Do Your Genes Make You Fat? - with Giles Yeo

say you've had steak and chips for dinner or something okay now if you've had steak and chips for dinner and you're really full and the way their waitress comes along and says do you want more chips do a mistake you go oh I'm gonna puke right so we all have had that feeling but yet when the chocolate cake comes you'll eat it so why is it specific for the chocolate cake I've just been locked away in a room apparently because a hundred years ago someone tried to run away but anyway I'm a geneticist by trade and the interesting thing is when you were asked what disease you study and because people study genetics for any number of different reasons you can do it for a nerdy reason I mean and that's perfectly I'm a nerd I mean this is by definition um but a lot of people use it to study diseases okay because how better to understand how something works then when something is broken and that's that that's the whole point and so when you're talking about a disease and I say I study obesity which is what I study the genetics of obesity immediately I become a bad person and the reason why I'm a bad person is because I'm perceived to give obese people fat people overweight people okay not used all non pejoratively an excuse okay I mean that's oh so this is an interesting point I mean philosophically philosophically does that mean if you study the genetics of any disease you are actually giving someone an excuse but you know that's rather broad I'm gonna fix today on obesity but specifically on body weight and that's what I'm gonna be talking to you guys about today and I want you to consider the next I don't know 50 or 55 minutes a rebuttal a rebuttal to that statement about whether or not I'm giving anyone an excuse when I'm actually trying to understand they're only trying to understand their biology so all your genes to blame when your jeans don't fit and I think it's a first it's a first question I should actually ask so how many people here think your genes are to blame when your jeans don't fit and don't be shy oh my god okay alright and and how many people don't think your genes are to blame when your jeans don't fit this lecture is for you that's that but somewhere in the middle the answers in the middle obviously the answer but that's no fun no one likes gray people like black and people like black and white all right so so here we go all right I think part of the problem and we're dealing with body weight is that we have all got really quite fixated about it and I think I don't think we have and I don't think I don't think that that's lying so leaving aside religion and philosophy okay for for the moment let's assume that these are our prime directives in life okay so we have to find and to eat food clearly we have to somehow avoid becoming food this is important right there is the reproductive element we have to survive long enough to reproduce and you kind of repeat the process right at some point at some point you fail and then you become an ex living creature and this these prime directives are the same for every single living organism no matter how many cells you're made of one all the way to trillions exact this is what is driven us all the way till now okay now clearly in today's environment when we do our foraging it's it's it's slightly less dramatic okay but they come with their own obstacles okay so I will at Adam Brooks Hospital and in Cambridge and Marks and Spencers other supermarkets are available open one of these marks I forgot what it's called their sandwich shop so they're so simple thank you simply food so it's the simply food it doesn't sell knickers it doesn't saw underwear it just sells food so and I was there with the whole rest of the hospital I felt like getting lunch one day okay so this is this is a this is a true story and in front of me shall we say there was a lady she may have been a doctor she may have been a nurse she was there in civvies so I didn't I don't know but she was plus-sized okay she was she was a large lady and she had started her whole lunchtime foraging expedition with all of the best will in the world right she had in her hand a yoghurt and she had a solid and if she had been able to pay for the goodies she had just picked up right there and then she would have walked out with what she wanted for lunch because that was her plan okay but clearly that is not what happens because what happens you have to get in line the IKEA line the Disneyland line okay and everywhere in the world and I have been to this is where your obstacles are because that is where they put all the temptations okay that there are there now this is a hospital right next to an obesity unit but let's leave that alone for a second but the pet what what's on the wall is themed so clearly Christmas is just over so it would have been Christmas chocolates now we are a couple of weeks from Valentine's so it's Valentine's chocolates once Valentine's is danda easter bunnies etc etc there's the chocolate for each month okay and and the whole the whole wall is actually Fulop so this lady in front of me I was following her behind being nosy and and so imagine this was a chocolate bar or some lovely treats okay so she picked it up she kind of looked at it she went and she put it back down okay this is this whole trip probably took 60 seconds maybe maybe 90 seconds okay she picked up another thing she put it down ten times she was tempted ten times she said no okay she got to the cash tools every time she put something down in my head I went quietly silently you know this kind of thing that gets you arrested whoo so and then she went up and so she went up to the cash till her god dropped and behind the cash till there's a pimply guy there right selling waiting to pay for her goods and she he goes two-for-one cookies for those of you who have been to stansted airport or Heathrow Airport at 5:00 a.m. in the morning to for the 45-minute flight to Edinburgh you're there to pick up a paper and they sell you a iPad size a bar of chocolate for a 45 journey anyway that's that's my so the bottom line is she cracked she walked out 99 p44 cookies the size of my head okay which is very big right so so and and so