[SPEAKER_01]: The patient is a 21-year-old male.
[SPEAKER_01]: He comes into the clinic for headaches, seven months of him, but he's otherwise healthy.
[SPEAKER_01]: And somewhere in the months after that, he starts gaining weight and it won't stop.
[SPEAKER_01]: 30 something pounds gained in a single season, but he's eating the way that he was told to, and he's staying active.
[SPEAKER_01]: The scale goes up anyway.
[SPEAKER_01]: Now, by the time we catch up with him, he's on four different hormones just to keep his body running, and his own doctors can't slow down the weight gain.
[SPEAKER_01]: Now, you already know, in your own body that you can't decide to be less hungry, not really, at least not any more than you can decide to be less thirsty.
[SPEAKER_01]: This is a case about what happens when that machinery, the part that runs your weight without asking, gets broken.
[SPEAKER_01]: And it's a good one, because for almost the whole time we've known about this, it was a life sentence.
[SPEAKER_01]: Diet didn't do anything, exercise doesn't do anything.
[SPEAKER_01]: Then this year, for the first time, a drug was developed and it did something that nobody had ever done before.
[SPEAKER_01]: We haven't done a medical mystery case like this in a long time, but this is a real case.
[SPEAKER_01]: It's published in the scientific literature, and I'm going to feed it to Dr. Barackie the way he'd catch up with it on a consult.
[SPEAKER_01]: One piece at a time, he's got to crack it with nothing but what I give to him.
[SPEAKER_01]: Same as you at home.
[SPEAKER_01]: This is the last episode in a series.
[SPEAKER_01]: We start with Will Power where your weight turned out to be a system just doing its job instead of a grade on your character or morality.
[SPEAKER_01]: We talked about calories in and calories out, where the equation is always true, but almost useless at the same time.
[SPEAKER_01]: We did a deep dive on protein, where there are a number of real mechanisms that have gotten turned into frightening conclusions, but the data doesn't really back up the outcomes that were suggested.
[SPEAKER_01]: And today, we're gonna close it with the medical mystery case.
[SPEAKER_01]: Again, this is a real medical case and it's for edgy attainment purposes only.
[SPEAKER_01]: I'm Dr. Jordan Feigenbaum, and this is the part of a medicine podcast.
[SPEAKER_01]: And with me as always, it's the second most handsome doctor in North America, Dr. Austin Baraki.
[SPEAKER_01]: All right, here's the deal today, Dr. Baraki.
[SPEAKER_01]: I'm not going to tell you a single thing about this case in advance, which I understand is your favorite way to work, walk an encode while I sit there holding the entire case, my hand.
[SPEAKER_01]: The audience is going to listen and watch if you're on YouTube or whatever and see if you still got it.
[SPEAKER_01]: If you get it, you look brilliant, but if you don't, well, that's content too.
[SPEAKER_01]: I'm going to give you
[SPEAKER_01]: I'm going to be 50, 50 odds, mainly because there are going to be multiple diagnoses and that figure, you know, you got to get at least one of them.
[SPEAKER_00]: So, these things are complicated, I've volunteered to put myself in the hot seat for these, I feel like my batting average over time, kind of speaks for itself, but, you know, no one bats a thousand for the whole career, so let's see if it happens.
[SPEAKER_01]: Is that a, yeah, was I just like a, you could have just said scoreboard, so, all right.
[SPEAKER_01]: So here's the case.
[SPEAKER_01]: It's a 21 year old male, previously healthy.
[SPEAKER_01]: He presents because for about seven months he's had headaches and weight gain.
[SPEAKER_01]: Now the headache he describes is dull, steady pressure like pretty much all over his head.
[SPEAKER_01]: It's not throbbing and it's not one side.
[SPEAKER_01]: It started about seven months ago and he's never been a headache guy and it's been slowly getting worse.
[SPEAKER_01]: More frequent and more painful.
[SPEAKER_01]: The mornings are the worst.
[SPEAKER_01]: Sometimes they wake him from sleep and they get worse when he bends over coughs or strains.
[SPEAKER_01]: He has a little nausea in the morning, but no vomiting.
[SPEAKER_01]: And over the counter painkillers kind of take the edge off, like Tylenol for example, but doesn't otherwise touch it.
[SPEAKER_01]: He denies any sort of head injury or recent trauma.
[SPEAKER_01]: And over the same period of time, his noticed his weight has been creeping up.
[SPEAKER_01]: He's gained roughly 35 to 40 pounds over the past year and a half.
[SPEAKER_01]: It's come on gradually, so he can't point to anything that really explains it.
[SPEAKER_01]: He says it's eating and his exercise routine hasn't really changed.
[SPEAKER_01]: If anything, he's done more exercise in the past few months.
[SPEAKER_01]: But he's now up to around 275 pounds and his BMI is 35.
[SPEAKER_01]: So that's what brings them into the office, new headaches that won't quit and wait that he can't explain.
[SPEAKER_01]: Dr. Baraki, what is your one-liner on this patient?
[SPEAKER_01]: Give it a little summary, and if you're playing along at home, if you're a medical mystery case enthusiast you pause it here, give you your one-liner and explanation for this patient, and then tune back in to see what Dr. Baraki says.
[SPEAKER_00]: Perfect.
[SPEAKER_00]: Yeah.
[SPEAKER_00]: Thanks.
[SPEAKER_00]: So I was jotting down some notes as you were speaking.
[SPEAKER_00]: So it sounds like we have a 21 year old, you know, previously healthy male with seven months of sounded like maybe progressive generalized headaches that are worst in the mornings associated with some nausea no vomiting and progressive waking over that period of time on the order of about 40 pounds.
[SPEAKER_00]: Those are kind of the more salient elements of the case.
[SPEAKER_00]: I'm going to kind of take them.
[SPEAKER_00]: piece by piece at first to kind of keep things straight and organize.
[SPEAKER_00]: And then we over the subsequent kind of analysis will try to see if we can piece it together in a way that that makes sense.
[SPEAKER_00]: I think that one of the mistakes that sometimes happens a lot and I see this with students and trainees.
[SPEAKER_00]: when we're seeing patients with multiple concerns, or multiple abnormal findings, is immediately jumping to trying to tie them together with one explanation.
[SPEAKER_00]: Everybody loves, you know, a good ockham's razor sort of situation where we can try to explain everything with one nice neat tidy explanation.
[SPEAKER_00]: But there is also the the corollary to that in medicine where essentially we say that people can have multiple diagnoses and we see that all the time, so it's not always the case that we have one single explanation.
[SPEAKER_00]: Two things can be true.
[SPEAKER_00]: Yes, this is true.
[SPEAKER_00]: This is true.
[SPEAKER_00]: So I'll start with the headaches and so headaches are a very common sort of experience.
[SPEAKER_00]: We generally break these down into the.
[SPEAKER_00]: set of so-called primary headaches syndromes.
[SPEAKER_00]: These are things that most people experience, like tension headaches or migraine type syndromes.
[SPEAKER_00]: But there are also features of headache presentations and symptoms that can start to raise concern for what we call secondary headaches, meaning a headache that is being caused by something else that is kind of organic identifiable.
[SPEAKER_00]: kind of like when we talk about patients who have back pain, there's the more generalized, like, quote, unquote, non-specific back pain, you can think about attention headache kind of similar to that, and then we have types of back pain syndromes that are much more specific due to a tumor in the spine, for example, in the same way that you can have a secondary headache due to a tumor in the brain.
[SPEAKER_00]: And so the way that I tend to break down once I'm in this territory of possible secondary headache syndromes are things that are, you know,
[SPEAKER_00]: What we call in the in the head skull like what are the parts of the brain that can potentially hurt?
[SPEAKER_00]: And so we have things like the eyes, the ears, the sinuses, the nose, the teeth.
[SPEAKER_00]: These are all things outside of the cranial vault that can cause pain.
[SPEAKER_00]: So you might have had a headache from, you know, prolonged eye strain, or you can have a headache from glaucoma, or you can have a headache from, you know, a bad sinus issue or a fracture in the in the face or, you know, a gentle problem,
[SPEAKER_00]: you know, into your gums or something like that.
[SPEAKER_00]: So those are things outside the cranial vault that can cause pain as well as the neck.
[SPEAKER_00]: And then within the brain, I think about what are all the parts that are within there.
[SPEAKER_00]: So there's the the the meninges.
[SPEAKER_00]: So patients have meningitis can have
[SPEAKER_00]: You know, headaches, there are, there's the actual, what we call the perancoma, the actual brain itself where you can have a mass in the brain and abscess in the brain, things like that.
[SPEAKER_00]: And then there are the ventricles that contain the fluid, the cerebral spinal fluid.
[SPEAKER_00]: And that's where we can have issues with high pressure in that fluid that can cause pain, as well as low pressure, can also cause pain in that sort of situation.
