DIR Semiar Series - Giles Yeo

hi everyone so I am especially excited to introduce Dr Giles Yao who from for the na NH di seminar series um I personally have been following his work and His science communication for many many years um I may be the unofficial head of his NH fan club I'm not sure but I I would take that position um this is all for a really really good reason um so Giles Yao is a professor of molecular neuroendocrinology and program leader of the MRC metabolic diseases unit in Cambridge a fellow of Wolfson college and honorary president of the British dietetic Association uh he was appointed as an MBE in the Queen the Queen's 2020 birthday honors for services to research communication and engagement I had to look this up um it means that he's a member of the most excellent order of the British Empire which sounds very impressive um he won the society for endocrinology medal in 2022 which I know is impressive um and as I mentioned he's a very prolific science Communicator presenter of science documentaries for BBC podcast host author of two very good books um I won't go on but I will just remind the audience that this is hybrid so if you are online please submit your questions in the Q&A on zoom and if you're in the room please use the mic uh so that those online can hear you so without further Ado I will bring you on up to to start the talk thank you very much uh Susan for inviting me I am glad I wasn't sent home and that's all I'm saying about it so um folks um so my name my name is um my name is Giles thanks I'm based at the University of Cambridge and I'll be here talking about um mapping well actually I'll be here to talk about the genetics of the genetics of body weight but I'm beginning this um Talk slightly differently there'll be two parts to this talk the first will be um my efforts or our efforts in mapping feeding circuits within within the human brain and we we can we can go with that then there'll be a pretty hard left turn and you'll and you'll see that inflection point pretty clearly when I then go um from there into into genetics but then using as well this um resource that we've created um um in order in order to do things and and so look I'm a I'm a geneticist by trade and I think being a geneticist is a perfectly upstanding thing to do you know my mother-in-law still speaks to me so yay um but um when people ask what I study um and I say I study body on one end of the spectrum just happens to sit obesity immediately I become the bad person and I become the bad person because I'm perceived as giving fat people overweight people people living with obesity terms I do not use in any pejorative fashion whatsoever and excuse which philosophically has always been a very interesting take for me because if I was studying the genetics of pretty much everything else okay um cancer dementia arthritis whatever you know would I suddenly be giving the those people suffering from those conditions and excuse no I'd be trying to understand biology mechanisms I mean God forbid I might be trying to help somebody but when we talk about body weights Suddenly It's infused with choice and so this this mish mash of a lecture which I've kind of a talk which I've put together hopefully there's some element of a of a rebuttal within there so mapping the feeding circuits in the in in in the human oop sorry in the human brain so um we work on this uh General schema um in which we try and understand the control of of food intake and your brain needs to know broadly speaking two pieces of information in order to influence your food intake internal internal pieces of information it needs to know how much uh fat you have your long-term energy stores ose tissue uh Mass which is how long you would last without any food um and it needs to know um what your short-term energy stores and this is going to come from your gastrointestinal tract um all of these are hormonal these long and short-term signals are hormonal they circulate in the blood clearly and then signal to a part of the brain called the hypothalamus for those of you who don't know where the hypothalamus is Bridge of the nose base of the brain sitting right above the pituitary in human beings is about the size of your thumbnail shape of an almond and within the context of body weight because hypothalamus does many things but within the context of body weight it acts as a fuel sensor so it acts as one of the key areas in the body which sensors these long and short-term signals your brain then responds and translates these signals and then influences your next interaction with a menu with a refrigerator or with a restaurant and and as I said there are genetic modifiers that run throughout this process and we now know that the genetics of body weight is by its very definition the genetics of how our brain influences our feeding Behavior okay so that that that is where uh we're actually coming from now I'll be focusing on one part of the of the uh of the brain the hypothalamus which I said but the hind brain also um performs some elements of this um of of the same effect so this is a a schematic of the um of the hypothalamus over here it's obviously a squashed um schematic of it and I highlight this um because a it's a it's a it's probably the most heterogeneous part of the brain so that's interesting in of itself but I've also drawn you know specific neuronal populations here like pomc neurons and arrp neurons and I highlight this only to say that we have a tendency when we draw and I drew this figure when you draw these figures um um like that where you you have a tendency to sort of think that these are homogeneous groups of neurons which they're not because I think within there within these pumpy neurons agrp neurons whatever neurons there is a lot of heterogenity therapeutically relevant heterogeneity I want to I want to argue that sits within there which is of interest to us to actually um to actually study and so we use single cell genomics as well as spatial technology in order to try and unpick the heterogenity of of single of of of the hypothalamus we began in the Mouse um and this is published I'm we just show just just showing this one thing where where what we did was using our own data as well as pulling together um 17 or 18 of the largest at the time um um single cell work in mice we sort of integrated all the data so that we could actually use it as a comparative database um um in order to do so and so we ended up we ended up on the um on on on the cover which is always a good thing couple of things though about this um this is version one and so this this version two is coming up soon hyperap 3D we call it but it says Mouse hypothalamic Atlas on on the journal cover I'm not complaining but I am complaining a couple things that's not a mouse brain that's the first that's the first problem and that's not the hypothalamus so entirely inaccurate but I didn't pick the I didn't pick the figure um the picture and so and you can go to the QR code and for those of you who care about this and actually play with the data but a big reason for us doing this initial work in terms of in terms of mapping the the mouse hypothalamus is to sort of use it as a testing ground for the algorith Ms and Technologies we were going to need to do for our Prime project which is to do the same thing within the human hypothalamus now the human hypothalamus for obvious reasons it's quite difficult to get to you can't get to a human brain legally um um you know from a living uh being um but now with a obviously the single cell and spatial Technologies as well as access to human brain donors from brain Banks we're now able to actually put this um um um put this together so we've used the MRC brain Bank Network for this but recently we've now got got access to the NIH brain Bank as well um and so we'll be begin to get uh brain samples as well from the from from the brain Bank this brain Bank Network I don't think is a I think is a rather dispersed um um Center for for that and so here is the human um our efforts okay which is John just gone in press and should be out hopefully in