I would have I probably was said a thousand extra calories she walked up with okay out the door of calories she did not plan she had not intended to buy because that was not her role that was there okay now I'm a human being and I judged so here's the question who's to blame do we blame the nurse because the nurse was weak-willed lily-livered a morally bereft do we do we blame Marks and Spencers thoughtful nor do we blame Marks and Spencers for putting the candy Wall of shame up there do we blame the government for not making Marks and Spencers not put the wall of a chocolate out there now I don't have an answer for you guys here and that's plausibly not my reason for being here but what I do think is that it is a relevant question okay because that is I don't think that is an unusual scenario I've given you guys you go pump petrol and you can buy chocolate you go to boots to pick up your glasses or or whatever you doing you can buy chocolate okay this is the food environment we're living in who we blame in many ways is neither here nor there it's a situation we actually have to have to deal with okay so this is the environment that we actually deal with so because when we talk about food and when we talk about food and take and when we talk about body weight and when we talk about body size we all judge why do we judge because we think we know about it when I'm watching the Olympics and I see gymnastics or whatever it is and and you know someone is doing this I don't judge because I can't do gymnastics so I'm watching wow you know by definition all of us are experts are eating because we are here today and we are alive so because of that we judge and you know the way we eat in our families is always weird you know it's all very stressful when you go on holiday with someone else's family because it's like oh I ad div' breakfast at 7:00 no I eat breakfast at 7:15 very stressful so because all of us are experts we judge and so it's become a toxic environment and it is not a new a judge judgment I have to say there'll be a strong religious theme I'm a religious but strong will just seem running through this oh these are the seven deadly sins okay and this is a fourth century religious construct okay so if you believe if you do believe then remember these are the sins which if you commit you'll end up on the eternal barbecue right so this is this we know this if you believe so and I would like to argue that three of these seven sins can have something to do with your feeding behavior or certainly your body size gluttony mr. creosote all right uh greed and smooth but in the past in the fourth century at certainly they would never have been in a food alright so if you were larger than average in the fourth century you were perceived to have taken food from other people who needed food thus the sin in today's environment does that make us all sinners it's the kind of question that keeps me awake at night right so so I mean so that I think it's a fair question to ask I think it's a relevant question I'm to asking that pretty much is what this talk is gonna be about this here it's the reason why people consider me a bad person okay so this is the Church of you okay and all of you would have seen some versions of these of these scales of off of balance but this is otherwise known as the second law of thermodynamics okay which means that you can't magic energy from somewhere and you can't magic the energy away so the only way and the only way ladies and gentlemen okay that you can actually gain weight is to eat more than you burn and the only way the only way okay is to burn more than you eat it's the physics but that is how you become obese okay so I think we're asking the wrong question in very many ways because how we become obese is physics why however have we become obese why do some people behave differently in this food environment why do some people like certain things more than others for example as I was for following the lady in front of me I had zero temptation there was not even one iota of temptation for me to take any chocolate now it's not that I don't like chocolate it's just that I can either take it or leave it now if it had been a bag of pork scratchings and don't judge me okay I mean I would have had it every day but that was my weakness that is something which I like and you might say what is that got to do with anything why why do some people prefer chocolate or pastry or pork scratchings or rice whatever whatever your weaknesses are all of you know what your weaknesses are okay why compared to something else there's an argument it could be cultural I absolutely but there's also a huge biological variation and I think I think we need to begin to think that now when you say well it doesn't net semantics it sounds like semantics you're doing play it isn't okay because if you actually deal with the how and you're dealing with physics now if that is the answer the be-all and end-all if it's simple physics then asking people to eat less and move more should solve the problem education should solve the problem do we actually need more education if you asked a six-year-old don't ask a six-year-old but if you could ask a six-year-old why do you think that man is fat okay now what what the six like I said this is the kind of stuff that gets gets you that you're a six-year-old we'll say that's because that person is eating too much if you ask your ninety nine year old grandma or grandpa both okay you know why is that person fat they'll say exactly the same thing we know why we become obese how sorry we know how we become obese if so in other words education is not gonna be the answer if however we begin to understand that where the variation lies ladies and gentlemen is in why we behave differently around food and all of us behave differently around food you begin to understand that one size cannot fit all okay because if the answer is don't buy any chocolates in your house Giles well it makes no difference to me because I don't like chocolate okay so you need to be able to understand why people do that and that is where the biological variation actually lies obesity is a problem we know it's a problem okay so this is a map which I'm sure many