releases leptin roughly in proportion to how much fat you carry. More body fat, more leptin, less body fat, less leptin. The brain mainly treats it though as a low fuel alarm, meaning that if you do not have substantive stores of body fat and you have a low leptin level, the brain picks it up and say, yo, we don't have enough energy on hand, you should eat. And so when leptin falls, the brain picks that up at those specialized cells and the agouti-related peptide neurons fire harder p-o-m-c neurons go quiet hunger climbs and the body throttles back energy expenditure reproductive function so on and so forth that's why you can also get hypogonadism as a result of this leptin going up though from an individual with high body fat does not produce the mirror image so somebody carrying around a lot of body fat has high leptin all day and they're not walking around full um there was a thought that well this just means they're resistant to the leptin signal as it turns out that doesn't appear to be the case, you can give these people, you can flood their system with leptin and nothing happens still.

49:00Jordan Feigenbaum:Effectively, it's just not an effective like satiating hormone, so to speak. That's not really where the efforts are. Unfortunately, it'd been nice if that were the case, but it just doesn't seem to work that way. So to summarize, there are two opposing sets of neurons. The break is these POMC neurons. They make alpha MSH, which lands on this MC4R receptor. and the message is to stop eating and burn energy. The accelerator is the AGRP, the agouti-related peptide neurons and their message is to get hungry and conserve energy. Don't be as active. Leptin is a minor player here unless it's low, in which case it says, hey, look, you should eat some more.

49:41Jordan Feigenbaum:But you don't get a vote in any of this. None of this is something you can control. And so I do wonder when I see the message, hey, you just have to know about your hormones. are these the neuroendocrine hormones that they're talking about because i i suspect not uh you break any single piece of this chain though you're gonna get the same result uh relentless hunger and obesity that can start in childhood uh and these have a bunch of different name diseases so for example in leptin deficiency super low levels almost non-existent levels of leptin kids are ravenously hungry every waking minute and they get a relatively uh profound obesity in when they're toddlers, but you got to give them leptin back.

50:20Jordan Feigenbaum:Usually metroleptin is the treatment. Hunger switches off. The weight comes down, stays down as long as they're on the, on the treatment. In POMC deficiency, you get obesity, uh, interestingly red hair, because it seems to be associated with that and adrenal failure. Those are little glands that sit on top of the kidneys, make cortisol and a number of other very important hormones. Um, because again, this hormone was doing multiple jobs, right? MC4R, uh, is the most common single gene, uh, obesity cause about one in 20 severe childhood cases. And we'll come back to that later. So Austin, there's a lot of different models here, all of them related to sort of the neurological function and its management or effect on body weight regulation.

50:59Jordan Feigenbaum:How do you think these models or do you think these models of obesity help in explaining obesity, maybe as you called common obesity, and or like how to manage it? Do you think these are useful?

51:11Austin Baraki:I think they are useful to get a sense that there are underlying mechanisms at play and those underlying mechanisms can be deranged to varying degrees. And so, for example, if somebody has an outright deficiency of one of one of these things, that's like the most extreme state. right and so that's a an example you mentioned like the monogenic etiologies of obesity where there is everything is okay except this one gene that has a mutation or a defect in some way and then it reliably leads to the kind of resultant phenotype of unchecked you know hyperphagia uncontrolled eating and weight gain just due to that one gene and if you target treatment to that one gene, then suddenly the whole syndrome kind of reverses, weight loss results, and healthy body weight can be restored to a great deal.

52:03Austin Baraki:That is a very compelling, very direct causal sort of scenario. That is unfortunately not what we end up seeing in all cases of obesity, because more generally speaking, it is much more often a polygenic sort of situation. It is not a single gene that is causing it, but rather kind of like a perfect storm of much more subtle minor kind of changes or variations in many, many, many, many different genes, not just a single severe genetic derangement. And so then you have this combination of more minor deviations or alterations in numerous genes set in our modern environment that then unleashes the downstream phenotype that we end up seeing in practice.