[SPEAKER_00]: And then lastly, there are the blood vessels and the blood vessels going to,
[SPEAKER_00]: the head, and so there are certain types of headaches that can emerge when patients have things like vascularitis of certain kinds.
[SPEAKER_00]: That's an abbreviated set of just what are all the parts of the head and neck that can potentially have some notice-septiv experience leading to pain.
[SPEAKER_00]: And then there's also kind of interesting ways that you can get a headache, totally unrelated,
[SPEAKER_00]: it to your head itself.
[SPEAKER_00]: These are things, for example, like caffeine withdrawal, having obstructive sleep bacteria.
[SPEAKER_00]: Certain medicines like being on nitrate medicines that are used for chest pain, for example, and certain other medicines that can cause headaches.
[SPEAKER_00]: These are like, there's no identifiable thing in or around.
[SPEAKER_00]: the head or the neck that can cause that explains the pain, yet it is still seemingly localized in or of pain to the head.
[SPEAKER_00]: So these are some of the things that I'm thinking about.
[SPEAKER_00]: Now when I hone in a little bit more on the specific description that this patient is having pain that is worst in the mornings associated with some nausea, worse with straining, things like that, these are all things that are kind of evocative of a pressure mediated phenomenon.
[SPEAKER_00]: The idea of
[SPEAKER_00]: elevated intracranial pressure being worst in the mornings, for example, is I think attributable.
[SPEAKER_00]: This is at least one of the the the tails that are passed down throughout medicine.
[SPEAKER_00]: This is not something that I had personally verified, but after a long night spent lying flat and the pressure kind of ends up going a little bit more to your head and then it ends up leading to it being worst in the mornings and then it improves over the course of the day when you're a little bit more upright.
[SPEAKER_00]: And maybe gravity is pulling a little bit more out of that territory in terms of the pressure distribution.
[SPEAKER_00]: So I am certainly concerned about a situation where we have, may have some elevated intra-cranial pressure that can come again from things like masses in the brain.
[SPEAKER_00]: tumors as well as elevations in pressure in the cerebral spinal fluid itself.
[SPEAKER_00]: So I'm currently already thinking ahead, you know, this is a patient who does not have what looks to me like a general like a primary headache syndrome.
[SPEAKER_00]: Once we're in secondary headache territory, what are the tools that I might use to investigate this?
[SPEAKER_00]: He's probably headed towards some form of neuroimaging to look for, for example, a brain mass of some kind, and then second and then then the other option to assess intercranial pressure specifically in that fluid
[SPEAKER_00]: and when we do a lumbar puncture on patients, we have a little monometer that I can hook up to the needle and then measure the pressure that way and potentially remove fluid to help to lower that pressure in certain situations.
[SPEAKER_00]: So that's kind of some of the next steps that I'm envisioning for this patient with respect to his.
[SPEAKER_00]: headache as long as I've also, you know, thought about and ask questions about those other those other things that I listed as possibilities.
[SPEAKER_00]: The other aspect relating to his weight gain is very interesting because if this was a 21-year-old previously, you know, healthy, lean, active, you know, no issues in this regard and then over the course of this same contemporaneous period of seven months, gaining 40 pounds abruptly, pretty unusual, you know, certainly
[SPEAKER_00]: a lot of folks out there have challenges with their weight, work with them every day.
[SPEAKER_00]: This is not the prototypical sort of story that I see, unless it was preceded by some major change in life circumstances that led to substantial changes in subsequent behaviors or something like that.
[SPEAKER_00]: This is also a situation where we can have so-called common obesity, the polygenic environmental mismatch that we talk about all the time, versus is this like a morbid?
[SPEAKER_00]: secondary obesity sort of situation situation where there is some actual clear identifiable trigger or cause for this sort of thing to develop.
[SPEAKER_00]: You know, these sorts of things range from congenital syndromes with our genetic issues.
[SPEAKER_00]: that people can be born with, leading to the development of obesity very early in childhood, or there can be kind of subsequent acquired issues throughout life that can contribute to, you know, arrangements, let's say, in appetite, satiety, signaling, things like that among other things that can rapidly predispose to increases in body weight and body fat levels.
[SPEAKER_00]: So then that brings me to the last part, which would be what's the overlap between these two things.
[SPEAKER_00]: Well, as we've talked about a ton before, there are a lot of very important circuits in the brain that relate to signaling things like appetite and satiety and our food seeking behaviors and things like that.
[SPEAKER_00]: Could there be some overlap here in the sense that whatever is causing his headache be at a mass lesion, for example, if he has a tumor of some sort, somewhere in his brain, in a very critical area related to his appetite regulation or his satiety signaling or things like that, which tend to be oftentimes localized.
[SPEAKER_00]: around the, you know, hypothalamic sort of pituitary sort of region of the brain.
[SPEAKER_00]: Very sub-cortical regions, again sub-cortical meaning like, kind of, you can oversimplify it and say, yeah, those are more of our sub-conscious areas, but there are also other areas of the brain that could be involved here as well, that are either directly impacting the function of those circuits or contributing to other issues, for example, you know, cushions, disease or something like that, that could be, that could be going on.
[SPEAKER_00]: So,
[SPEAKER_00]: Overall, that's kind of the first pass that I'm taking here.
[SPEAKER_00]: The next steps on him would be doing an examination, looking to see have, for example, other neurological signs on exam that would help me to localize, you know, could there be a mass that is impacting a specific area of his brain because he has some other neurological finding?
[SPEAKER_00]: Almost regardless of what I find.
[SPEAKER_00]: Actually, yes, I will go ahead and say, regardless of what I find on exam, he is going to end up getting some neuroimaging.
[SPEAKER_00]: And so, you know, but I'm making the neurologists in the audience, which I know we actually have a few happy by saying we're going to do a neurological exam and try to localize first because to be fair, you know, when you find certain things on exam, it might actually change what type of imaging you order or what specific areas you image.
[SPEAKER_00]: So, you know, are we just going to image the brain or we're going to also image other areas because, you know, neurological diseases can sometimes affect different areas of the the new axis.
[SPEAKER_00]: So to speak.
[SPEAKER_00]: So that's probably where I'm going to start before I go down further into.
[SPEAKER_00]: you know, the obesity evaluation because the headache and the concern for intercranial pressure is the more pressing issue.
[SPEAKER_00]: Right now that's the thing that has me more concerned than the weight gain over that period of time.
[SPEAKER_01]: A nice little turn of phrase there, the more pressing.
[SPEAKER_01]: issue.
[SPEAKER_01]: Okay.
[SPEAKER_01]: Let's get you some, let's give you some information here.
[SPEAKER_01]: So on his exam, his vital signs are unremarkable.
[SPEAKER_01]: He doesn't have a fever.
[SPEAKER_01]: His heart rate blood pressure are normal.
[SPEAKER_01]: On physical exam, he's a well-appearing young man comfortable and no apparent distress with generalized obesity.
[SPEAKER_01]: His face appears normal.
[SPEAKER_01]: It's not round or red.
[SPEAKER_01]: His facial features are also normal.
[SPEAKER_01]: So no heavy brow, no enlarged jaw.
[SPEAKER_01]: His neck also appears normal.
[SPEAKER_01]: On an I exam, you took some extra time to perform a thorough I exam, you checked his visual feels by confrontation, so basically at the bedside, he covers one eye and looks at your nose, and you bring a finger in from each side and ask when does it come into view.
[SPEAKER_01]: On both of his eyes, he does not pick up your finger until it's well past the edge.
[SPEAKER_01]: He's missing the outer half of his vision on each side, the part that would catch someone walking up on his left or his right.
[SPEAKER_01]: Then you look in the back of each eye with the ophthalmoscope at the optic disk, which is the spot where the optic nerve enters the eyeball.
[SPEAKER_01]: Now, normally that disk sits pretty flat with the crisp sharp edge, but his are swollen and puffed up with blurred margins, also on both sides.
[SPEAKER_01]: The rest of his neurological exam is otherwise normal, normal strength, reflexes, and sensation, no other cranon nerve findings were observed.
[SPEAKER_01]: Let me give you some lab information, your lab, at your office works very quickly.
[SPEAKER_01]: And so you have these labs while he's still there.
[SPEAKER_01]: His CBC is complete blood count is normal, white cells, red cells play, let's all arrange.
[SPEAKER_01]: So no parent infection or anemia is metabolic panel is normal too.
[SPEAKER_01]: So electrolytes, kidney function, blood sugar, all where they should be, liver enzymes are also normal.
[SPEAKER_01]: His hemoglobin A1C is normal.
[SPEAKER_01]: His thyroid is normal, TSH, and free T4
[SPEAKER_01]: is morning cortisol, which you thought to draw, and again, came back very quickly, is normal, again, cortisol is that sort of stress hormone and too much of it would be indicative of like a cushions syndrome you alluded to.
[SPEAKER_01]: His testosterone level because, you know, Pete Higgs said, decided to call into the office and try to get testosterone level in the ER, okay?