a in a few in a few weeks and you can see here a um map for those of you who work with single cell data um this is this is what this is and we have divided it up from non-neuronal cells and neuronal cells that are here and then there's a a circular dendrogram a circle of life shall we shall we say in which we can actually then see the various neuronal populations we've only given the first four levels here so there's actually more um visual but it actually goes up to six levels and there are 450 or so different types of different types of of of population 40% neurons 60% non neurons um from from there so if you then um the first thing we did was to actually compare the human database to the mouse database okay because yes we use mice as a model but how similar because it's one of these things right where the vast majority of feeding circuitry at the moment the our understanding has come from has come from Mouse work and we are very very good at now removing specific NE specific genes from specific neurons at specific times but how many of these populations actually exist in the human in the human context and so this pretty diagram over here broadly speaking it's most of the populations that matter do exist in both humans and mice broadly speaking which is why we use mice as models and that's absolutely fine but what I want to and I'll give you one specific example later there are relatively nuanced but therapeutically relevant differences that are well worth actually trying to understand when we when we're looking at these and I'll highlight one of those um one one one of those in in in a bit and so we also use spatial transcriptomics in order to try and understand this and so this is uh um a few brain slies and you can see here for example you can see the the the spatial markers here's the arute nucleus here's the ventral medial hypothalamus here's the paraventricular nucleus not a lot there because it's a different slice um and then here you can see this the the reasons why spatial transomics is important um these are glutamatergic neurons these are gabaergic neurons and you can see that there is a enrichment of glutamatergic neurons within the ventral metal hypothalamus whereas gabaergic along the outside so there are always spatially distinct um things that we can actually tell tell from here now that was not at the time when we did when we did that work it wasn't single cell level okay now you can get single cell um um genomics sorry single cell spatial transomics and so we needed to sort of put the Single Cell stuff together with the spatial stuff together and so we used a basian approach called cell to location which is written by the Bor lab from the sang Institute in order to deconvolute the single cell data into the into the spatial into the spatial data and so this is what it looks like um we've taken just the ventromedial hypothalamus and at level three we find five different um five different clusters of of of cells of neurons and this is what it looks like when you actually map it from a spatial perspective they all map within the ventom medial hypothalamus that's because it's not surprising that was our what we choosing it but you can see that each of the five and they're colorcoded each of the five different um um clusters here maping different so the blue one for example Maps um here whereas the dark blue here and you can see spatial distinction now this is just a pretty picture for now obviously but this is whole transcripton which means that you can ask any questions you actually you actually want and from here you can then begin to actually ask um some some useful some useful questions so for example now this is the hottest thing since hot things these are the new the new anti-obesity drugs that are that actually around tepati or semaglutide which is either OIC or um wovi and tur zepeti which is either Zep bound or monjaro um and they target the in receptors so if we actually map The enrtin receptors where do they actually sit certainly within the human hypothalamus right because all of the the previous work about mapping this have all come from Mouse um um have have all come from from the mice and so if we didn't do that and let's focus on the gp1 receptor so gp1 receptor is the receptor for semaglutide so OIC and and movi so first piece of information is that the glp1 receptor in the brain at any rate because obviously there's also peripheral there also peripheral receptors in the brain is exclusively neuronal okay so that's the first piece of information and then we can then have a look to see well where within the hypothalamus and what spatial what spatial um relevance is there so here for example um is something within the paraventricular hypothalamus and because it coexpresses sim1 um it is interestingly only the only part of the hypothalamus that also coexpresses the Gip receptor so glp1 receptor is for if semaglutide tepati targets both the Gip and the gp1 receptor so this is the only part of the hypothalamus that is coexpressed everywhere else they're single operators they they they are completely separate separate sets of sets of neurons and if you see where they map from a spatial perspective they map within the par ventricle hypothalamus now how about and how about then within the arute nucleus so another part of the of the hypothalamus so here we see two distinct types of of populations of the Gip receptors once that coexpress the leptin receptor and PC I'll come and talk about these in a second and ones that Express the the calcitonin receptor and these then map in completely different areas they all Express the gp1 receptor but they map in completely different areas so for example the ones that coexpress leptin receptor and PC are expressed down here whereas the ones that Express the calcitonin receptor are completely different parts of the hypothalamus wrapping um um wrapping the ones with the with the leptin banoon pathway now this is relevant because at the moment Nova norisk who make semaglutide are testing combinatorial therapies including semaglutide together with their calcitonin receptor Agonist ktide called kagema so so it is important to know you know particularly where where the cells expressing gp1 receptor calcitonin receptor and where they're actually um coexpressed um as well now here is probably one of the first um species specific difference that that we actually find so in human beings if you actually in mice let's do mice first in mice if you have a neuron that has gp1 receptor and leptin receptor and then there are separate populations of cells which express pump C and the gp1 receptor in in humans and this is in mice they separate populations in mice in humans if you have the glp1 receptor and PC you always express the leptin receptor as well so there are a group of a single group of neurons relatively nuanced but given that they're drugs targeting all these cells with within the brain I think it's important to to actually understand um what they're Express what they're Express with now how about the Gip receptor now the Gip receptor um unlike the glp1 receptor within the brain is not exclusively neuronal in fact it's mostly non- neuronal 60% non- neuronal 40% neuronal okay and and largely they're expressed within within Olen sit so this big lump of cells over here so of the 480,000 cells 450,000 cells 200,000 are olender sites 10% of of them Express the drip receptor what the hell are they doing there no clue okay we have no idea what they're what what they're doing there at all and if you um if you look at the neurons they're not particularly interesting they're there they're expressed within with within neurons so I'm not going to show you any pretty pictures but if you look at the non-neuronal cells then the oligodendrocytes have spatial distinction that's fine we're still trying to figure out what the hell they're doing there but here is a really interesting population of cells the ependymal cells okay which also Express the Gip receptor and you can see that where they actually sit if they line the wall of the third ventricle of the of the hypothalmus it's