52:50Austin Baraki:But they are not wholly distinct things in the sense that, oh, well, if there's a monogenic form, it's just this one gene and it's out of their quote-unquote control. But anyone else who has quote-unquote common obesity, they are just quote-unquote choosing it. That is not an accurate way to, you know, derive a conclusion here. It's just that there is a varying degree of function that can emerge from these different genetic variations between people. And so then it's just a result of, again, that perfect storm of many genes. And, you know, we'll throw back for folks for whom this is kind of a novel argument.

53:24Austin Baraki:This is actually not a novel argument. It's been around quite a while. And there's some really actually quite accessible material out there if you're interested in learning more about it. Going back to Dr. Stefan Guilene's book called The Hungry Brain that we have talked about at length in the past, going back years, and his research even went back, well, you know, has roots decades ago where people have been working this out. And you can see that even in, you know, what we'll call common obesity, that a huge proportion of the kind of phenotype that results, the experience, the results of obesity in that situation can be clearly related to a wide variety of genes, mostly those regulating appetite in the brain.

54:05Austin Baraki:Many, many, many fewer of the genes at play or that have been implicated are kind of more in the periphery. And this is a contentious argument in the space sometimes people who have been much more for example in the in the low carb community have argued that it really is much more related to the function of fat cells and things like that which if that were true then there would be a variety of you know downstream predictions and implications that have not really panned out in practice and so when we see that the vast majority of the genetic kind of relationships and explanatory power has to do with genetic variations and function in the brain and appetite regulation that is what has really honed us in on this It's just that these monogenic forms that you're describing are the most extreme, most severe versions of this that are completely uncheckable through any degree of choice or willpower or anything unless they're directly treated.

54:51Austin Baraki:Whereas the more polygenic forms, there's a lot more variation and heterogeneity. Some people are able to, quote unquote, check it on their own, whereas others need more help.

55:01Jordan Feigenbaum:Yeah. Yeah, well said. But, you know, it is possible that there are, you know, pleiotropic effects of some of these genetic differences between individuals where like, okay, these areas of the brain are primarily involved in not only weight regulation, but also hunger, satiety, but also maybe in various responses to the environment, you know, that some people would call willpower related to food related behaviors. both of these things can be true but i think where we come back to is that all of this is suggesting that the conscious level choices that happen at the dinner table at the you know in the kitchen at the you know when you're out to eat or whatever are not really as conscious as you you would otherwise expect there's just many layers of input that are going on under the hood and trying to white knuckle it through that is probably not the way to do it now here's an interesting thing.

55:54Jordan Feigenbaum:GLP-1 drugs still worked on this patient despite apparently his pituitary gland, much of it being removed, other sort of trauma to those levels of the brain. And I thought that was pretty interesting. I'm like, look, if this guy had a problem previously at the area that we think these drugs work, how in the heck did he respond to terzepatide, for example? Because we know that these GLP-1 drugs, semaglutide and the dual agonist terzepatide all work on the circuit that we've been describing. They reach into the arcuate nucleus, into the brainstem, and they push the same POMC brake and they quiet the accelerator.

56:32Jordan Feigenbaum:They don't really rev up the metabolism. They don't increase the amount of calories you're burning. Ritatratide appears to do that on some level. That said, this guy's pituitary gland and part of his hypothalamus were apparently pickled yet it still worked so there are some additional receptors there's kind of a backdoor way into the circuit through the brain stem that appears to be preserved which seems to be the way that worked on this patient but so even when the injury sort of to the area we can still access it through the through these medications which kind of just speaks to how powerful they can be do you have any experience with that in your practice with people who you know, maybe take these medications and they don't really work.

57:16Jordan Feigenbaum:And do you, does that make you go searching for some sort of other reason or you're just more concerned with the management? You're like, okay, well, what do we do now? Or maybe a little bit of both.

57:23Austin Baraki:Yeah, it is a little bit of both. As you know, as an internist, of course, I can't help but maintain a broad differential in these situations. We've talked about in a lot of contexts how you apply any intervention to a biological organism like a human, and you're going to see a variety of responses. It could be getting a group of 100 people and putting them on a training program, and you're going to see some people have huge results, some people below average results, and then a lot of people, you know, somewhere in between. And that's not that different than what we see when we put people on GLP-1 receptor agonists.