[SPEAKER_01]: That was normal.
[SPEAKER_01]: His pro-lactin, however, is moderately elevated at 23, where the top of normal is 18.
[SPEAKER_01]: This is a hormone that the pituitary gland makes.
[SPEAKER_01]: Now, you couldn't get him into the MRI right away.
[SPEAKER_01]: And so, unfortunately, I'm not going to ask you to review this young man's case and see if this changes your diagnosis or finds your diagnosis in any way.
[SPEAKER_01]: If you're playing along at home, this would be another place to pause.
[SPEAKER_01]: I'm sure you got everything that Dr. Barack had mentioned before in his eight-minute monologue.
[SPEAKER_01]: Let's see if this updates your thinking.
[SPEAKER_01]: Dr. Barack, what do you think about this patient?
[SPEAKER_00]: Yeah, well, the case has advanced rapidly here and a lot of this fits with my prior suspicions in particular that this patient does have an elevation in intercranial pressure.
[SPEAKER_00]: And we have several findings to suggest that the main one being the, what's what you describe as papaladima, the swelling in the back of the eyes, in particular in both eyes, suggest that we have this kind of generalized increase in pressure in the brain.
[SPEAKER_00]: And then the other question again remains is this due to some sort of mass lesion mass effect, a tumor and abscess, something like that going on in the brain, or is it due to a generalized increase in the fluid pressure, which can happen
[SPEAKER_00]: the visual field finding that you described, the fact that he cannot see the outer half of his visual fields on both eyes is one of those findings that we all learn about in medical school has a fancy name called by temporal hemionopsia.
[SPEAKER_00]: And that basically localizes the lesion to the pleasure of all the neurologists in the audience to what's called the optic chiasm.
[SPEAKER_00]: So basically the nerves,
[SPEAKER_00]: that go to our eyes, the back of the eyes, they go back from there and they cross in the middle of the brain, that's the chiazum part, and that is right around where the pituitary is.
[SPEAKER_00]: And so now we are much more suspicious that there is maybe some sort of lesion like a mass in the what's called the cella, which is where the pituitary sits, that is also compressing on this optic chiazum, and then therefore impacting the patient's visual fields on either side.
[SPEAKER_00]: And at the same time, the fact that there is this extra mass that should not be there in the skull, and since the skull is not a very accommodating place for things that shouldn't be there, that leads to the increase in pressure that then manifests in not only the headaches, the nausea, the worse with coughing, worse with straining, as well as the increased swelling in the back of the eyes that we saw on exam.
[SPEAKER_00]: Now, the
[SPEAKER_00]: There are a variety of different types of masses that can happen in the cella and in the pituitary in particular, the most prototypical one that we tend to think about is something called a adenoma or a macro adenoma in particular here, a large adenoma that is large enough to cause this mass effect and
[SPEAKER_00]: potentially the visual effects as well, and so there are a variety of different cell types in the pituitary gland, and each of the different types of cells in the pituitary gland can turn into a macro adnoma.
[SPEAKER_00]: Some are way more common, and some are way way less common, and so the prolactin that you mentioned, for example, patients actually prolactinoma is not that unusual of a type of benign tumor that can happen in the pituitary gland, and oversecrets prolactin
[SPEAKER_00]: There are also other types of pituitary masses, cellar masses like a cranio for angioma, or another one, and so some of these can also have some of these other impacts on pituitary hypothalamic function because these organs are literally connected the hypothalamus in the pituitary.
[SPEAKER_00]: And so now we're starting to gain some, again, more momentum, more suspicion, what could be a potential tie into the weight gain that he experienced, could it be due to some sort of,
[SPEAKER_00]: hormone-related issue because, again, the hypothalamus and pituitary or hormonal producing and secreting organs, so if there's some disruption in that hormonal axis, and even outside of the typical hormones that we think of, there are a lot of these other kind of signaling circuits related in appetite and satiety, leading to syndromes, for example, the generalized condition of what's known as a hypopholamic obesity, as a secondary cause of obesity to differentiate from what we call again, more common.
[SPEAKER_00]: sort of obesity.
[SPEAKER_00]: So this is where more of my suspicion is headed at this point.
[SPEAKER_00]: The lab evaluation that you had done most of it was essentially what I expected.
[SPEAKER_00]: I wasn't really expecting him to have major arrangements in many of these tests good so far.
[SPEAKER_00]: I guess because he's 21 and previously healthy and this has only been going on for seven months that his A1C hasn't gotten terribly deranged quite yet.
[SPEAKER_00]: The the cortisol interpreting that is imperfect in this situation for reasons that I'll set aside for now but the testosterone, the
[SPEAKER_00]: you know, the IGF1, some of those things is actually kind of useful here.
[SPEAKER_00]: The pro-lactin, as you noted, is like kind of mildly elevated, not, you know, crazy off the charts, slam dunk, super, super impressive here, but it's something that I'm noting, but yes, this patient, again, he has clear neurological signs.
[SPEAKER_00]: deficits evidence of increased intercranial pressure just needs the MRI.
[SPEAKER_00]: MRI of his brain with special, you know, I would usually be discussing this with the neuro radiologist to make sure we like protocol it properly to take extra close look at the cellar.
[SPEAKER_00]: It's going to be with contrast to make make sure that we're getting the right kind of pictures of the right area of the brain based on our exam findings.
[SPEAKER_01]: Yeah, well, ask and you shall receive.
[SPEAKER_01]: We have some MRI findings and to your credit, they did focus on the pituitary and the cello.
[SPEAKER_01]: Now, if you're not familiar with this term, cello, the Dr. Baroque is used before.
[SPEAKER_01]: This means saddle.
[SPEAKER_01]: In fact, you have this specialized boney anatomy in your skull, the cello, Tercica, where the pituitary gland sits.
[SPEAKER_01]: And so, again, hopefully that makes our anatomists in the audience.
[SPEAKER_01]: I know we have at least one.
[SPEAKER_01]: So the MRI comes back and there's a large mass close to five centimeters across centered in the cello, a little money pocket at the base of the skull that holds the pituitary gland and extending up above it.
[SPEAKER_01]: It's mostly cystic, full of fluid filled pockets with some solid parts that take up the contrast and a bit of layered blood inside of it.
[SPEAKER_01]: It does appear to be pushing up against the optic chiasm, this sort of x-shaped spot, just above the pituitary where the nerves from the two eyes come together and cross.
[SPEAKER_01]: And it's also pushing up against the third ventricle, one of the fluid-filled chambers deep in the middle of the brain and the fluid chambers behind it are enlarged.
[SPEAKER_01]: So Austin, he got this whole work up, and now I'm going to ask you to give us the first diagnosis.
[SPEAKER_01]: There's going to be two diagnosis in this case.
[SPEAKER_01]: And so he's playing along at home.
[SPEAKER_01]: He should pause and come up with your diagnosis.
[SPEAKER_01]: So Austin, what's going on with this patient?
[SPEAKER_00]: Yeah, it's, I don't know, kind of satisfying when the things that you are predicting you will find are in fact the things that you find and so I think there's a couple like lessons here that I would point out first is that you always have to be cautious about the same phenomenon we talk about elsewhere in terms of like confirmation bias right not the idea that we're, you know,
[SPEAKER_00]: Finding exactly what we look for, looking for the exact thing that we want to find, but rather that I had, you know, at each step of the journey, a set of suspicions.
[SPEAKER_00]: And based on the possible predictions at each stage, it would take me down different paths.
[SPEAKER_00]: And as you start to see more and more of a...
[SPEAKER_00]: You know, your predictions supported by the things that you find.
[SPEAKER_00]: You start to build momentum sort of in that direction.
[SPEAKER_00]: You always need to, in the back of your mind, think about like, what's the possibility that this is just a totally accidental unrelated irrelevant sort of finding that I'm missing something.
[SPEAKER_00]: I keep that in mind every day when I'm working with people to make sure because sometimes you can get distracted by red herrings and things like that.
[SPEAKER_00]: This is not one of those situations because this is a very substantial finding in the brain.
[SPEAKER_00]: And it fully explains the symptoms that the patient presented with mainly in terms of the the headaches syndrome and things like that.
[SPEAKER_00]: So the specific descriptions that you gave, because a large mass in the cello,
[SPEAKER_00]: that is mostly cystic with some fluid pockets, some solid components.
[SPEAKER_00]: All of those sorts of things in particular in a 21 year old previously healthy male patient.
[SPEAKER_00]: This is pretty suggestive, I think of a cranial for angioma.
[SPEAKER_00]: I am not an expert, you know, neurologist neuro radiologist, but I know enough to think that this is most likely the type of mass that he has.