of you have seen different versions of um and I would say that just one message two messages I want you to get now clearly the obesity in what we call the developed economies you're a Western Europe North America the Anglophone countries um it's well rehearsed okay I mean you can't open a newspaper you can't watch the telly and you know documentaries are made by it I'm responsible for some of them and then what then happens is you actually see so that's not what I'm here to talk about while obesity is a problem we have not reached the maximum of our problem okay because big why because of this little corner of the world over here okay the Indian subcontinent and China now that's what a quarter a third of the world lived there okay so sure they're probably 300 million Chinese and 300 million Indians who have as much disposable come as anyone here and go on vacation so these are the Chinese folk the Indian folk we all see when we go on vacation okay because they have they have cash there are 1 billion Chinese people out in the sticks there are 1 billion Indian people out in the sticks where unlike here in the West the poorer you are the more likely you are to be to become a weight this is a complex question we can discuss later but in India and in China at the moment currently the poorer you are the skinny you are because you have enough food ok so but as these countries become more prosperous whatever words you want to use become more developed in inverted commas ok and the government's try and drag these countries out of out of the at least the poor people out of poverty it come with it devices the temptations the diet ok so we're nowhere near the maximum of this problem and we've got to really try and think about trying to fix this problem before an additional 2 billion people ok become at risk of actually becoming becoming obese so this is another way of looking at at the data so the data its plotting what is it plotting so does I'm sorry this is like the L'Oreal ad this is a bit of science so so when we're actually where you have here what you're plotting is BMI or body mass index so body mass index is your is your weight in kilograms divided by your height in meters squares the way to control for your body size in effect ok and what it's doing is its plotting your BMI so above between 20 and 25 is know is supposedly normal this is not perfect 25 and 30 is overweight at above 30 is obese right and what it has here is it plots the BMI it plots how many people have it and it plots males and females and then in the fourth dimension it plots time ok and so if you actually have here and you see what happens in 1984 boom okay the average BMI for a male in 1984 was probably around 22 to 23 so the average BMI in 1984 was normal boom 2014 which is where the data has got to at the moment the average BMI is now 27 or 28 okay so the average BMI today okay is overweight now if you actually ask the question as it goes between 1984 and 2049 look at the crowd there are some young people here who clearly we're not born in 1984 but I think a large proportion of the people here were born in 1984 and have lived throughout this entire change so let's go back to my title slide are your genes to blame when your jeans don't fit in this particular through that prism through that question the answer is clearly no right because this change in our body weight has occurred against the background of no genetic change we haven't we haven't suddenly evolved a second head right evolution doesn't what happen over this period of time so we actually have a situation here where clearly we have become more obese because of the change in environment and I use that as a hold all to include socio-economic class the type of job you do how much exercise you take anything that's not genetic okay so and that's gonna be true okay that's why we've become fat here we however is the critical point if you actually look at the histogram at the graph in 1984 if only the environment plays a role in other words if we only respond to the environment and all of us respond in the same way and the histogram from 1984 should move should have moved up in its entirety upwards so that you end up with a shape that looks like the Golden Gate Bridge okay that's if you actually have a shift in in BMI a hundred percent to do with environment but that is not the case ladies and gentlemen what you get is you get a change in shape of the histogram assuming that everybody alive here was alive here mostly speaking okay it's gonna case the only way you change a shape is if everyone in that graph behaves differently when the environment changes so we why don't we say in the field is why have we become obese we've become more obese because we need too much change an environment bla bla bla we know the answers to that how obese we become do we gain weight at all that is powerfully a biologically determined and powerfully genetically determine now how do we know that is genetically determined at all a large part of it not all but a large part of it have actually come from twin studies so some of you here may know what twin studies are but let me pray see it just for it just very briefly okay so there are identical twins and there are non identical twins so identical twins for all intents and purposes are genetic clones of each other they said they share 100% of all their genetic material whereas non identical twins fraternal twins share as much genetic material as you would with your brother or sister 50% of genetic material so you could take any given trait and ask the question well if I have if I share all my DNA okay and this is a trait versus if I share only half my DNA what is how much how much does the do the genes play a role and how much does the environment play a role okay I'll give you an example let's do if I had hair okay it would be black and I would like to argue that peroxide aside ladies that that that hair color is powerfully genetically determined age will change it I understand that but probably genetically determined with very little environmental input okay now how about in the other end of the spectrum freckles now freckles are clearly gonna be powerful genetically influenced but even amongst