very very very specific now monjaro tepati is more effective subtly more effective than semaglutide people have been wondering why is it because it targets both incretin receptors in other words is it dual organism um or does The Binding of the gp1 receptor here enhance excess of the drug to the whole hypothalamus I don't know know the answer but now at least we because we know where they're expressed we are in a position to actually be able to to at least ask the questions that that that were that were there okay and I can show you any number of other things but I won't bore you to that so genetics turned now okay where we then decided to try and map the genetics data onto these neuronal neuronal clusters or cellular clusters and so if we actually take gwas genes first and there are over a thousand of gwos L sign so if you take the Locust uh um G the clear the nearest Gene to the Locust with the BMI G was hits um and map and ask which of the 452 um hypothalamic clusters if any do they are they actually enriched in and we actually find that 291 of these cell types are are enriched for these BMI GW genes and if you see where they map and on the left hand side what you can see here is you can see where they are within hypothalamus neurons or non or non neurons and you can see that the enrichment is exclusively within neurons so while I say that the genetics of body weight is the genetics of how our brain influences feeding Behavior it's not just a geographical area it is specifically a neuronal neuronal signal that we see okay so that was interesting in in in of itself then what we asked was okay well of these thousand genes which were driving the enrichment and when we did that then we found that the enrichment were not driven by all thousand genes but were driven specifically by 426 genes so now we have this we then did a gene burden analysis an xwas okay to to actually find whether or not rare changes within the coding regions of these genes have influence on population level on population level changes so just briefly what an xwas is gwas clearly you take an individual signal you ask whether or not it co-segregates um with a specific trait if it's 50/50 then it's random if not and you take each individually and it has to be common enough to appear on on an alumina chip or what have you all right the difference and so it has to be common and it's largely non-coding because 98% of the genome is non-coding but an xwas is what happens is you do whole exome sequencing at scale so we're looking now at at the whole of UK biobank for example half a million people has been done and now you can look at the coding regions and look at all the changes rare or common now an it's called an xwas or a gene burden analysis because instead of each individual signal being the statistical Mo you're testing against what you do is you aggregate all of the changes within a given Gene so the gene has become the statistical Moy you then aggregate all of the changes rare or not into it it's a gene burden and ask changes in a specific Gene loss of function changes is it associated with body weight change at the population level okay that's the what that xw is and we found six of those genes did reach population level of significance now a few of them are positive controls okay the mc4 receptor pcsk1 uh the calcitonin receptor where is the signal the calcitonin receptor and PC so these we have known are actually at at the population level but we also identified a couple of new genes um that I want to talk to you about so I'm I'm going to focus now and actually change the tenor of the talk entirely to go to a purely genetics talk where I'm going to focus on the melanocortin pathway I'll talk about that in in in a second um and then I'm going to end with this new Gene we identify called bassoon okay and and and that has that has population level changes in terms of in in terms of uh body weight so now the leptin melanoon pathway so for those of you who don't know what that is this is the fat sensing part of the um of of the brain and so leptin is a hormone it's an ocine that circulates in proportion to the amount of fat you have so the more fat you have the more leptin you have and it signals to the hypothalamus as I um as I say within the hypothalamus leptin signals to a population of neurons called the pom C neurons are pro opio melanocortin pump C is sliced and diced by prohormone convertases into biologically active peptides melanocortin peptides hence the leptin melanocortin pathway which signals to the mc4 receptor the melanocortin 4 receptor and three receptor I'll touch on that briefly as well in order to influence in order to influence body weight now for this part of the talk there are a couple of narratives so so first is that any all mammals and any higher vertebrates that has a demonstrable fat mass will have a Le meanon pathway because this is how we sense the fact okay um so that's unsurprising it's a conserved pathway what was surprising and still is I think to those of us within the fields is that genetic disruption of the pathway as a strategy to influence feeding behavior is also conserved across and so I'm going to highlight just a couple of um um some traditional but some surprising animals that have naturally occurring mutations within the pathway which actually influences their their their their feeding Behavior so palom SE okay first of all so where is the first genetic evidence that pom SE results in severe obesity so this is work actually done by my colleagues at the charate hospital in Berlin anet grus Huda and pomy is a complex molecule because it does any number of different things it signals to five different melanocortin receptors um and you can see that if you have a human um pumpy uh mutation this is a homozygous mutation this child has um is that he has bright red hair because of a lack of M antin action at the melanocortin one receptor which is important for um skin coloration and hair color so natural red heads will have homozygous mutations within the MC1 receptor making their head Bri bright bite red okay it's a recessive it's a recessive disorder but actually disorder trait but actually um 40 to 45% of white northern European Caucasians will be heterozygous for polymorphisms when in mmc1 receptor and you know the phenotype because you are not you're unable to stand in the sun without Factor 500 okay so you you you can't there's no protection at all from the Sun heterozygous for the MC1 receptor it's got isolated act deficiency because it doesn't have act that's a product of pumy and it's got hyperphagia and obesity because of a lack of melanocortin action at the MC at the mc4 receptor so I we knocked out the mice in um in 2000 in order to actually uh in order to understand the biology but we've also been more recently working on Labrador Retrievers now Labrador I don't know if there are any Labrador owners in in in the crowd over here but they're it's the most popular pet dog in the UK and I think North America as well and in in the UK we use them to sell toilet paper that that it's the it's the andrex puppy now and this is work that was led by my Veterinary surgeon colleague Elanor Elanor raffen um because these dogs are tremendously food motivated very food motivated you you got to keep all your compost bin shut everything because they'll in there eating everything that everything everything everything there and what is interesting is that a percentage of Labradors have this deletion in PC okay so they have a they have a sort of broken um fat sensing fat sensing pathway now not all the Labradors have it and so you can do when you do a genotype phenotype correlation and what you see here is a weight in kilograms you can see a gene dosage effect so the heterozygous um Labradors are on average 2 kilos heavier than the wild types and the homozygous on average four kilos heavier and that doesn't sound like an awful lot but Labradors only get to around 30 to 35 kilos so so 4 kilos is a lot of dog now then when we did food motivation and in this particular situation the food motivation was done by questionnaire