[SPEAKER_00]: The other things that you describe there are not things that necessarily help you narrow down what exactly it is when you say it's pushing against the the nerve bundles it's pushing against the third You know ventricle and there's chamber enlargement those are just consequences of the mass being there you could have any type of mass that gets that large Doing that sort of thing now different types of masses Will manifest with different findings if they're even able to get that large some of them would show up a little bit sooner some of them a little bit later
[SPEAKER_00]: but a large, mixed, cystic solid cellar mass, like when you summarize it that way, it's like, yeah, probably a cranial for angioma, especially it's been going on this long, and he hasn't died from some sort of infectious complication, like his tuberculosis and his brain or something like that, right?
[SPEAKER_00]: So that's kind of where I am at right now.
[SPEAKER_00]: 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
[SPEAKER_00]: enlargement of the chambers.
[SPEAKER_00]: That's called Hydrocephalus, and that is a situation where you can have, you know, maybe has two reasons for the elevated pressure and the papilladema and things like that.
[SPEAKER_00]: But that's kind of besides the point right now.
[SPEAKER_00]: So right now, I am most suspicious that this patient has a cranial for angioma and may secondarily have a syndrome of hypotherlamic obesity.
[SPEAKER_00]: 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 as going to be the way that this gets addressed.
[SPEAKER_00]: And so that is well beyond my knowledge base and skill set.
[SPEAKER_00]: I do not have the dexterity to remove a tumor from the very middle of somebody's brain.
[SPEAKER_00]: I'm going to be calling with some other expert to help handle that.
[SPEAKER_01]: Yeah, no, this is good.
[SPEAKER_01]: This is the one I was curious if you would get the specific diagnosis, and I'm going to give you full credit.
[SPEAKER_01]: It is a cranio pharyngeoma.
[SPEAKER_01]: A quick note on the name, because this is some pretty good trivia.
[SPEAKER_01]: The full name is Adamantanomatis cranio pharyngeoma.
[SPEAKER_01]: Adamant means hard, unbreakable, as the same route as Adamantium.
[SPEAKER_01]: Here's why that's in the name.
[SPEAKER_01]: Under the microscope, this tumor looks like the tissue that builds the hard enamel on a developing tooth.
[SPEAKER_01]: 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.
[SPEAKER_01]: Adam Antium strikes again.
[SPEAKER_01]: So he's got this diagnosis of a mass, which is doing two things at once.
[SPEAKER_01]: It's pushing on his optic nerves and it's threatening his pituitary gland and you really can't leave that in.
[SPEAKER_01]: So as you predicted, he did go to the operating room.
[SPEAKER_01]: Neurosurgery took it out.
[SPEAKER_01]: They did a transphenoidal approach.
[SPEAKER_01]: Basically, there's a bone in your skull called the spinoid bone.
[SPEAKER_01]: So they went through that transphenoidal to reach the cellar.
[SPEAKER_01]: That little saddle spot and take this out.
[SPEAKER_01]: Now pathology comes back and it gives us this actual diagnosis.
[SPEAKER_01]: which unfortunately it's benign, but it is in sort of the worst possible real estate.
[SPEAKER_01]: 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.
[SPEAKER_01]: That region can take a hit.
[SPEAKER_01]: So right after surgery, this pituitary story shows up on cue.
[SPEAKER_01]: can't hold on to water.
[SPEAKER_01]: He's putting out leaders of the loot urine, so post-op diabetes and syphetis, and his other pituitary hormones are off too.
[SPEAKER_01]: He ends up on thyroid hormone, cortisol hormone replacement testosterone, and Desma Preson.
[SPEAKER_01]: He's got basically what we call pan-hypo pituitaryism acquired, and that's the result of the surgery.
[SPEAKER_01]: So the tumor's gone.
[SPEAKER_01]: His vision, problem's been addressed, and gets better.
[SPEAKER_01]: His hormones are being replaced.
[SPEAKER_01]: He should be fixed.
[SPEAKER_01]: but he's not.
[SPEAKER_01]: Over the next three months, he gains another 33 pounds.
[SPEAKER_01]: His appetite is way up as far as he reports way before, way up from where it was before surgery, and he says he's never full.
[SPEAKER_01]: He describes eating and just not registering any sort of feelings of fullness.
[SPEAKER_01]: But his replacement hormones are dialed in.
[SPEAKER_01]: His thyroid is replaced to target, for example, the tumor that was pressed on everything is gone.
[SPEAKER_01]: So, Dr. Barack, you have any thoughts on what's going on.
[SPEAKER_01]: You know, tumors gone.
[SPEAKER_01]: He's gaining weight faster than ever.
[SPEAKER_01]: What's up with this patient?
[SPEAKER_01]: Again, if you're playing along at home, pause now and see if you can come with a diagnosis.
[SPEAKER_00]: Yeah, super interesting.
[SPEAKER_00]: And, you know, I know that you said this is a longer episode with a lot of twists and turns.
[SPEAKER_00]: You skipped over, you know, a lot of the fun part there when you talk.
[SPEAKER_00]: you know, brought up the post-op pan-hypo pituitorism situation and managing his diabetes and cipidus 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.
[SPEAKER_00]: You know, you hope that
[SPEAKER_00]: in some situations maybe there's some, you know, postoperative sort of stunning and things might wake back up over time, but a lot of the time that's not necessarily the case.
[SPEAKER_00]: And I've had plenty of patience over the years with very isolated types of, you know, hormonal deficiencies of their pituitary hormones or a handful of folks with pan-hypo pituitars and pan-meaning like all of the pituitary hormones that are just
[SPEAKER_00]: not working due to trauma, due to surgery, resection, injury, radiation, all sorts of things, affecting the pituitary gland, the pituitary stock, and the hypothalamus.
[SPEAKER_00]: And it can be really challenging.
[SPEAKER_00]: 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.
[SPEAKER_00]: 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.
[SPEAKER_00]: The most difficult of these has to do with that water regulation, the diabetes and cipidus and the use of Desma Preson in that patient.
[SPEAKER_00]: 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 you know most of the time our bodies handle this for for ourselves, but this is a situation where now if this is a permanent state for the patient they're going to have to be closely regulating this basically for the rest of their life, which is which is quite challenging.
[SPEAKER_00]: So wanted to wanted to mention that as a very interesting element of this case.
[SPEAKER_00]: Now, my prior suspicion had to do with the Crania for in geoma, you know, being associated with a syndrome of hypophilamic obesity in this patient and it seems like his weight gain has continued to accelerate.
[SPEAKER_00]: And so there is this.
[SPEAKER_00]: growing and as a persistent and growing concern for hypotherlamic obesity in this patient, that despite, you know, resection of the tumor, despite cutting it out, the total function of the hypotheraute thalamus and it's kind of relevant appetite and satiety, you know, modulating circuits is not normalized, maybe they were both down in parallel, maybe there was some kind of irreversible complication that affected that and led it to, not necessarily wake up.
[SPEAKER_00]: 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 hydrochordazone and things like that as one example, you know, is there some concern around that 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.
[SPEAKER_00]: So that would be kind of the first step is making sure that all the things that we had proven and established to date have been sufficiently, you know, addressed.
[SPEAKER_00]: the remaining sort of strategies, step one, you could tell them to eat less and move more.
[SPEAKER_00]: And I say that mostly ingest because we know that that is 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 secondary underlying driver of their, their,
[SPEAKER_00]: seemingly insatiable appetite, lack of satiety, and as a result, perpetual weight gain in this situation.
[SPEAKER_00]: So the remaining steps are going to be medical treatment directed at the obesity itself at this point.
[SPEAKER_00]: And so we have a few different strategies, as well as consideration, if it gets to that point, I wouldn't jump to something like metabolic bariatric surgery just yet, because I think that there's still likely some potentially medically treatable neurological issue here that we can
[SPEAKER_00]: And so those options include are some of our favorites that we talk about a lot, things like GLP-1, receptor agonists like transeptotide being our favorite at the moment, until more effective ones become more available.
[SPEAKER_00]: But more specific and more unique to the syndrome of hypotherlamic obesity, there are sometimes more targeted agents.
[SPEAKER_00]: Some of these are specific to certain types of congenital syndrome.
[SPEAKER_00]: So you've actually talked about some of these things.
[SPEAKER_00]: 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 and that context.
[SPEAKER_00]: I don't think that that is the underlying driver here.
[SPEAKER_00]: Instead, the other option that I would consider,
[SPEAKER_00]: is a medication called set melanotide, which is something that is used in hypotherlamic obesity.
[SPEAKER_00]: It is something that I did not have a great deal of experience with prior to getting way down further into the weeds in obesity care and obesity treatment.
[SPEAKER_00]: I've had a couple of patients at this point for whom it has either been deemed appropriate or for whom we are actually using it.
[SPEAKER_00]: And so there are some trial data that medicine is called an MC4 receptor agonist
[SPEAKER_00]: It is thought to have much more specificity to the management of hypotherlamic obesity in general.
[SPEAKER_00]: Oftentimes when it is related to these types of situations when there's a hypopotuiturism at the same time that raises the suspicion as well.
[SPEAKER_00]: There are a few other more niche treatments that I have less and less experience with and we'll kind of reserve comment on.