identical twins whether or not they appear how many appear will entirely determine what do I like to wear t-shirts do I like to stand in the Sun so that's an example of a powerful genetic trait which have a huge environmental influence okay so those are almost two two extremes you can actually look at now if you do the maths and actually look at it then the heritability of body weight amongst identical twins okay I understand it's around 70% and you can read they're there for the their environmental element is going to be 30% for some perspective height heritability of height is around 85% okay so it's not as high as height but it's pretty close okay there's actually a huge genetic influence and at the bottom line is there is a genetic influence for everything every single trait of ours it just depends how much okay it depends on how much of a genetic trait compared to how much of the environment that actually does play a role okay and where there are genes there are molecules and ethology to study and the first real molecular handle okay that we actually had and got about about there being a molecule that controls food intake rather than just entirely a willpower came from the identification of this obese Mouse this fat mouse over here this mouse has a naturally mutation in the gene called leptin okay I'm gonna spend quite a bit of time on leptin because it's it really opens up our eyes about about the whole process so leptin is produced from fat and so the more fat you have the more leptin you have leptin circulates in the blood it then signals to the brain how much fat we have I'll come back down and actually and actually talk about this so this mouse has a mutation in the gene and as a result becomes severely obese because of this mouse which was actually identified in 1994 okay this is the first molecule we now have a general understanding a simple a relatively simple framework for how we actually think about body weight control and food intake control okay and simplistically put we have circulating hormonal and nutritional cues so these can be nutrients themselves such as glucose fat protein okay or they can be proxies for those nutrients so insulin for example is a very good proxy for for glucose it does other things but it's a very good proxy for the level of glucose in your blood critically these all circulate in the blood they signal to the brain your brain responds and translates and influences your next interaction with food there are genetic modifiers that run throughout the entire process which you can in harness this is the reason why I'm a geneticist you can in harness these genetic modifiers in order to understand how biology works okay so it was at this point that my colleagues professor Radley well professor sir now so we have a half hour lab meeting around a round table I just don't think I know exactly now stop now so um um so professor rattly and professor Farooqi at the time start start at this but Steve in particular steve-o Ratley he asked I think a relevant question so the mouse as I said was a naturally occurring Mouse and that became obese so Steve asked a question um simply put is well is this just a weird mousy thing I think I think there's a fair question mice have whiskers and a tail and we don't have whiskers and a tail and it doesn't mean that's something that happens to a mouse can happen to human being but the question was if a naturally occurring mutation can make a mouse fat can a naturally occurring mutation make a human being fat fair question to ask long story short yes it can okay so Steven siddharth professor roughly professor for identified these two cousins and these two cousins have a mutation in that exact same gene called leptin now it's not the same mutation but it's the same gene okay and so remember leptin is produced with fat so what do children what do human beings which don't have this gene look like well I've highlighted the you can see the picture I've highlighted the key points in red which I'll come back to so they are born of normal birth weight so they come out perfectly looking looking like a normal sized baby but then they become hyper fake after winning theorem when they moved to solid food hi perform or fade year for eat now hyperphagia is a pathogenic term so you can't say I was type of fated this Christmas you guys dude you ate you ate too much so what hyperphagia is is hyperphagia is an abnormal pathological eating behavior these kids these kids have to have that freezer doors locked up because they will they would have gone in to eat the frozen fish fingers okay so now you might think oh fish fingers I'll come back and give you an example with that weird though it sounds it's not gonna be as weird as it does sound okay so you can read the rest and you can see what there's a lot of fat here um their normal height okay so they're not shorter they have normal height they don't undergo puberty okay and they have a bit of a wonky immune system which seems to be an odd thing to bring out in an obesity talk okay but it is these last two okay that actually have provided really for us a real understanding of what leptin actually does but before I get there so leptin as I said circulates in the blood and signals to the brain okay so it's a hormone it's a fat hormone now if we actually take the analogy of type 1 diabetes for example where you don't have insulin and what the type 1 diabetics do they inject themselves after every meal around around so often with insulin in order to control their glucose levels okay so the once again this is work done by Steven Siddharth they ask the question well can we do the same thing with leptin what happens if you actually inject yourself a daily with leptin like you do incident and exactly the same kind of pump their arm that that actually goes in now this is a three-year-old weighing 42 cue grams okay for those Europeans amongst you you understand how heavy that is for prospective times two point two four pounds divided by fourteen for stone but for perspective I am 75 kilos so we're looking at a three-year-old who's two thirds of my body weight this is not playstation obesity this is not I've had too much coca-cola obesity there's something wrong with a kid