to the owners not the not the dogs um but actually they're modified feeding Behavior questionnaires for parents okay to to their children because some people consider pets as their children but modified questionnaires and it works and you see exactly exactly the same exactly the same pattern over here and the interesting thing about studying food behavior in dogs I'm not a doggy person um but obviously I'm also vet is that you can't use a traditional Buffet ad libitum test meal and the reason you can't do that is because dogs in particular Labradors don't actually know when to stop so if you given them all they will really literally harm themselves so at the moment what Elanor does for example one of the studies in addition to question is is there is a sausage in a cage study sausage in a cage as you might imagine you have a sausage you have a cage and you can't get into the cage without opposable thumbs okay and so the dogs don't and so the experiment is how long will the dogs focus on the sausage in the cage a bloody long time is the answer okay when when it doesn't when it and so that's the some of studies that that we're actually that we're actually doing okay so this is what I was saying a couple of kilos per um per deletion alio um and3 of a standard deviation of body weight for those of you who follow the BMI GW studies three times the effect of fto but this is not the end of the real the story a couple reasons why first only 20 to 25% of pet Labradors have this deletion um and so um but 95% of pet Labradors are really food motivated so Elanor right now is throwing the genetic book at this omix and was and whatever at it okay in order to try and find and she's got a paper now actually impress um at science in which we've actually she's identified a few more genes as um as well so Point number one point number two there's a dunum um to this to this particular tale so Pat labors are have a wonderful temperament which is why we have them as pets but Labradors are also very very very trainable in fact they're so trainable they're primarily used as assistant dogs guide dogs for the blind in particular and guide dogs are like the Navy Seals of the dog world I mean they've been trained within an inch of their life because they're about to be given a human being to look after for the rest of their life and they and the the the training pyramid is very steep loads of failure nothing happens to them they become pets um but you get the few the proud the guide dogs and they're trained interestingly using pavlovian approaches with food okay 80% of successfully trained guide dogs have this deletion in PC so here here's the concept okay imagine if I'm if I'm the guide dog and I'm bringing home visually impaired Mr Smith okay and what happens if suddenly a chicken runs across the road now in doggy algorithm what are the chances of having chicken for dinner is it 50/50 is it 8020 it doesn't matter because the successfully trained Guy dog understands that it has a 100% chance of getting dinner if he brings Mr Smith home safely because of the selection pressure that's actually applied um applied upon there so we ended up also on the cover of this particular uh journal the human being is Elanor she's who still leads the study um and uh Jasper is the is the chocolate lab that's there one of our one of our participants so for those Labrador owners who go back home and the dogs have big googly eyes and said oh Jasper loves me he doesn't love you he's hungry it's true I'm just telling you the truth ladies and gentlemen just telling you the truth so so this is where I actually ended up on um on in terms of from a chronological order where I ended up on the scene this was my first um paper out of my postdoc and we identified that mutations within the mc4 receptor which pomc binds to so we're now working down the pathway pomc binds to the mc4 receptor results in severe obesity but here we get is where I think it gets interesting now it's interesting enough that the next few slides are focus on the mc4 receptor and there are number of interesting things about the mc4 receptor so first it doesn't only make you eat more it actually changes your feeding Behavior so this is not work that's done by me it's done my done by my colleagues so this study over here uses a chicken curry eaten M study I'll explain I'll explain it in in what in in in a second why all right so first of all the study participants you're going to have people with mutations in the mc4 receptor all heterozygous mutations um so therefore have severe obesity um you have body weight matched individuals but without the uh without the mutation in mc4 receptor and then you have controls now the study is you walk and let's start with a curry study there three trays of Curry now why Curry because you can adjust the amount of fat that goes into the food by whisking in vegetable oil all right now it won't change the flavor but it might change the texture and some people like greasier food other people don't it's a it's a you know it's a personal personal taste so you come in all three groups you taste all three curries you rate the one you like the most and then you eat then you eat the one you want so you could you as you might imagine there's a normal that's a distribution but all of the people with mc4r uh mutations go for the high fat option all of them so were we surprised well we thinking well we know that mutations in the pathway make you eat more maybe one of the mechanisms is by making you eat more energetically dense food then we get to the eat and mess study which was interesting so what is eat and mess eat and mess is what happens when you take a Pavo Pavo drop it onto the floor and scrape it back into a bowl all right so it's an eatan mess but what happens there is you can adjust the amount of sugar in eaten mess in the whipped cream and in the merang so now you reset the study up but now with a goldilock selection of the amount of sugar and here's the interesting thing the mutations the the carriers of mutations in the mc4 receptor all went for the lowest sugar option so now one mutation one Gene and suddenly we like high fat food and the low sugar low sugar option here for that so it doesn't only make you eat more it changes your feeding Behavior interesting fact number one interesting fact number two it's more common than we thought okay so we were studying it as a rare condition within severe on onset obesity but then we begin to realize in in true severe obesity so 99.9 centile we were probably finding it anywhere from 6 to 10% of the population so really quite relatively High uh but in severe obesity but what happens in the general population so this we worked with our colleagues um in Bristol um who work with the aen longitudinal study of parents and children all right and it's a it's aan because of the river aan which actually come come comes out by Bristol and this is a Birth Cohort rather than a disease cohort so in other words we didn't go out and find severely obese people this women pregnants between 1990 and 1992 were invited to come to the study in Bristol and then their offspring have been followed up since then so now they're in the 30s obviously it's colloquially it's called the children of the 9s study um but it's called alpc it's 12,000 participants so we screen and is an all okay so anyone there so we screened the mc4 receptor um in this cohort and found that 3% have lost of function mutations in the mc4 receptor so if you extrapolate that to the UK population 66 million people it's 200,000 individuals all right if you extrapolate that to the US population there more than a million people with mutations within the mc4 receptor and there is no good reason to imagine why there are differences certainly in these rare loss of function mutations rather than Snips in prevalence in different populations because we found mc4 mutations in pretty much every um um population we have looked for to date and as you'll soon see in most creatures as well all right so 3% okay which is a lot which is a lot of people so what does it look like what happens in the wild