[SPEAKER_00]: But I think that
[SPEAKER_00]: 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.
[SPEAKER_00]: Make sure there's no recurrence of a of a mass or anything like that.
[SPEAKER_00]: Probably get him on to his appetite and then start working down the process of, hey, is this patient appropriate for the use of Sentinel-Annotized.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: No, it was great.
[SPEAKER_01]: Very, very well explained.
[SPEAKER_01]: It does have acquired hypoethylamic obesity.
[SPEAKER_01]: They did investigate virtually all of the hormones again just to verify.
[SPEAKER_01]: They did do repeat imaging.
[SPEAKER_01]: It was no recurrence.
[SPEAKER_01]: And so, yeah, at this point, you're like, okay, this does appear to be acquired hypoethylamic obesity.
[SPEAKER_01]: And so,
[SPEAKER_01]: generally speaking, we are going to get into the weeds on this a little later like why this neurological circuit is so important, but just briefly inside of this the hypothalamus, this specialized area in the brain.
[SPEAKER_01]: There are circuits of nerves, some that drive hunger, others,
[SPEAKER_01]: called fullness or satiety.
[SPEAKER_01]: 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.
[SPEAKER_01]: For example, now this tumor, this cranial pharyngeal, almost sat right on those nerve cells, right right on that circuit and the surgery to remove it,
[SPEAKER_01]: you know, damage that area too.
[SPEAKER_01]: So now the break was gone.
[SPEAKER_01]: Effectively this individual is persistently hungry, persistently seeking food, and yeah, unable to will power himself out of this.
[SPEAKER_01]: So hunger is just on the whole time, fullness never registered, and removing the tumor kind of made it worse, which is why you had additional weight gain.
[SPEAKER_01]: So what happened, they put this patient on to his appetite at the time, set my line of tide was not approved.
[SPEAKER_01]: And unfortunately, they only followed this patient for four months afterward.
[SPEAKER_01]: That's when the case report kind of stopped.
[SPEAKER_01]: And he was on, was not on maximal dosage.
[SPEAKER_01]: So during this four month interlude, he lost nine kilograms.
[SPEAKER_01]: So what is that?
[SPEAKER_01]: Twenty pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of pounds of
[SPEAKER_01]: you know, before we move on to some of the pearls, some of the takeaways here.
[SPEAKER_01]: Just in your opinion, would you agree that, although this is very complicated and you weren't, you know, we're not there.
[SPEAKER_01]: We're not saying anything bad about these these these individuals.
[SPEAKER_01]: This is just suboptimal management of acquired obesity.
[SPEAKER_01]: In this case, assuming he never lost any more weight, did not get back to his baseline weight, right?
[SPEAKER_01]: He only lost 20 of the 60 pounds.
[SPEAKER_01]: And so you
[SPEAKER_01]: Do we need to add additional as the candidate for metabolic bariatric surgery?
[SPEAKER_01]: You know, effectively to me, this is a case of while complicated initially to diagnose and manage and whatever.
[SPEAKER_01]: the problem still kind of is there the unmanaged obesity or insufficiently managed.
[SPEAKER_01]: I don't know, is that kind of how you feel about this?
[SPEAKER_00]: Yeah, you're right.
[SPEAKER_00]: Hard to say without being there, I think, you know, this patient took a while to show up.
[SPEAKER_00]: 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.
[SPEAKER_00]: And, you know, 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.
[SPEAKER_00]: Because
[SPEAKER_00]: It could have been identified and addressed probably earlier along the way with some some earlier presentation, and then once it was identified and addressed, you know, on one hand, I can see maybe the clinicians perspective, oh, the tumor was rejected.
[SPEAKER_00]: This should all just melt right away on on the on the back end, maybe, but also there's also the question of should anti obesity therapy have been initiated a bit sooner.
[SPEAKER_00]: 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.
[SPEAKER_00]: He's going to be on hydrochordesone twice a day.
[SPEAKER_00]: He's going to be on testosterone every week.
[SPEAKER_00]: He's going to be on thyroid hormone every day.
[SPEAKER_00]: He's going to be on a bunch of other hormone replacements and things like that.
[SPEAKER_00]: You could have initiated Trezzepatide 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 pan-hypopotutorism.
[SPEAKER_00]: And so maybe they said, let's let him 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.
[SPEAKER_00]: before addressing it.
[SPEAKER_00]: 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?
[SPEAKER_00]: 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.
[SPEAKER_00]: 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 trisepotide or set in the land of title a little bit earlier versus a little bit later in this situation, given that he's so young in this situation.
[SPEAKER_00]: And with appropriate treatment could probably get back down to healthy body weight and body composition.
[SPEAKER_00]: I might have gone about it slightly differently, but there's also a patient related factors to consider.
[SPEAKER_00]: I would have had a conversation with him about like,
[SPEAKER_00]: Look, man, this sucks, how much are you willing to do at the stage of the game, you know, or do you want us to take it step by step and then I might have 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, a couple of weeks or something like that.
[SPEAKER_01]: Yeah, yeah, I think it just speaks to ultimately the importance of these neurological circuits, right?
[SPEAKER_01]: And that if those become faulty for whatever reason,
[SPEAKER_01]: You know, big trouble in little China, it's very, very challenging to manage.
[SPEAKER_01]: And so yeah, when I read this case, I was like, ooh, twists and turns.
[SPEAKER_01]: And I was waiting for the big payoff at the end.
[SPEAKER_01]: It's like, and we put them on.
[SPEAKER_01]: There's appetite or set in the land of time, you know, and then ultimately ended up fine.
[SPEAKER_01]: Unfortunately, not the happy ending.
[SPEAKER_01]: But I presume if this patient was followed for a long enough period of time, I suppose, you know.
[SPEAKER_01]: getting this kind of treatment and management is a sign that is access to great medical care.
[SPEAKER_01]: Yes, a very expected pretty good, pretty good outcome.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: But yeah.
[SPEAKER_01]: So I wanted to start off some of these takeaways with this hypotherlamic 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, what is happening in brain?
[SPEAKER_01]: Sure.
[SPEAKER_01]: So we make this case all the time that your body weight primarily is managed at the level of the hypothalamus.
[SPEAKER_01]: You, your genes kind of decide these guardrails, a lower and upper bound, right?
[SPEAKER_01]: And your environment moves you around and side them.
[SPEAKER_01]: But what's regulating this is your hypothalamus.
[SPEAKER_01]: It sits at the base of the brain and there's a small cluster of cells in that area called the
[SPEAKER_01]: This is positioned right where the blood brain barrier is leaky, so it's 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.
[SPEAKER_01]: The first makes a large protein called perpio melano cordon, POMC for short, which basically the cell chopped into smaller pieces,
[SPEAKER_01]: It is released when these POMC neurons fire, and the travels to a neighboring region of the hypothalamus were a plugs into a receptor called MC4R.
[SPEAKER_01]: Activating MC4R reduces food seeking behavior food intake.
[SPEAKER_01]: So on and so forth.
[SPEAKER_01]: Now, in opposition to that, there's a second group of neurons that makes a goody-related peptide AGRP named after a strain of fat yellow mice that led to its discovery.
[SPEAKER_01]: So this travels to that same MC4R receptor, but instead of switching it on, it jams the lock so alpha, MSH can't.
[SPEAKER_01]: Now, these neurons also silence those POMC neurons sitting next to them.
[SPEAKER_01]: So,
[SPEAKER_01]: AGRP basically wins two different ways.
[SPEAKER_01]: One, they block the signal downstream by blocking the receptor, and they shut up the upstream sort of neurons, ultimately increasing food intake.
[SPEAKER_00]: Yeah, it's a super interesting set of pathways, very complex and probably not that easy to absorb through, you know, purely audio format without like a graphical image representation.
[SPEAKER_00]: 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,
[SPEAKER_00]: even test questions on it, things like that.
[SPEAKER_00]: It's like, man, how am I going to remember these things?
[SPEAKER_00]: And so I did some trial and error trying to figure out, I've never been much of a nemonic person, but basically the neuropeptide Y and PY and a Goody related peptide, which is like one of my favorite named peptides in the body, just an interesting cool name.
[SPEAKER_00]: That's one pathway.
[SPEAKER_00]: And then you said the POMC and like CART related as the other pathway.
[SPEAKER_00]: And so,
[SPEAKER_00]: I think I might have even used like a Google or like an AI tool, which sounds like help me come up with some kind of nemonic for this.
[SPEAKER_00]: And it said, hey, N.P.Y.
[SPEAKER_00]: NeuropeptideY can stand for, I need pizza yesterday.
[SPEAKER_00]: And so that is the path with that I remember as being what we call a rexogenic, meaning it promotes appetite, food seeking behavior.
[SPEAKER_00]: And then you just remember that the other ones, the other one.
[SPEAKER_00]: And so that made it much easier for me to keep these straight in my mind.