57:53Austin Baraki:I have plenty of patients who are hyper responders. I think I had one patient recently who, you know, they've been on terzepatide. They've only ever used like 2.5 milligrams, which is the lowest starting dose, and they've lost like 36 % of their starting body weight. That is beyond above average, right very very very uncommon certainly not an expectation that i set uh for for people that this is like a realistic outcome and probably not even one that they expected but some result of their susceptibility to the effects of this medicine combined with their lifestyle habits and many other things set them up for that degree of success meanwhile i have other patients who get up to the maximum dose of trisepatide at 15 milligrams for example and even with excellent lifestyle habits they're still having a tough time and telling me doc i'm still hungry and what else can we do can we try some combination therapies can I get enrolled in a clinical trial for RETA at this point which I'm trying to refer people to see if they're eligible for you know those types of studies with RETA or with Alora Lintide and things like that as next generation kind of promising agents and so there is this baseline heterogeneity in response that we expect to see of course I will tinker with how are we taking it you know what are the what are the underlying habits that we're using to to support it is our dosing reasonable is there anything else going on that could be holding us back?

59:04Austin Baraki:Are you also on other medicines, for example, that can be promoting of appetite and weight gain? There are many of those medicines, particularly a lot of psychiatric medicines that can sometimes contribute to weight gain and other things that I might try to adjust. And then lastly, if there are some suspicious elements based on their history or their comorbid conditions that might start to raise suspicion of could this patient have one of these underlying genetic syndromes? How far back in their life does this go? Could this have been something congenital that's been missed this whole time. Again, that is much tougher to tease apart.

59:34Austin Baraki:It's not easy evaluation to do. It does definitely require some specialized expertise in a lot of situations. But I start to look for, are there any of these other kind of syndromic features? Because there are the monogenic forms that you described that have pretty clear-cut sorts of phenotypic features that we expect. There are not necessarily monogenic, but still what are called syndromic forms of obesity. And those, there are a whole bunch of those. And unfortunately for, you know, me, those are things that I've had to relearn because I threw out most of my pediatrics knowledge after getting through school and entering, you know, internal medicine residency where I only handled adults.

1:00:10Austin Baraki:But it's part of the knowledge base for this field that I'm having to kind of refresh because it is relevant if somebody gets missed and doesn't get diagnosed until later in life. So that's kind of the spectrum as I think about the intervention, knowing there's some baseline heterogeneity? What are the rest of the habits around it? Are there any meds that are holding them back or other things that are preventing them from being able to have success? And then are there any signs of either a syndromic ideology or a potential genetic contribution that needs to be addressed? Of course, in the last one, this is actually the patient that I alluded to recently that I've seen who does have evidence of hypopituitarism.

1:00:42Austin Baraki:And so then it's like, okay, well, does a hypo response to something like terzepatide now mean that we actually ought to pursue set melanotide for a patient like this because they are not having the response that we're looking for and if there is a suspicion or possibility they could have acquired hypothalamic obesity maybe we need to step up the therapy to address things more directly that way which is

1:01:00Jordan Feigenbaum:what we're doing right now yeah that's a great segue into the next part of this let's go back to that break for for a second the pomc uh neurons that make this alpha msh alpha msh again presses on this mc for our receptor and that's your stop eating signal now what if there was a medication that directly interacted with that MC4R, that receptor, so effectively that your stop eating signal would be activated as long as you were taking that drug. Sounds like me, like cheating. Well, I guess that some people might say that, but satin melanotide is a drug that does exactly that. It skips the whole potentially broken section of the circuit, pushes on the brake pedal itself.

1:01:43Jordan Feigenbaum:And you've talked about this before, But when people have this sort of acquired hypothalamic obesity, we don't really have good medications for a long time. And up until recently, you know, it's look, you got to diet harder. You have to exercise more. You can take some of these other medications. But look, if that circuitry upstream isn't functioning correctly, it's like we don't really have much for you here. Right. And then came Transcend. transcends a phase three trial, 142 patients with acquired hypothalamic obesity, ages four and up. I don't know if anybody was telling a four-year-old, like, you just got to try harder.