okay so at 18 years old because you remember this is a longitudinal study at 18 years old heterozygous mutations in the mc4 receptor mean that you are on average nearly 18 kg heavier so 40 lb okay that's a lot of weight heterozygous mutation this 18 kilos average is roughly speaking 5 BMI points so it's a lot of BMI points 20 to 25 25 to 30 and of that 18 kilos average 15 kilos is fat 200,000 people more than a million people within within um within this country potentially having mutations interesting point number two interesting point number three there is now a drug that targets the system so this is the same group that identified the first kids with the bright red hair for pump seed deficiency um and they work together with the pharmaceutical company Rhythm Pharmaceuticals um with an mc4r agonista drug called set meanti okay so this is the original paper the proof of concept paper um it's all color coded so just follow uh just look at the red growth curve that we actually have here and the study here is set pantide so daily injections which binds to the mc4 receptor um in the two in two kids with no pump C homozygous pump C mutations and just to give you an idea of scale so patient one in red at 18 years old patient 1 is 160 kg all right so that's what 350 lb there and there about these are big people okay so and then patient one is treated so patient one is treated for 42 weeks so the xaxis is uh is weeks the Y AIS is weight in kilograms and what you can see here is after 42 weeks of treatment patient one has lost 50 kg 5 now the longitudinal data is now out just came out of a couple of years ago same color coding look at the red patient one again and the x-axis Still Remains weeks so we see now that it's gone out to 7 years 350 weeks or so couple of things you can see that the maximum weight loss is achieved around the 2year mark 110 weeks or so 70 kilg has disappeared a whole of me has disappeared from this human being because of daily injections of um of set meanti and so this drug so there's a drug that targets the system and is really energ I the field so this drug is now approved um by the FDA for now um has now been approved uh for rare genetic causes of obesity so pomc deficiency pcsk1 which is the enzyme that chops up pomy deficiency leptin receptor deficiency um B Beal syndrome and a couple of other rare disorders and is currently being trialed and tested for mc4r deficiency it's I don't think it's going to be a OIC Blockbuster thing it doesn't appear to work particularly effectively in generalized obesity but certainly when it comes to specific genetic causes of obesity this is a this is actually a well uh uh worked out system now okay interesting point number three the last interesting point is if you think about 3% it's not super rare it's not super common but you know that evolution is pretty damn good at stripping out a change that has negative consequences no matter how small to your reproductive uh capabilities so it's kept it around for some different for some reason what happens when we look at other species okay so for example let's look at the livestock industry okay now these pigs not that pig that Pig's from Google but the pigs within within this particular um um paper here are breed for bacon okay that's just what they are they're bacon pigs so what are what are livestock Farmers what are they doing okay well they do selective breeding right you pick specific traits that you want from uh growth trajectory fat to lead Mass ratio whatever it is and then you do selective breeding we've done this for Millennia this is how this is how we domesticated animals all of these pigs have mutations in mc4 receptor and these are not genetically modified Pig naturally occurring mutations which because of selection pressure has then been enriched all of them have mutations in the mc4 receptor and this is not some weird mamalian thing neither okay so let me introduce you ladies and gentlemen to the blind Mexican cavefish which really begs two questions why are they blind and why are they Mexican I'm going tell you the answer so the big asteroid that came down and killed all the dinosaurs 65 million years ago hit what is now the Gulf of Mexico or maybe the Gulf of America anyway so so so in into the Gulf of Mexico and when it hit the when it hit the the bottom of the ocean cracks form they had underwater caves fish got stuck in them hence they are Mexican cave fish they're blind because there's not a lot of light there's no light in an underwater cave so over millions of years their eyes evolved away why am I telling you any of this because there's also not a lot of food in an under water cave so any Mexican cavefish who was remotely Blas about the planton that was floating by and then snap it up became an ex fish every single blind Mexican cavefish and there are a lot of them okay have mutations within the mc4 receptor ladies and gentlemen where is the choice okay people think feeding behavior is a choice I'm talking about a fish pigs labors a million people potentially in this country okay where is the choice if you supply enough of a selection pressure on an existential trait and really there are only two true existential traits reproduction and feeding you fail at one you fail at L we understand this so if you put a powerful enough um selection pressure on an existential tra it begins to hardwire Behavior including feeding Behavior where ladies and gentlemen is the choice now let me briefly segue into the MC3 receptor now there are five melanocortin receptors three of which are peripheral two of which are Central in the brain the two Central receptors are the mc4 receptor which I've just talked to you about and the MC3 receptor melanocortin 3 receptor they're all through genome duplication so they're all homologues of of of each other now the MC3 receptor was not a straightforward story um and we were studying it at the same time we started studying the mc4 receptor which was the late ' 90s and equivocal okay you would look at all of the studies done prior to this paper I'm going to tell tell you about and actually it was a 50-50 thing thing about whether or not the MC3 receptor had to do with body weight or not so now however because we are in an era where I'm going to argue that that genetics has been democratized what do I mean by this where you actually have the large cohorts UK biobank um any number of other cohorts have now been sequenced whole genome sequenced even where we can now just ask the question about about these now we used three different cohorts which are probably worth uh uh telling you about we use elbac which I already told you about this is the long udal data but relatively small 12,000 okay UK biobank half a million healthy UK controls okay that gives you power because of it but it's cross-sectional and genes and health now genes and health is an interesting conglomeration of four different cohorts it's a study 50,000 individuals a study in the UK which focuses on UK South Asian people of South Asian descent in from the UK in particular people of Bangladeshi and Pakistani descent so in in London for example example is East London jeans and health which is roughly 5050 people from Pakistani descent or Bangladeshi descent born in Bradford which is in north of England which is pretty much exclusively from Pakistan and a population in in Manchester and a popul population in Birmingham 50,000 participants why these populations these separate studies were originally set out as because they were immigrant based populations as a sociological study to see um you know insecurity and education what what have you and it then became a more broader genetic study but because of the but because there are increase of consanguinity so cousin cousin marriages within these populations we were then able to identify rare homozygous loss of function mutations so elpac for longitudinal data UK biobank for power genes and health for rare homozygous loss of functional mutations which were able to harness all three to understand the biology of the MC3 receptor so first UK biobank so for UK biobank we