[SPEAKER_01]: Yeah, and I like that it's important to note that these aren't subtle effects.
[SPEAKER_01]: If you switch on these agudi related peptide neurons in a mouse that just finished a meal, it starts eating again almost immediately.
[SPEAKER_01]: If you switch them off in a starving mouse, it'll walk past the food.
[SPEAKER_01]: In humans, loss of function mutations in the MC4R that receptor as the most common single gene cause of obesity we know of.
[SPEAKER_01]: Uh, you know, somebody listening the audience might say, well, what about Leptin?
[SPEAKER_01]: I hear about Leptin all the time with the heck, we've talked about this a number of times on the podcast, but this is also one of the hormones that the architect nucleus is sampling in that leaky blood brain barrier.
[SPEAKER_01]: Uh, 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.
[SPEAKER_01]: The brain mainly treats it though as a low fuel alarm, meaning that if you do not have substantial stores of body fat and you have a low leptin level.
[SPEAKER_01]: The brain picks that up and says, yo, we don't have enough energy on hand, you should eat.
[SPEAKER_01]: And so when leptin falls, the brain picks that up at the specialized cells.
[SPEAKER_01]: And the agudi related peptide neurons fire harder.
[SPEAKER_01]: POMC neurons go quiet, hunger climbs, and the body throttles back energy, expenditure, reproductive function, so on and so forth.
[SPEAKER_01]: That's why you can also get hypogonatism as a result of this.
[SPEAKER_01]: Let them go in up, though, from an individual with high body fat, does not produce the mirror image.
[SPEAKER_01]: So somebody carrying around a lot of body fat has high leptin all day, and they're not walking around full.
[SPEAKER_01]: There was a thought that, well, this just means they're resistant to the leptin signal.
[SPEAKER_01]: As it turns out, that doesn't appear to be the case.
[SPEAKER_01]: You can give these people, you can flood their system with leptin and nothing happens still.
[SPEAKER_01]: Effectively, it's just not an effective like satiating hormone.
[SPEAKER_01]: So to speak, that's not really where the efforts are.
[SPEAKER_01]: Unfortunately, it would be nice if that were the case, but it just doesn't seem to work that way.
[SPEAKER_01]: So to summarize, there are two opposing sets of neurons.
[SPEAKER_01]: The break is these POMC neurons.
[SPEAKER_01]: They make alpha MSH, which lands on this MC4R receptor, and the message is to stop eating and burn energy.
[SPEAKER_01]: The accelerator is the AGRP, the agudi related peptide neurons, and their message is to get hungry and conserve energy.
[SPEAKER_01]: Don't be as active.
[SPEAKER_01]: Leptin is a minor player here unless it's low, in which case it says, hey, look, you should eat some more.
[SPEAKER_01]: But you don't get a vote in any of this.
[SPEAKER_01]: None of this is something you can control.
[SPEAKER_01]: And so I do wonder when I see the message, hey,
[SPEAKER_01]: You just have to know about your hormones.
[SPEAKER_01]: Are these the neuroendocrine hormones that they're talking about?
[SPEAKER_01]: Because I suspect not.
[SPEAKER_01]: You break any single piece of this chain, though, you're going to get the same result.
[SPEAKER_01]: Reletless hunger and obesity that can start in childhood.
[SPEAKER_01]: And these have a bunch of different named diseases.
[SPEAKER_01]: So for example, in leptin deficiency,
[SPEAKER_01]: Super low levels, almost non-existent levels of leptin.
[SPEAKER_01]: Kids are ravenously hungry every waking minute, and they get relatively profound obesity in when they're toddlers, but you gotta give them leptin back.
[SPEAKER_01]: Usually Metro leptin is the treatment.
[SPEAKER_01]: Hunger switches off, the way it comes down, stays down as long as they're on the treatment.
[SPEAKER_01]: In POMC deficiency, you get obesity, interestingly, red hair, because it seems to be associated with that.
[SPEAKER_01]: and adrenal failure, those are little glance that sit on top of the kidneys, make quarters on other very important hormones.
[SPEAKER_01]: Because again, this hormone was doing multiple jobs, right?
[SPEAKER_01]: MC4R is the most common single gene obesity cause about one in 20 severe childhood cases, and we'll come back to that later.
[SPEAKER_01]: So Austin, there's a lot of different models here.
[SPEAKER_01]: All of them related to sort of the neurological function in its management or effect on body weight regulation.
[SPEAKER_01]: How do you think these models or do you think these models of obesity help in explaining obesity?
[SPEAKER_01]: Maybe as you call common obesity and or like how to manage it, do you think these are useful?
[SPEAKER_00]: I think they are useful to get a sense that there are underlying mechanisms at play and those underlying mechanisms can be deranged to two varying degrees.
[SPEAKER_00]: And so, for example, if somebody has an outright deficiency of one of these things, that's like the most extreme state, right?
[SPEAKER_00]: And so, that's an example you mentioned like the monogenic ideologies of obesity, where there is everything is okay except this one gene that has a mutation or a defect in some way.
[SPEAKER_00]: and then it reliably leads to the kind of resultant phenotype of unchecked hyperphagia, uncontrolled eating and weight gain.
[SPEAKER_00]: 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 is results and healthy body weight can be restored to a great deal.
[SPEAKER_00]: That is a very compelling, like, very direct causal sort of scenario, right?
[SPEAKER_00]: That is unfortunately not what we end up seeing in all cases of obesity because in more more generally speaking, it is much more often a polygenic sort of situation.
[SPEAKER_00]: 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 a
[SPEAKER_00]: many, many, many, many different genes, not just a single severe genetic deragement.
[SPEAKER_00]: 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.
[SPEAKER_00]: But they are not wholly distinct things in the sense that
[SPEAKER_00]: 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 to be see, they are just quote unquote choosing it.
[SPEAKER_00]: That is not an accurate way to, you know, derive a conclusion here.
[SPEAKER_00]: It's just that there is a varying degree of
[SPEAKER_00]: 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.
[SPEAKER_00]: And you know, we'll throw back for folks for whom this is kind of a novel argument.
[SPEAKER_00]: This is actually not a novel, it's been around quite a while.
[SPEAKER_00]: And there's some really actually quite accessible material out there if you're interested in learning more about it.
[SPEAKER_00]: Going back to Dr. Stefan Giene'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, that has roots decades ago where people have been working this out.
[SPEAKER_00]: And you can see that even in, you know, what we call common obesity, that a huge proportion of the kind of phenotype that results the experience, the results of obesity, that situation,
[SPEAKER_00]: can be clearly related to a wide variety of genes, mostly those regulating appetite in the brain.
[SPEAKER_00]: Many, many, many fewer of the genes at play or that have been implicated are kind of more in the periphery.
[SPEAKER_00]: And this is a contentious argument in the space sometimes.
[SPEAKER_00]: People who have been much more for example 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 downstream predictions and implications.
[SPEAKER_00]: That have not really panned out in practice.
[SPEAKER_00]: 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 has what is really honda sin on this.
[SPEAKER_00]: It's just that these monogenic forms that you're describing are the most extreme most severe versions of this that are.
[SPEAKER_00]: completely uncheckable through any degree of choice or willpower, or anything unless they're directly treated, whereas the more polygenic forms, there's a lot more variation in heterogeneity.
[SPEAKER_00]: Some people are able to, quote, unquote, check it on, quote unquote, on their own, whereas others need more, more help.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: Well said, you know, it is possible that there are, um, you know, platropic 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.
[SPEAKER_01]: But also maybe in various responses to the environment, you know, that some people would call willpower related to food related behaviors.
[SPEAKER_01]: 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.
[SPEAKER_01]: You would otherwise expect there's just many layers
[SPEAKER_01]: and trying to white knuckle it through that is probably not the way to do it.
[SPEAKER_01]: Now, here's an interesting thing.
[SPEAKER_01]: GLP one drugs still worked on this patient despite apparently his pituitary gland much of it being removed.
[SPEAKER_01]: Other sort of trauma to those levels of brain and I thought that was pretty interesting.
[SPEAKER_01]: I'm like, look, if this guy had a problem previously.
[SPEAKER_01]: At the area that we think these drugs work, how in the heck
[SPEAKER_01]: did he respond to Tersepotide, for example, because we know that these GLP-1 drugs are some agglutide and the dual agglist Tersepotide all work on the circuit that we've been describing.
[SPEAKER_01]: They reach into the Arquuit nucleus, into the brainstem, and they push the same POMC break, and they quiet the accelerator.
[SPEAKER_01]: They don't really rev up the metabolism.
[SPEAKER_01]: They don't increase the amount of calories you're burning.
[SPEAKER_01]: Retatur Tide appears to do that on some level.
[SPEAKER_01]: That said, this guy's pituitary gland in part of his, you know, hypothalamus were apparently pickled yet it still worked.
[SPEAKER_01]: So there are some additional receptors.