okay so and the kid doesn't have have leptin look what happens after daily injections of leptin okay we now have a child who's seven years old that weighs 32 kilograms and you would not ban an eyelid okay at this job because he looks perfectly normal perfectly normal child now because of daily injections have leptin now at the time so this picture was probably taken in 2001 or 2002 all right at the time the leptin license was owned by the American pharmaceutical giant Amgen now to have been a fly on a wall in the board room and the results came in I think they must have wet themselves they must have thought all our Christmases in one go right because they thought we must have solved obesity which they hadn't because it's now 2018 and I'm still here banging on about it right so the question is why did leptin which some of you may have heard of but most of you would not have why have you not heard about it why can't you go to boots and buy leptin right and it's not like Amgen actually didn't try they pay millions for it okay because they thought they were gonna make trillions oh it's not like they didn't try they gave left into skinny people to fat people to boys to girls to mint women to people of all colors and the universal rule was this it didn't matter if you had a BMI 18 like Kate Moss okay or if you were BMI whatever like Santa Claus I don't know what it's BMI is but he's probably pretty big okay so but if you had a functioning leptin system you did not respond to leptin at least in terms of food intake so the question however is why given that I've shown you if you don't have leptin you respond to it exquisitely sensitive ly okay so the question is why we weren't thinking about it correctly now when leptin was first discovered all of us were bamboozled in an in the field leptin comes from the Greek word Leptis for thin and so people were thinking well if leptin is produced from fat and if the more fat you have the more leptin you have it must act as a negative feedback loop right the more leptin you have it goes to your brain then when you have too much fat it tells your brain to eat less and then you lose fat so we thought that it was there to tell you you had too much fats and to stop eating because you're getting too fat but if you think about it a little bit carefully when in evolution would we have gotten too fat when would we have had too much food that we needed to worry about this never is the answer and so there is no evolutionary reason for us to develop something to stop us from eating so cut a long story short leptin does not function when there's too much of it leptin functions when there's too little of it when you don't have enough of it why because when you don't have enough leptin you don't have any fat and if you don't have any fat you are starving what leptin biological role is is to turn on the starvation response okay what is the starvation responsible first thing is to eat okay now that might seem obvious all of us know that if we're really hungry the simplest foods a piece of bread some rice a little bit of cheese tastes like manna from heaven it's really delicious okay the fuller we become the more picky we become okay so this is universal this is this is actually what what what happens now imagine if you were actually starving plane crash in the Andes your partner is looking delicious started okay now would you if you're actually starving would you eat frozen fish fingers to keep yourself alive of course you would all of us become hypothetic when we are starving in order to keep ourselves alive what else happens okay the other thing which happens is your body begins to triage calories for your brain now your brain is about 2 to 3 percent of the weight and volume of your body ok but at rest such as now it is using 25% of the glucose that is circulating in your blood it's a hugely metabolically expensive organ using the glucose so because it does all the command-and-control it controls everything that you do ok including including eating so what happens is your body begins to save energy and save calories for you for your brain what does it do it begins to shut down metabolically expensive pathways which are not immediately necessary for example reproduction okay now ladies we know every month loads of wasted calories okay so but haha yeah that's just true mystery but at the edge of starvation at the edge of starvation those wasted calories are going be the difference between life and death okay so what happens your brain shuts it off it doesn't allow that to happen additionally if you were actually starving the last thing you're gonna want to do is to plop a baby out under the Serengeti because you're not gonna be able to feed the baby so like I said your body just shuts off reproduction second thing that's very expensive and I won't go into in any detail is your immune system it's inexpensive a situation so your brain also also shuts it off so the question is alright is it reversible okay because because for it to be a good starvation signal it's got to be reversible if it's going one in one direction and you can't reverse it then it's a stupid starvation signal so is it reversible yes it is hyperphagia daily injections the kid the child is clearly eating normally now which is why is lost all the weight reproduction remember this picture I told you was taken in two thousand and something her his older cousin is now a young lady okay carried a baby to term she now has a family okay the first leptin deficient creature okay in all of time in history to carry a pregnancy to term because of daily injections of leptin okay so reproduction fixed and once again the immune function that was also fixed so that ladies and gentlemen is leptin role as it goes away to turn on the starvation response so I'll give psych just a couple more couple more examples what happens however when the signals to the brain okay so when leptin actually gets to the brain and I'm I won't boy anymore everyone city I know that's not the most exciting thing in the world to listen to but when it actually hits the brain it hits a class of neurons in a hypothalamus which is the base of the brain just here in your nose to the middle the hypothalamus okay