1:02:19Jordan Feigenbaum:Good luck. Now, over one year, BMI dropped by about 16 % on the drug and it rose by about 3 % on the placebo. That's a pretty big swing against placebo and their hunger followed that as well. In a disease where diet and exercise basically doesn't change anything, this is a pretty big result. Now there are some side effects here. One in five patients had their skin darkened because the receptor of this drug hits also controls skin pigment to some degree. Nausea, vomiting, headaches were also some of the side effects reported on top of that. It's also a daily injection at this particular time. And while it does press the brake, it doesn't necessarily repair the whole circuit.

1:02:59Jordan Feigenbaum:So you basically have to take it indefinitely. Now, setmelanotide is not a new drug. It's been FDA approved since late 2020, but back then it was only for the rare single gene forms of obesity like POMC deficiency, PCSK1 deficiency, and leptin receptor deficiency. Now what's new this year is in March, the acquired hypothalamic obesity indication got FDA approved. And that is the exact situation our patient was in. So this isn't a brand new drug or molecule. We already had it for the congenital forms and this year just got approved for the acquired one, but it's still the only MC4R agonist on the market.

1:03:35Jordan Feigenbaum:Our patient came along before that approval, so he got terzepatide instead and, again, lost about 9 kilograms, roughly 6 % of his body weight. And, again, that follow-up was also limited, so unclear how well he did after that. But setmelanotide would have been great for this patient. Do you have patients right now on setmelanotide? Is that something you're working with?

1:03:53Austin Baraki:That's what I was just alluding to, is having one patient actively were trying to get on it because they have panhypopituitarism and there's a suspicion for acquired hypothalamic obesity. And I previously worked with one patient who was on it, but they're no longer following with them anymore at this point. Yeah, so not a super common thing. What's the cost of this thing?

1:04:09Jordan Feigenbaum:Is it crazy expensive? It sounds expensive.

1:04:12Austin Baraki:Yeah, this is a situation where it's going to be through insurance coverage and you have to fight a lot of battles to get it done. And so the ultimate cost is not directly borne by the patient, I suspect. And you know how much price distortion there can be when working through the insurance system. So I am not actually aware of what would the straight-up cash pay price of this medication be. I suspect it is high.

1:04:29Jordan Feigenbaum:Yeah, per vial cash price appears to be$3 ,300 to$3 ,700 for a one mil subcutaneous vial. Estimated annual cost is about$300 ,000 for pediatric patients and$440 ,000 a year based on for adults.

1:04:45Austin Baraki:that tracks for, you know, new therapies like this. I think it's one of those areas that's costs are insane. That's unfortunate, but inevitably going to come down as this field advances as, you know, it takes me back. You know, you mentioned that it's like a once daily injection has more intolerability, maybe decent efficacy, but not ideal efficacy. If you just rewind, take us back to 2005 when Xenotide was approved, you know, the original GLP-1 agonist that was used for diabetes, twice a day injection, right? not super great efficacy for a lot of the things we now clearly care about. And then over the subsequent 20 years, went from a twice-a-day injection that was mediocre to now we have once-a-week injections that are fantastic and coming up soon, likely to be a once-a-month injection that is currently in later-stage clinical trials.

1:05:31Austin Baraki:So this field is just likely to continue advancing and get better and better, particularly at addressing these underlying mechanisms. And maybe even, it will be nice, is if some evidence pans out where we can have a better way to identify almost like people's unique mechanisms of obesity? Because I mentioned like there's the common obesity, it's like this hand-wavy, polygenic sort of thing. What explains why some people respond better or worse to GLP-1 agonists? What explains why patients with diabetes lose less weight on GLP-1 agonists compared with those without diabetes? All these sorts of things.