[SPEAKER_01]: There's kind of a back door way into the circuit through the brainstem that the appears to be preserved, which seems to be the way the work on this patient.
[SPEAKER_01]: But so even when the injury sort of to the area, we can still access it through these medications, which kind of just speaks to how powerful they can be,
[SPEAKER_01]: 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 and do you 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?
[SPEAKER_01]: Or maybe a little bit of both?
[SPEAKER_00]: Yeah, it is a little bit of both, as an internist, of course, I can't help but maintain a broad differential in these situations.
[SPEAKER_00]: We've talked about in a lot of context how you apply any intervention to a biological organism, like a human, and you're going to see a variety of responses.
[SPEAKER_00]: 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.
[SPEAKER_00]: And that's not that different than what we see when we put people on GLP one receptor agonists.
[SPEAKER_00]: I have plenty of patients who are hyper responders.
[SPEAKER_00]: I think I had one patient recently who, you know, they've been on Trezzepatide, they've only ever used like 2.5 milligrams, which is the lowest starting dose.
[SPEAKER_00]: And they've lost like 36% of their starting body weight.
[SPEAKER_00]: That is beyond above average, right?
[SPEAKER_00]: very, very uncommon, certainly not an expectation that I set for people that this is like a realistic outcome and probably not even one that they expect it, but some result of their susceptibility to the effects of this medicine combined with their lifestyle habits and many of the things set them up for that degree of success.
[SPEAKER_00]: Meanwhile, I have other patients who get up to the maximum dose of Trezzepatide 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
[SPEAKER_00]: hungry and what else can we do?
[SPEAKER_00]: Can we try some combination therapies?
[SPEAKER_00]: Can I get in rolled in a clinical trial for Redda at this point?
[SPEAKER_00]: Which I'm trying to refer people to see if they're eligible for those types of studies with Redda with a Laura Lindtide and things like that as next generation kind of promising agents.
[SPEAKER_00]: And so there is this baseline heterogeneity in response that we expect to see.
[SPEAKER_00]: 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 support it?
[SPEAKER_00]: Is our dosing reasonable?
[SPEAKER_00]: Is there anything else going on that could be holding us back?
[SPEAKER_00]: Are you also on other medicines, for example, that can be promoting of appetite and weight gain?
[SPEAKER_00]: 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.
[SPEAKER_00]: 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?
[SPEAKER_00]: Could this have been something congenital that's been missed this whole time?
[SPEAKER_00]: Again, that is much tougher to tease apart.
[SPEAKER_00]: Not easy evaluation to do does definitely require some specialize.
[SPEAKER_00]: 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.
[SPEAKER_00]: There are not necessarily monogenic, but still what are called
[SPEAKER_00]: 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 pediatric knowledge after getting through school and entering internal medicine residency where I only handled adults but it's part of the knowledge base for this field that I'm having to kind of refresh.
[SPEAKER_00]: because it is relevant if somebody gets missed and doesn't get diagnosed until later in life.
[SPEAKER_00]: 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?
[SPEAKER_00]: Are there any meds that are holding them back or other things that are preventing them from being able to have success and then other of these signs of either a syndromic ideology or a potential genetic contribution that needs to be addressed?
[SPEAKER_00]: Of course, in the last one, this is actually the patient that I alluded to recently that I've seen.
[SPEAKER_00]: who does have evidence of hypopotuitarism.
[SPEAKER_00]: And so then it's like, okay, well, does a hyporespons to something like trisepotide now mean that we actually ought to pursue set malenotide for a patient like this because they are not having the response that we're looking for.
[SPEAKER_00]: And if there is a suspicion or a possibility, they could have acquired hypotlamic obesity, maybe we need to step up the therapy to address things more directly that way, which is what we're doing right now.
[SPEAKER_01]: Yeah, that's a great segue into the next part of this.
[SPEAKER_01]: Let's go back to that break for a second.
[SPEAKER_01]: The POMC neurons that make this alpha msh alpha msh again, presses on this MC for our receptor.
[SPEAKER_01]: And that's your stop eating signal.
[SPEAKER_01]: Now, what if there was a medication that directly interacted with that MC for that receptor?
[SPEAKER_01]: So effectively, that your stop eating signal would be activated, as long as you were taking that drug?
[SPEAKER_01]: Sounds like they like cheating.
[SPEAKER_01]: Well, I guess, I guess that some people might say that, but Sedinolenotide is a drug that does exactly that.
[SPEAKER_01]: Skips the whole potentially broken section of the circuit pushes on a brake pedal itself.
[SPEAKER_01]: And you know, you've talked about this before, but when people have this sort of acquired hypothalamic apiece, we don't really have good medications for a long time.
[SPEAKER_01]: Um, and up until recently, you know, it's, look, you got a diet harder, you have to exercise more.
[SPEAKER_01]: You can take some of these other medications, but look at that circuitry upstream isn't functioning correctly.
[SPEAKER_01]: It's like, we don't really have much for you here, right?
[SPEAKER_01]: Um, and then came a transcend as a phase three trial, 142 patients with the choir, type with the Lemicobesity ages four and up.
[SPEAKER_01]: I don't know if anybody's telling a four year old, yeah, you just got a try harder.
[SPEAKER_01]: Uh, good luck.
[SPEAKER_01]: Now, over one year, BMI dropped by about 16% on the drug, and it rose by about 3% on the placebo.
[SPEAKER_01]: That's a pretty big swing against placebo, and their hunger followed that as well.
[SPEAKER_01]: In a disease where diet and exercise basically doesn't change anything, this is a pretty big result.
[SPEAKER_01]: Now, there are some side effects here, one in five patients had their skin darken because the receptor this drug, it's also controls skin pigment to some degree, nausea, vomiting, headaches, we're also some of the side effects reported on top of that.
[SPEAKER_01]: It's also a daily injection at this particular time, and while it does press the break, it doesn't necessarily repair the whole circuit, so you basically have to take it indefinitely.
[SPEAKER_01]: Now, set Molanotide is not a new drug.
[SPEAKER_01]: 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.
[SPEAKER_01]: Now, what's new this year is in March.
[SPEAKER_01]: the acquired hypothalemic obesity indication got FDA approved and that is the exact situation our patient was in.
[SPEAKER_01]: So this is 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 MC for our agonist on the market.
[SPEAKER_01]: our patient came along before that approval.
[SPEAKER_01]: So he got to his appetite instead.
[SPEAKER_01]: And again, lost about 9 kilograms, would roughly 6% of his body weight.
[SPEAKER_01]: And again, that follow-up was also limited.
[SPEAKER_01]: So unclear how well he did after that.
[SPEAKER_01]: But Sentinel-Anotide would have been great for this patient.
[SPEAKER_01]: Do you have patients right now on Sentinel-Anotide?
[SPEAKER_01]: Is that something you're working with?
[SPEAKER_00]: That's what I was just alluding to is having one patient actively we're trying to get on it because they have pan-hypopotutorism and there's a suspicion for acquired hypothelemic obesity.
[SPEAKER_00]: And that previously worked with one patient who was on it, but there no longer following with them anymore at this point.
[SPEAKER_00]: Yeah, so that's not a super common thing.
[SPEAKER_01]: What's the cost of this thing?
[SPEAKER_01]: Is it crazy expensive?
[SPEAKER_01]: It sounds expensive.
[SPEAKER_00]: 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.
[SPEAKER_00]: And so the ultimate cost is not directly borne by the patient I suspect, you know, and you know how much price distortion there can be when working through the insurance system.
[SPEAKER_00]: So I am not actually aware of like what would destroy the cash pay price of this medication be as expected as high.
[SPEAKER_01]: Pervile cash price appears to be 3300 to 3700 for a 1 mil subcutaneous vile estimated annual cost is about $300,000 for pediatric patients and $440,000 a year based on.
[SPEAKER_01]: for adults.
[SPEAKER_00]: That tracks for, you know, new new therapies like this.
[SPEAKER_00]: I think it's one of those areas that's costs are insane.
[SPEAKER_00]: That's unfortunate, but inevitably going to come down as this field advances.
[SPEAKER_00]: As, you know, it takes me back, you know, you mentioned that it's like a one-staley injection has more intolerability, maybe decent efficacy, but not ideal efficacy.
[SPEAKER_00]: If you just rewind, take us back to 2005 when Accentatide was approved.
[SPEAKER_00]: You know, the original GLP1
[SPEAKER_00]: 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.
[SPEAKER_00]: So this field is just likely to continue advancing and get better and better, particularly addressing these underlying mechanisms.