a population of neurons they're called the pom C neurons okay so why talk about the pumps in neurons we know that it's important because if a human being has mutations in pom C or ever mouse has mutations in pom see we did that work okay we result it results in severe obesity so I could show you those but I thought I would go over some more recent data and this is our work on Labrador Retrievers so just just a question how many of you guys here own Labradors Labrador owners oh wow good all right hello Labrador owners so um this work by the way was led by my veterinary surgeon colleague Eleanor effing okay and now the Labradors are the commonest pet dog in North America and in the United North America and in the UK okay in the UK there are a hundred and fifty thousand new Labrador puppies that are registered every single year okay and we use it to sell toilet paper for heaven's sakes right so the and rex the and rex puppy so but I'll point to the Labrador owners in a crowd leave your compost bin shut otherwise the Labrador will eat everything within the compost bin so Labradors are well known to be very very greedy food motivated whatever you want to whatever you want to do and this is where our interest became right ken could we identify the biological aspect to its to its actual feeding behavior once again I'll cut a long story short the bottom line is Labradors as it turns out have a deletion in in this pom c gene okay now it's not a complete deletion only this bit and not all Labradors have it which will become relevant in two seconds okay so not all Labradors have it because not all Labradors have it you can ask what happens two Labradors with the mutation and what happens the Labradors without the mutation and so here this is body weight and in effect what this shows here is just weight and if you haven't if the dog has no mutation one copy of the mutation remember we all have two copies of every single gene or two copies of the mutation and you can see here they get heavier each copy of the deletion is worth around two kilograms or five pounds okay that doesn't sound like a lot until you remember that a Labrador only gets to around 30 to 35 kilos okay so this is quite quite a lot of body weight what happens to food motivation food behavior you see exactly the same pattern okay where you actually see this this this increase here in in in in behavior so if you have the mutation of the dog has the mutation name of a food motivated now is this a dog thing because we all know that many dogs will go and actually eat and actually eat all the food that is there so the answer is no because we ended up sequencing 38 other dog strains I mean chihuahuas shih tzus Great Danes you know wolf hounds everything no mutation of this in any other dog except for the flat-coated retriever now I'm not a doggy person I don't know if anyone owns a flat-coated retriever oh my god okay hello flat-coated retrievers we love you so so flag go to retrievers are the are the closest relative to to the to the Labrador and they're both descended from the st. Johns water dog okay which is a Canadian fisherman's though now extinct okay so that you might smell well why does this dog have a mutation so a couple of things first not all flat coats have it either but when the flat coats have it this is the same to grass that's body weight and that's food motivation they have exactly the same phenotype as they do as as do two Labradors why is this mutation there at all well sanjana's water dog was a fisherman's dog okay it was bred to jump into the cold water and dragged back nets or what or what have you in Labrador which is pretty cold right so you can imagine that one day a fisherman was going down go and there you go go get whatever I can't do a Canadian accent go go get the net so but he probably picked a dog who was willing to go in and get it a because it had a little bit of padding around it okay and B was motivated enough to go because he was giving it treats okay and so that was probably what happened to the first mutation that was selected for and it's then kept in - in in inner dog strains ever since so the question is this not all Labradors and flat codes have it as I said but they're worth around two kilos each for those of you mathematically inclined that's around point three standard deviations of body weight right so here the numbers I don't know the prevalence in a flat codes I'm sorry I'll look it up so oh calculated so what happens here however the Labradors is in pet Labradors around 20 to 25 percent will have the dilution okay that are actually there but here's the other interesting thing about Labrador owners okay the other reason you have them is because they're lovely family dogs because of their fantastic temperament they're fantastic dogs and they're very trainable they're so trainable there are in North American and UK primarily used as guide dogs guide dogs for the blind okay now I would I think you agree that the guide dog is like the Navy SEAL of the dog world okay so they go to guide dog camp and you know the few the proud the guide dogs and what happens there's a lot of failure because they go up and those who fail go into the pet industry okay but but the ones that succeed are then given a human being to look after for the rest of their lives so very few make it okay but but the ones that I make it are trained within an inch of their life and they are trained with food okay now if we look at the guide dogs okay in terms of the percentage 80 percent of guide dogs have this mutation okay so we which is odd because what happens is we started off by studying food motivation okay which is why I studied clear we've been discussing at the entire time but have certainly taken a step into trainability okay so what why does this happen you can imagine a scenario so you if you're trained using food using standard Pavlovian techniques then you can imagine here is Fido or whatever the name of your dog is here we go and here is bringing the visually impaired list mister Smith home okay now say a chicken runs across the road okay so what are your chances of a chicken dinner right you're probably looking 8020 whatever their numbers I don't what the real number is I