just say okay where are all the mutations within the MC3 receptor we functionally characterize them and look for the loss of function mutations and we're now in a position to understand what happens when you don't have the MC3 receptor so I've colorcoded the phenotype in in the heat map Green is increased purple is decreased and when you have a heterozygous mutation in MC3 receptor you have a delay in puberty age of manarchy in girls age of voice breaking in boys now how much of a delay now this depends on the level of dysfunction if you look at this particular mutation over here f 45s it is a dead uh um MC3 receptor mutant okay we've tested it completely dead um 1 in 700 carriers in UK biobank so we found over a thousand of them if you have a heterozygous mutation half a year delay in puberty now remember these are not you know kids that are in a puberty Clinic these are just regular normal people normal distribution half a year is a pretty long time for delay in puberty now if you then focus on on this particular mutation up here v44 I now that is found in one in 10 UK biobank carriers so we want 50,000 carriers delay in Pub and it's close to Wild heght in terms of the function and in terms of the delay and puberty 3 weeks but because we have 50,000 individuals we're able to actually pick this uh do down so delay and puberty this delay and puberty is associated with a reduced um somatic growth okay so this includes atout height sitting height leg length Total Lean mass as well as reduced igf one but crucially if you look at all of the anthropometric traits to do with obesity so BMI waste of hit ratio risk of type two diabetes entirely white okay so within the context of population genetics the MC3 receptor while associated with timing of puberty and somatic growth is not an obesity it's not an obesity Gene we found one at the moment we have more now but we found one rare homozygous loss of function mutation dead receptor so is a null okay um and when one uh person from genes and health and you it's a g240 W uh mutation found in an individual of bangladashi origin completely dead receptor and he displayed um exaggerated phenotypes compared to heterozygous carriers for example he did not go into puberty till he hit his 20s which is pretty late but crucially he's not infertile because he has three kids so the MC3 receptor influences the timing of puberty but it's not required for it's not required for for puberty so how might this be happening well so what we did here was um we then went back to our single cell of single cell data and you can see where these are so I've mapped just just for context I've mapped where pom C the liand for the melanin receptors sit we found three different populations of pomy one that Express the leptin receptor one that expressed calcitonin receptor and ones that Express so three and you can see that they sit in different parts of the hypothalamus now look at what happens with you actually look at the MC3 receptor and you first of all you can see a completely different pattern of expression and there three different populations of MC3 receptors we see MC3 receptors expressed on kisspeptin neurons now kisspeptin and its receptor gpr54 is required for puberty if you have mutations in either kisspeptin or his receptor you're infertile so it does appear that MC3 receptor on kisspeptin um neurons influences the timing of puberty it's coexpressed with um GH R growth hormone releasing hormone neurons and we think that this is where it's um mediating its growth uh phenotypes um and so this is what we think is happening so where what where are we with this Central leptin melan quoten pathway and so we have a model this is a model um of we think a bifa model of nutrient sensing by the central leptin mananan pathway so so what are the secular Trends in human biology today well we are certainly getting fatter we are getting taller and we're going into puberty earlier and it doesn't matter which populations we're studying this is pretty much true um um at at all the different populations and we think that this is being mediated at least in part by the central leptin meanin pathway so you have these signals long-term energy signals coming in leptin as I talked about insulin which I haven't talked to you about today and then via the manano neurons via the mc4 receptor regulates appetite and energy storage I've talked to you at length about that but via the MC3 receptor regulates growth a cool of lean mass and a timing of sexual maturation now I'm going to I'm not talking too long okay just just a few more minutes and so I'm going to end on bassoon so bassoon is one of these new genes that we identified using this this Gene burden analysis two different Gene burden analysis one from the hypermap study I just showed you but one through a study which I did with my epidemiological colleagues so bassoon is a pre or BSN is a pre synaptic protein with a role in exocytosis mediated neurotransmitter release and it's called bassoon because it's bound to Piccolo because scientists think we have a sense of humor but but I think the Deep disappointment for me is if you're going to have a metaphor well lean into it where's the rest of the orchestra I don't see no clarinet where the violins anyway it's just bass and Piccolo so anyway so what we then did was this is based on um on on actually inspired by a study and this is the first example from regeneron abbar atel in science in 2021 so relatively recently the first example of this Gene burden analysis this xwas at scale so they sequenced 640,000 exomes including the whole of UK biobank as well as a number of other studies based here in the United States okay and um an identified a number of genes that I described to you using that g that Gene burden analysis that are novel and are linked to and are linked to to obesity okay for that so our question John Perry who's my epidemiological colleague and and ourselves asked the question okay well you got to do a number of filtering steps to get to the stage right so what qualifies as a loss of function this that what have you and so if we make different filtering decisions would we identify different genes okay and turns out we could and so when we then did different um um filtering choices we then identified two completely new genes bassoon okay which I'm going to tell you about and apba1 which I won't U talk to you guys about today now let me just explain what these stick and and line and stick diagrams actually actually are they're like a six-dimensional um figure which for genetic nerds is is is older older age and so what happens here is that blue line I can't get this straight the blue line over here there we go is the transcript okay just the transcript all the introns have been spliced out now where you meet a perpendicular line pointing up or pointing down that's where there's a mutation that's been identified the if it's pointing above the line it is increased body weight below the line is decreases body weight the distance away from the transcript is the significance at the population level that is linked to obesity or body weight and the size of the blob the number of mutations we identifi Six Dimensions okay from there now the one thing we want to get from here is that most of the perpendicular lines are pointing up that's the point all right and so it increases body weight but if you actually look at the effect size at the population level now this is very very rare in half a million UK biobank carriers we found 65 carriers of protein truncating variants which is what we used okay so stop gains um um either through frame shifts or nonsense mutation stop gains and we find that it has a larger effect size the emc4 receptor at the population level so so for body weight it's the largest effect size we've seen at the population level today now the other interesting thing about this is that it associated with adult obesity so UK biobank is a cross-sectional study all of the individuals the half a million individuals were recruited when they were between the ages of 45 and 60 years old and that's fine in fact the