[SPEAKER_00]: And maybe even it will be nice is if some evidence pans out where we can have a better way to
[SPEAKER_00]: Identify almost like people's unique mechanisms of obesity because I mentioned like there's the common obesity It's like this, you know hand-wavery polygenex sort of thing What explains why some people respond better or worse to GLP one-aggressed what explains why patients with diabetes lose less weight on GLP one-aggress compared with those without diabetes all these sorts of things
[SPEAKER_00]: I know that, you know, the whole idea of quote unquote precision medicine is controversial and it's not something that's really paned 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 chemotherapy as a result, this is a situation where, for example, you know, I can envision a scenario where if we did have some biomarker way,
[SPEAKER_00]: in the future to assess, oh, this person's, you know, obesity is being, they're a degree of function along this, you know, appetite signaling pathway is normal, whereas this other pathway is less normal, maybe we'll have tools to better target those so that we can turn more hyporesponders into hyper-responders, which would be awesome.
[SPEAKER_01]: That would be great.
[SPEAKER_01]: Which brings us to a little prelude for an upcoming episode, and this kind of ties our entire series together.
[SPEAKER_01]: Why are we so worried about body fat in the first place?
[SPEAKER_01]: Right, this patient came in primarily complaining about headaches.
[SPEAKER_01]: Fixed that problem, and now we've been focused on the whole back half of this podcast on, is body fat.
[SPEAKER_01]: Why is he persistently carrying too much body fat?
[SPEAKER_01]: And what does that even mean?
[SPEAKER_01]: and you and I have kind of wrapped about an analogy here and so we're going to debut it here on the barbell medicine podcast here and we'll have a whole episode about this upcoming.
[SPEAKER_01]: The thought here is that your body fat tissue is effectively a garage.
[SPEAKER_01]: It's job is safe, storage, keeping the surplus energy out of the house.
[SPEAKER_01]: Now how big that garage is, it gets mostly set before you're born.
[SPEAKER_01]: Some people have a double garage and some people have a shed.
[SPEAKER_01]: Some people
[SPEAKER_01]: 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 in the space around the heart, now around the kidney we're discovering, you can think of these 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.
[SPEAKER_01]: Now, people, some people are born with essentially no garage, a condition called lipodistrophy, and they get diabetes very young, even though they're lean, very lean in some cases.
[SPEAKER_01]: And people who carry genes for a bigger garage hold more fat and get less disease, not more.
[SPEAKER_01]: This rule fat, which we've talked about a number of times on this podcast, this is the fat that's around your internal organs.
[SPEAKER_01]: It is dangerous, it's a real warning sign, but it is a downstream of sort of this storage problem.
[SPEAKER_01]: So you can think of it as conferring some risk for sure, but also as an indicator that something else's problem upstream and it's a storage issue.
[SPEAKER_01]: You can't fix it by cutting it out.
[SPEAKER_01]: If certains have tried to do this, nothing really improves.
[SPEAKER_01]: Liposuction has also tried to remove the fat physically, nothing improves.
[SPEAKER_01]: You can vacuum 20 pounds of it off a person with liposuction and the metabolic health doesn't really change at all.
[SPEAKER_01]: 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.
[SPEAKER_01]: For example, this also happens with substantial weight loss, including individuals taking these GLP ones.
[SPEAKER_01]: But the main problem here still is storage.
[SPEAKER_01]: right.
[SPEAKER_01]: And so we're kind of coming back to this.
[SPEAKER_01]: Why is body fat?
[SPEAKER_01]: Why are we focused on this?
[SPEAKER_01]: And what's the real problem?
[SPEAKER_01]: It's not necessarily the amount of body fat.
[SPEAKER_01]: And it's not necessarily just the distribution.
[SPEAKER_01]: It's more of, do you have a fat storage problem?
[SPEAKER_01]: Are you running out of room, right?
[SPEAKER_01]: And that kind of goes back to, well, how much could you store?
[SPEAKER_01]: The sort of idea of a personal body fat threshold, something that doesn't exceed your storage.
[SPEAKER_01]: And if it does, now or more concerned with the flux, what is happening in and out of that storage that you're kind of overdone?
[SPEAKER_01]: Does that kind of make sense to you the way we're describing it?
[SPEAKER_01]: We're workshopping this analogy here a little bit, but that's kind of the way I'm thinking about it at present.
[SPEAKER_00]: Yeah, I think you summarized our, you know, 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.
[SPEAKER_00]: And this is something that has a lot of relevance in other areas as well, for example,
[SPEAKER_00]: blood lipid metabolism, the flux of lipids through your system as they pass through.
[SPEAKER_00]: It'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.
[SPEAKER_00]: Similarly, when you look at well-trained ultra-indurance athletes, for example, and you do some muscle biopsies on them.
[SPEAKER_00]: They actually have a fair amount of what's called intra-myoselular triglyceride fat stores in their muscles.
[SPEAKER_00]: And you might say, what I don't understand, these folks are, you know, in many cases, extremely healthy, insulin sensitive, not a hint of, you know, blood sugar issues or type 2 diabetes or anything.
[SPEAKER_00]: Yet, they have fat in their muscles that might otherwise make me think that they have some, you know, storage problem.
[SPEAKER_00]: It might be unhealthy or something like that.
[SPEAKER_00]: Well,
[SPEAKER_00]: 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 insufficiently physically active or completely inactive.
[SPEAKER_00]: For whom the body fat is spilling over from those healthier subcutaneous areas around the legs and hips.
[SPEAKER_00]: to less healthy areas, the viscera, the liver, the pancreas, and into the muscles, yet there is no meaningful flux.
[SPEAKER_00]: It's accumulating, but it's not being used.
[SPEAKER_00]: It's not passing through.
[SPEAKER_00]: It doesn't have a purpose in that way.
[SPEAKER_00]: Then that is what can significantly lead to the downstream accumulation of downstream metabolites and inflammation that worsens insulin resistance leads to type 2 diabetes and all the complications.
[SPEAKER_00]: That we're hoping to avoid the things that I hope to avoid but unfortunately see very often in the in the hospital setting and things like that.
[SPEAKER_00]: And so, you know, the idea of like, well, okay, so we're talking about flux.
[SPEAKER_00]: What does that mean for me?
[SPEAKER_00]: What what needs to happen to improve that flux?
[SPEAKER_00]: Well, this stuff needs to move through the system at a more rapid clip and I'll 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 in the system as well.
[SPEAKER_01]: Yeah, I think that's the major thing, you know, when it kind of leads to this philosophical discussion, like, what does obesity even mean?
[SPEAKER_01]: If we just say, look, it's excess body fat that causes harm or a little reductionist there, but like you try to simplify your, like, our what does excess body fat actually mean?
[SPEAKER_01]: It's like, all right, well, it has to be beyond what your garage can store.
[SPEAKER_01]: And now, because your garage is overflowing, you have this flux of fat out.
[SPEAKER_01]: And unless it is turning over rapidly, it can be a, it can sit there and do harm.
[SPEAKER_01]: That's the easiest way I figured out how to describe it.
[SPEAKER_01]: So what would you do to increase the turnover exercise is probably the number one lever that we have?
[SPEAKER_01]: GLP-1 medications, those sort of medications also tend to increase it's 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 him as like discordant sort of health benefits from GLP-1s.
[SPEAKER_01]: 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?
[SPEAKER_01]: And it's like, well, not only are there GLP1 receptors in these other tissues that seem to have some sort of benefit, but also because you've affected the flux.
[SPEAKER_01]: And once that flux has changed in your favor, where the fat is being turned over and moved around the body more efficiently.
[SPEAKER_01]: It has less time to do its dirty work just sitting in the tissue.
[SPEAKER_01]: And so if we can move that flux exercise, GOP ones, in many cases, other lifestyle changes like a calorie restriction, if somebody could stick to that for a period of time, all as well.
[SPEAKER_01]: 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.
[SPEAKER_01]: And it's like, well, that's kind of true, but also not quite
[SPEAKER_01]: It's not just too much body fat, it's too much body fat for a particular individual.
[SPEAKER_01]: And because it is outstrip 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 the flux.
[SPEAKER_01]: And we're going to get into that in a future podcast.
[SPEAKER_01]: Anything else before we sign off here, Dr. B?
[SPEAKER_00]: No, been a little while since we did a mystery case.
[SPEAKER_00]: I enjoyed it as always.
[SPEAKER_00]: I think that, you know, to the extent we're acquiring new listeners, if you enjoyed going through that journey together, go back in the backlog.
[SPEAKER_00]: There's plenty of other very fun and interesting mystery cases that we work through to teach other interesting topics along the way.
[SPEAKER_00]: So, check them out.
[SPEAKER_01]: Yeah.
[SPEAKER_01]: All right.
[SPEAKER_01]: Well, that is a wrap on the Barbell Medicine podcast mystery medical case.
[SPEAKER_01]: The man who couldn't stop gaining weight before you guys go anywhere, please leave us a five star rating and a review.
[SPEAKER_01]: It really helps drive traffic to our podcast so we can keep bringing you other latest nuance and health and fitness.
[SPEAKER_01]: For Bar, everyone at Barbell Medicine, I'm Dr. Jordan Feigambam.
[SPEAKER_01]: That's Dr. Austin Baraki.
[SPEAKER_01]: We'll catch you next week and every week right here on the Barbell Medicine podcast.