never chased the chicken but the glabra door is trained to know that it is a hundred percent chance of getting a dinner if he brings mr. Smith back oh okay so when your Labrador stuff two googly eyes and they're loving you hungry sure it's not true oh my god not true terrible anyway dog food heading my way so this is we got in the cover of of actually this magazine this journal Cell Metabolism that's Eleanor and who did the study and that's Jasper one of our one of our participants interestingly chocolate Labradors have a slightly higher percentage of the mutation and therefore could plausibly explain why they're more you know greedy but anyway let's leave that alone so I'm just looking at the time I probably have time to go over this then there's one other gene okay then I'll then I'll stop talking now I won't stop talking about genes there's only about genes so so what happens is leptin goes it tickles the pom C neurons and then pom C neurons have to go on the signal to something else and they signal to something called the mc4 receptor or the Milano cotton four receptor in the actual chronology of things this was 1998 and I was a young postdoc and this was my first paper okay so this is where I appeared on the scene with regards to with regards in in in the in endocrinology but now you'll be unsurprised that if you have a mutation in the mc4 receptor which binds to pom c you're gonna be you're gonna be severely obese as well but this is now we probably now know that mutations in mc4 receptor on the Communist cause of what we call monogenic obesity which means that if you have it if you have a mutation in the gene you'll end up being you end up being obese the Communist cause of monogenic obesity ever okay and how common was not that common but it's common so for example if we actually look at people with a BMI above 30 now I'm a BMI of 27 so that's that's just not that far away from me right so people with a BMI above of 20 of 30 have a 1% chance of carrying a known mutation within the mc4 receptor so you can almost think about that saying that FC 4 is probably responsible for 1% of the obesity that's out there the trick is what's happening with the other 99% obviously okay so it's it's not common but 1% is actually quite a lot given the number of people that are actually above a BMI of 30 but my point is this so so this work just as Jay let you know this work was done by me as a young postdoc in a lab using cells in in a tissue culture hood right whereas this work that was done here was done by my colleague Sarah Farooqi professor Farooqi in a clinical research facility okay entirely separately this was done in using molecular findings now there mc4 receptor we know what binds to it and we know when it binds to we can actually measure the activity of the of the receptor so you'll be other surprised to know with thousands of different mutations out there that there gonna be some more severe mutations and they completely killed after okay you can see here no activity that's normal and these are just all dead and you'll be unsurprised to know that with a receptor with thousands of mutations there gonna be some which are a lot less damaging maybe anywhere from 30 to maybe 70% damaging this is work that was like I said that in a clinical research facility in which they were measuring food intake buffet food intake it works better for children little children because they don't know they're being watched not so well for adults because it's difficult to measure a food intake normally in an adult if you know you're being watched but these were done in kids now this these meals are nearly 5000 calories okay and see this control here my son was one of those controls when he was four years old okay no was ridiculous thing in the world is to see a four-year-old facing this is a what's the critical thing about experiments it's got to be exactly the same except for the variable and the variable here is the genetic status and so Harry was Harry was normal and so a four year old facing five thousand calories there's just it's quite funny so what did he do he drank his milk he had a bite of toast he threw the Rice Krispies in the ground and that was it that was his breakfast right so the nurse was picking up all the rice krispies and everything was measured in anyway so the bottom line is this here is leptin deficiency here is treated leptin deficiency okay you can see the huge improvement all of the kids with malonic with mc4 receptor mutations were tested you know in one big batch and only split up after the lab results and here's the bottom half so these are done in entirely synthetically okay and this isn't done in a lab the lab results which I managed to do predicted how much a child would eat and actually a buffet meal what does this mean it means that this is not an on-off switch the mc4 receptor is not ordered up the whole palm CMC floor system it's not on and off its a rheostat okay because it doesn't matter that whether something is there or not it depends how many of them are on the surface it depends on how good the quality of the receptor there is no sir on the surface it's an entirely tweakable system that is actually there but those are as I said monogenic disorders which means that you have a single gene causing a disease there many other monogenic diseases out there muscular dystrophy is a monitor it's a monogenic disease cystic fibrosis is some monogenic disease leptin deficiency is a monogenic disease okay but the vast majority of the BMI problems show showing you at the outset of this talk have not nothing to do but are not coming monogenic there gotta be complex diseases involving multiple genes multiple complex reasons interactions with in with environments that are actually going to be over there okay and with new genetic techniques that I've actually come come on we now have a better idea of what's going on so this is Jackson Pollock diagram over here you guys forgive me for this we you don't have to read every single gene that's not the point they're two messages I want you to get away from this from this particular graph okay the first thing as I hope you'll see that there are two broad groups of genes these are genes which are known