1:06:04Austin Baraki:I know that the whole idea of quote-unquote precision medicine is controversial and is not something that's really panned out too well in most of medicine so far, although if anywhere it has in oncology where they do like specific genetic testing of people's tumors and might select particular chemotherapies as a result, this is a situation where, for example, I can envision a scenario where if we did have some biomarker way in the future to assess, oh, this person's obesity is being, their degree of function along this appetite signaling pathway is normal, whereas this other pathway is less normal.

1:06:38Austin Baraki:Maybe we'll have tools to better target those so that we could turn more hyporesponders into hyper responders, which would be awesome.

1:06:44Jordan Feigenbaum:That'd be great. Which brings us to a little prelude for an upcoming episode. And this kind of ties our entire series together. Why are we so worried about body fat in the first place? Right, this patient came in primarily complaining about headaches, fixed that problem. And now we've been focused on the whole back half of this podcast on his body fat. Why is he persistently carrying too much body fat? And what does that even mean? and you and I have kind of wrapped about an analogy here and so we're gonna debut it here on the Barbell Medicine Podcast here and we'll have a whole episode about this upcoming.

1:07:21Jordan Feigenbaum:The thought here is that your body fat tissue is effectively a garage. Its job is safe storage, keeping the surplus energy out of the house. Now how big that garage is, it gets mostly set before you're born. Some people have a double garage and some people have a shed. Some people have no storage at all. Now, whatever doesn't fit in that garage spills over into the house and it goes to the liver first, then to the pancreas, then the muscle, then the space around the heart, now around the kidney we're discovering. You can think of these as boxes stacked on the stairs that break your neck when you trip down them and trip over them, not the ones neatly parked in the garage.

1:08:03Jordan Feigenbaum:Now, some people are born with essentially no garage, a condition called lipodystrophy. And they get diabetes very young, even though they're lean, very lean in some cases. And people who carry genes for a bigger garage hold more fat and get less disease, not more. Visceral fat, which we've talked about a number of times on this podcast, this is the fat that's around your internal organs. It is dangerous. It's a real warning sign, but it is a downstream of sort of this storage problem. So you can think of it as conferring some risk for sure, but also as an indicator that something else is a problem upstream and it's a storage issue.

1:08:41Jordan Feigenbaum:You can't fix it by cutting it out. Surgeons have tried to do this. Nothing really improves. Liposuction has also tried to remove the fat physically. Nothing improves. You can vacuum 20 pounds of it off a person with liposuction and the metabolic health doesn't really change at all. Now, the hopeful part here is that if you get the fat out of the organs, you reduce the visceral fat, sometimes you can get improvements like diabetes remission, for example. This also happens with substantial weight loss, including individuals taking these GLP-1s. But the main problem here still is storage, right?

1:09:17Jordan Feigenbaum:And so we're kind of coming back to this. Why is body fat? Why are we focused on this? And what's the real problem? it's not necessarily the amount of body fat and it's not necessarily just the distribution it's more of do you have a fat storage problem are you running out of room right and that kind of goes back to well how much could you store this sort of idea of a personal body fat threshold something that doesn't exceed your storage and if it does now we're more concerned with the flux what is happening in and out of that storage that you're kind of overdone. Does that kind of make sense to you the way we're describing it?

1:09:57Jordan Feigenbaum:We're workshopping this analogy here a little bit, but that's kind of the way I'm thinking about it at present.

1:10:01Austin Baraki:Yeah, I think you summarized our behind the scenes conversations pretty well and then tying it up towards the end there with that term flux, which might be a term that maybe some folks are not quite as familiar with, but it basically describes the flow of energy through the system. and this is something that has a lot of relevance in other areas as well for example in blood lipid metabolism the flux of lipids through your system as they pass through that's part of the reason why snapshot blood tests for example have limited ability to give you a full picture of this kind of thing similarly when you look at well-trained ultra endurance athletes for example and you do some muscle biopsies on them they actually have a fair amount of what's called intra-myocellular triglyceride fat stores in their muscles.