only longitudinal thing that you study from UK biobank is cancer okay it's probably one of the largest ongoing cancer studies that that that are actually going on but there is one question okay within within you fill in your millions of questions that are there there's one question and the question is regarding your childhood is at 10 years old in fact you can you can think about whether or not you know the answer to this at 10 years old were you below average weight average weight or plumper than average the British study now I don't know about you guys I don't know much of what happened to me when I was 10 years old but I did know that I was heavier than average because everyone told you all right and actually when you did and and went back and checked the the the validation for this entirely correct if mc4 receptor just as an example I told you. 3% if you actually look at the signal big large signal I was larger as a kid because big kids big adults and most of the mutations within the malan within the leptin malan way big children all right bassoon not a sausage zero signal from from adult obesity sorry from childhood obesity it's an adult specific onset obesity now the interesting question which we can't answer at the moment because of how rare it is and the fact that is only based on this one question is when in adulthood so I guess there are a few options we could consider puberty I think this is the least likely option because 10 years old is too close to you being able to get the puberty but if it was py that would imply hormones I was I I I would have thought you could then well did it occur at the freshest 14 or freshest 15 uh um stage now that implies choice so you've left you've left home now you you can go to the cafeteria buy what you want woo and then you gain weight that's that's a different mechanism because now it's it's feeding Behavior question or is it middle-aged bread okay because something just happened when I turn 50 whatever okay now each of those would have a slightly different mechanism we don't know is the answer but clearly it's a something uh um has happened some acrel of of biology has happened that you have really quite a large change in body weight but specifically in adulthood and no signal at all in in in child in childhood and you can now see as well as the distribution now here is then the complexity and the slight Nuance of it so this is the distribution of body weight the furthest I would I can signal this um so the furthest right in terms of this graph that is UK biobank the TRS so these are all the people 400,000 or so with no mutations in bassoon or mc4 receptor and this is the distribution of body weight in the British population okay the warmer colors are people who are overweight or have obesity and so what this tells you is in the average British population 2third of the population have obesity or are overweight and I think the numbers are probably slightly higher here in the United States but there we go um okay now this is where it's interesting if you then take a look either mutations in the mc4 receptor or bassoon it increases your likelihood of being overweight or being obese and that's fine or having obesity that's fine but you can see that even with a mutation in the mc4 receptor you can be of healthy body weight and so when we when we first published that mc4 paper in 1998 now we called it a number of different things we called it a dominant mutation okay and we called it a monogenic cause of obesity which are big words all right and dominant is a after all following the words of a 17th century uh um Franciscan monk okay big words but if you look at this data here now these are all loss of function mc4 mutations but yet you can be normal body weight so is it dominant right I mean what what are we what are we talking about here so clearly there's background genetic information there there's a number of other things and is it monogenic because so it clearly is a key genetic driver but I just think we need to be more nuanced in our genetic terms which we all learned and know when we were in high school dominant you know menal and his peas you know but I think we do need to have a slightly more nuanced view um um of of of genetics so in conclusion obesity is a chronic relapsing disease of the brain and that's what it is the pathways underpinning obesity are conserved through Evolution using spatial transcriptomics in combination with N Seek we provide a de detailed sensus of hypothalamic cells in a spatial context and using this resource we have identify new genes previously not linked um to to to BMI so this is so with that I want to thank my senior colleagues St rattley uh Tony Cole the guys in bold have done the work this is work that was done in close collaboration with my colleagues from the max plank um Institute in Cologne yens Bruning Lucas stle um my uh farmer colleagues from from Nova nois um but more importantly the brain banks for which we can't actually um get any of the work uh done and this is this is the team and if you can travel by then um we are organizing the seventh International Milano CED meeting in k cdge and with that ladies and gentlemen I'm very happy to take uh questions thank you so [Applause] much thank you this was uh super interesting at then um I think I latched on to the point when you were talking about the Cave Fish and you were talking about the fact that the Cave Fish had this like you know theoretical lack of preference for types of foods they're just not picky yes you know and I'm I'm wondering whether or not you had any of the like eating Behavior or eating info about those people who have like uh like bassoon for instance of whether or not these individuals are then also less picky about the foods that they eat they have preferences but they don't they might have a wider swap of foods that they're willing to eat okay but soon we don't know because um it's they're rare and UK bio bank doesn't have recall by genotype however um certainly when it comes to mutations within the leptin melanin pathway then we do have have data about this lepin deficiency in particular so the first one which I didn't I didn't show you is they don't have any preference for food at all so in other words because I guess I guess the analogy I will use is this so because leptin deficiency means that you have no leptin obviously in a normal situation because it reflects fat Mass you don't have leptin when you don't have fat when don't you have fat when you're starving okay now we know that that we are if you're really hungry the simplest Foods taste the best bit of bread bit of rice bit of cheese if you're really really full uh you need to have you need to have desserts okay you need to have something really really you become picky with your food if you're starving actually starving like the the kids with um leptin deficiency and to a degree mc4 deficiency you then you eat anything because you think you're starving so you then lose the the perception of it and their brain Imaging studies actually so my colleagues I'm not a brain imager my colleagues have actually have actually done this way if you take people with uh with no mutations in in the pathway and if you put them in um uh fasted and therefore hungry and show pictures then your brain will will will squash together pictures of dessert and pictures of broccoli for example all right if you're really really hungry whereas the moment you are full then suddenly you your brain only lights up with the calorically dense food if you take kids with leptin deficiency they they look like they're starving because their brain thinks they're starving even though they're very very large but and even if you even they're fed they have no discrimination between the two but when given leptin suddenly they're able to discriminate between energy dense foods and energy unded umum foods Foods again so so within the LEP and pathway they don't discriminate between um between Foods no oh okay cool that's really interesting thank all right well our next person comes up I'll ask a question from online yep right here um so uh first question is do you see epistatic feeding obesity growth effects among individuals with rare variance in different genes ah okay that's a good question so um these mutations in these genes are rare enough where if you have a mutation in the mc4 receptor like a like a whack and graping mutation you don't have mutations in other genes we haven't found any any in in in this particular pathway any overlaps yet obviously they're going to be overlaps but just in terms of if I can add to that to that answer um what we then did was in our um alpack paper the one where we looked at mc4 receptor we then applied a polyenic risk score for regular BMI GW Gene so polyenic obesity and what happens we took the the top death a and the bottom death a and and then put against the prism of mc4 deficiency and even with a monogenic condition whatever that means um if you're in a top desile you're heavier if you're in a bottom desile you're lighter even with mc4 mutations so your back your other your genetic background does matter even when you have mutations within within this particular pathway I think it'll metal less with with leptin deficiency but that's so rare is difficult to be to to to be certain about but yes there are there are definitely your your background genetics matters um so I would just thinking about um first I really enjoyed your talk it's really amazing um for the MC for Gene are there has that been linked at all with like B eating disorder or how do Bing disorder play into this larger picture so binging disorder is a very is a very different thing there was an early um New England joural thing about saying whether or not there's an increase in binging disorder I I think there probably is a slight overlap but binging disorder is different from hyperphagia so hyperphagia is a biological drive to eat because your brain thinks you are hungry or don't have enough fat so therefore it's it's a hunger driven thing binging I'm not an eating disorder a person but binging I think you eat without being the hunger so I think there are different drivers for for for the binging there's a slight overlap with people in mc4 deficiency but I think that that is then a misdiagnosis of what binge they think that the hypophagia is binge eating I think Bing eating disorder is an eating disorder which is the first part of bulimia obviously with the binge eating and a purging um but I think that's a drive to eat that is non homeostatically driven it's driven for other for other reasons um um entirely and just as an addendum to to that question because as a related question when we first started studying the severe obesity people then ask was anorexia Noosa the opposite the severe obesi and actually it was a fair enough question um turns out it's not healthy leanness so people who are just congenitally just lean and annoyingly healthy okay is the opposite of obesity okay because if you look at it from AP polyenic perspective they have they have the lighter versions or genes whatever you want to call that anorexia all of the signals which should tell the the person suffering from the condition that they're starving leptin levels are down blah blah blah blah are all there where the anorexia comes from is the ability of the brain to ignore the signal and so if you actually look at the genetics of anorexia um then what you see is an overlap although not complete overlap an overlap with obsessive compulsive disorder so and and it requirement to control something within the context of anorexia it's the food intake element and so therefore you're able to to actually ignore so the Eating Disorders are now more of a psychiatric condition as opposed to a homeostatic uh uh condition but this has only come out really in the last 10 years that we begin to know this I was as a followup is it is do you find or has it been found that there are a lot of people misdiagnosed with disorder when they actually have like hyper I think probably I I don't know how many people but based on this because this New England um paper that came up was quite a long time ago now but I would say 15 years ago now said that it was um that mc4 receptor is is is enriched for binging disorder there is no evidence of that at all given the fact that we found so many people um it's more the hypophagia element to it so I do think there is a misdiagnosis of binge eating versus versus hypophagia [Music] yes okay I'll ask another online question uh first fantas fantastic talk um are the mc3r or mc4r mutations associated with any other phenotype than puberty and body weight the mc4r is widely expressed in the brain and the MC3 are only slightly less so and a person who eats more might deliberate less about food choices than someone who eats less could there be an effect on Executive functioning or impulsivity that's a lot of multi-part questions U the the answer for the MC3 is I don't think it influences feeding Behavior actually in in terms of human beings so let's let's let's put that as side the mc4 receptor I I I know that people who are actually studying it I'm not going to answer the question because I don't know the answer specifically about whether or not it influence influences impulsivity I think that actually if you consider the mc4 receptor is a genetic version of being hungrier then I think you can probably sort of answer that question within the context of of um of impulsivity there is addition there are additional phenotypes to do with the mc4 receptor in particular because the feeding Behavior mc4 receptor phenotypes come from the hypothalamus which is what I've actually showed you but mc4 receptor is widely expressed throughout the brain it Al it also has has an important effect on autonomic output so what I mean by this so for example people with mc4r mutations um actually have a lower blood given their obesity lower BL blood pressure and lower resting um lower resting heart rate okay in fact if you actually um for their body weight okay for their body weight lower incidences of cardiovascular disease as well okay in fact if you wonder where would I find an enrichment for people with mc4r deficiency given what we now know of everything I think you need to find people who are tall who are big very big okay very tall and very big and actually if you look within Athletics I think you can find you can find people NFL linemen I bet you if I looked that we will probably go above 20% mc4 deficiency because that's what because you need to be large and not kill over because of a coronary and these people have lower heart rates resting and so so so for that that that's the first thing Sumo Restless probably I can I can think of um I can think of as well so big Sports rather than rather than uh fast that's where I think we will find naturally occurring mc4 mutations sounds like a cool study um I'm gonna ask the last question will the NFL fund me I don't know yeah that's that's the right y um okay so oh there AR so there's a question as to whe whether any of the Obesity genes known play a role in uh surviving starvation or severe malnutrition good question I don't know I don't know the answer to that I do know for example for specific diseases slightly tangential that if you look at certain there are certain diseases um hunting disease for example rare rare situation where you end up with um neuro degeneration where you do a lot better if you start at a higher body weight now I think it's more simple sorry more simple it's more complex than Simply Having a larger Reservoir so you have a larger reservoir of of of energy so therefore you you do better and survive longer I think it's more complex than that and people are trying to understand well hang on a second why do these people who are larger do better when they actually hit something like neuro like neuro degeneration so that's not exactly the question that's being asked but I think there is likely to be maybe not pathway direct um um elements that are there but we can take from the Huntington study whether or not this might be the case and so we're out of time so I just want to thank one more time our speaker today thanks folks