1:10:47Austin Baraki:And you might say, what I don't understand. These folks are, you know, in many cases, extremely healthy, insulin sensitive, no, not a hint of, of, you know, blood sugar issues or type two diabetes or anything yet they have fat in their muscles that might otherwise make me think that they have some, you know, storage problem might be unhealthy or something like that. Well, there are some adaptive mechanisms to where that might actually be useful for their muscular function, but also the key difference is going to be an aspect of flux for those who are you know insufficiently physically active or completely inactive for whom the body fat is spilling over from those healthier subcutaneous areas around the legs and hips to less healthy areas the viscera the liver the pancreas and into the muscles yet there is no meaningful flux it's accumulating but it's not being used it's not passing through it doesn't have a purpose in that way then that is what can significantly lead to the downstream accumulation of downstream metabolites and inflammation that worsens insulin resistance, leads to type two diabetes and all the complications that we're hoping to avoid, the things that I hope to avoid, but unfortunately see very often in the hospital setting and things like that.

1:11:53Austin Baraki:And so the idea of like, well, okay, so we're talking about flux. What does that mean for me? What needs to happen to improve that flux? Well, this stuff needs to move through the system at a more rapid clip. And I'll maybe hand off the mic and let you describe what does it mean to get this stuff moving through the system at a more rapid clip in addition to potentially modifying the total amount

1:12:13Jordan Feigenbaum:in the system as well yeah i think that's the the major thing you know when it kind of leads to this philosophical discussion like what does obesity even mean if we just say look it's excess body fat that causes harm or a little reductionist there but like you try to simplify you're like what does excess body fat actually mean it's like all right well it has to be beyond what your garage can store. And now because your garage is overflowing, you have this flux of fat out. And unless it is turning over rapidly, it can be, uh, can sit there and do harm. That's the easiest way I figured out how to describe it.

1:12:48Jordan Feigenbaum:So what would you do to increase the turnover? Exercise is probably the number one lever that we have. GLP one medications, those sorts of medications also tend to increase this mostly by limiting energy in. And so now by default, you're going to have a higher turnover. And the interesting thing, and maybe a better explanation of why we see some of these, I call, I think about them as like discordant sort of health benefits from GLP-1s. People think about the main health benefits come from the weight loss, but a lot of them start before the weight has even been lost. And you're like, well, how the heck does that turn up?

1:13:20Jordan Feigenbaum:And it's like, well, not only are there GLP-1 receptors in these other tissues that seem to have some sort of benefit, but also because you've affected the flux. And once that flux has changed in your favor, where the fat is being turned over and moved around the body more efficiently, it has less time to do its dirty work just sitting in the tissue. And so if we can move that flux, exercise, GLP-1s, and in many cases, other lifestyle changes like calorie restriction, if somebody could stick to that for a period of time, all is well. And so, yeah, this deserves a full episode because, again, I think when folks think about obesity, they have a picture in their brain, and then it's just too much body fat.

1:14:01Jordan Feigenbaum:And it's like, well, that's kind of true, but also not quite specific enough for our liking. It's not just too much body fat. It's too much body fat for a particular individual. And because it has outstripped their ability to store it in a safe way where it doesn't leak out and do harmful things. The real problem here is basically flux. And we're gonna get into that in a future podcast. Anything else before we sign off here, Dr. B?

1:14:30Austin Baraki:No, been a little while since we did a mystery case. I enjoyed it as always. I think that to the extent we're acquiring new listeners, if you enjoyed going through that journey together, go back in the backlog. There's plenty of other very fun and interesting mystery cases that we work through to teach other interesting topics along the way. So check them out.

1:14:48Jordan Feigenbaum:Yeah. All right. Well, that is a wrap on the Barbell Medicine podcast, Mystery Medical Case, the man who couldn't stop gaining weight. Before you guys go anywhere, please leave us a five-star rating and a review. It really helps drive traffic to our podcast so we can keep bringing you all the latest nuance in health and fitness. For everyone at Barbell Medicine, I'm Dr. Jordan Feigenbaum. That's Dr. Austin Baraki. We'll catch you next week and every week right here on the Barbell Medicine podcast.

1:15:19I'll see you next week.