to play a role in our body weight and our body shape as it turns out okay about 200 genes we now know off so these genes up here in the pink blob or magenta blob on the top left-hand corner have to do with what we call our waist-to-hip ratio so it's the circumference of your waist over the circumference of your hip and what you see if you do that is it indicates your shape okay ah do I have a big stomach and a small bum do I have a skinny stomach and a big bum do I look like a sausage right so so and and and it looks to your body shape and your body shape is pretty much unless you're on ostrich burger pretty much where you put your fat if you look at a skeleton the skeleton differs in in in in height but pretty much looks exactly the same whereas your fat gives you your body shape okay so this these these are genes which indicate where you put your fat these genes over here have to do with your BMI independent of where you put your fat so these are how much fat you have first message that I want you guys to take away where you put your fat has absolutely nothing genetically okay with how much fat you have okay these are appear to be separate so these as it turns out genes of where you put your fat have to do with fat biology so how that divide you know that kind of question whereas how much fat you have has to do with your brain as it turns out we know and in the genes in which we know what they do have to do with food intake so where you put your fat has to do with your fat how much fat you have has to do with your head and how much you actually eat this is another way of looking at the data this is known as a Manhattan plot okay and it looks like a Manhattan plot because it looks like the skyline of Manhattan now this is a gene here which I've studied sadly for the past ten years of my life many pain many tears okay but there we go that's what it is well I only highlight this for one reason these are not mutations I want to be crystal clear what these things are these are single nucleotide polymorphisms little changes so half of you here half of you here will have the bullet will carry at least one risk copy of FTO so if you carry one copy you are on average one and a half kilograms four pounds heavier than the person next to you if you carry two copies you're on average three kilograms or seven or eight pounds having the person next to you okay half of you guys so these are not mutations these are polymorphisms all of you will have some mix of any of these genes here okay so why am i bringing this up because if you look at these genes and these are remember looked at millions of people now in very subtle changes what do you see that is pom C that is the mc4 receptor mc4r and this sits downstream of leptin signaling the left-hand receptor so these are the same genes I've been talking to you about throughout this entire talk except if you have very big severe mutations you end up being severely obese whereas little subtle changes into it influence where you sit on a normal distribution of body weight okay so here is a situation imagine there are ah you have 200 genes or so maybe a hundred genes that you can actually measure and you can create a risk score okay because your genetics is empirical you can measure it relatively cheaply and it's empirical you can create a risk school that is there and you can have a notional risk so what is the risk or you can have one copy of each gene that the score of one two copies of each gene is a score of two and no copies which is zero so clearly your notional maximum for 100 genes is two hundred and notional minimum of zero but this being biology we don't have none and we don't have all we have an average number and most of us here will have an average number of these different variations of the genes and kind of shift about here but here's the interesting thing when you actually plot the number of these risk alleles you have versus your BMI you get a linear relationship which means that the more of these factors you have the heavier you are likely to get okay so this is Paula Jennings complex biology complex genetics in action but it's more complex than but then you actually imagine the number of people who have asked me oh that's very exciting okay because you can calculate this number so everyone wants to know that risk oh I want to know my risk oh I'm gonna know my risk oh why don't people want to know their risk or a because people want to know that risk or but they want to know are they at a risk of becoming obese okay and so people ask me because because because I may not be obese yet but I want to know if I can become obese so people are asking me can I find people over here and predict that they're gonna become obese before they become obese the answer sadly is maybe some point in the future but not yet okay and I'm gonna explain to you I'm gonna explain to you why people are now trying to do this okay so I live in a little village yeah it's very posh um in in in in Cambridgeshire it has two windmills one of which is broken you can buy flour there it has two churches one of which is deconsecrated they're right next to each other okay it's got a pub and that's pretty much it but it has someone from superdrug or whatever actually walking up and posting a genetic test into my door there we go okay Cambridge but but you can actually ask any number of things that that are there including it can predict how fast you'll run you know how you know how much your heart beats complete I was gonna use a rude word yes yes oh well that that is there why because the companies are fundamentally misunderstanding and and how fat you become a fundamentally misunderstanding the difference between population level risks and personal productivity okay so what do I mean by that exactly I'm gonna give you an example this is exactly the same example I give the medical students when I'm actually teaching I'm teaching the first-year medics about the difference between risk and predictability okay so just to be clear these companies are not lying to you about your genetics because that is empirical and they can measure it and anyway they lied about whether or not you had this version or not you could sue them because then you say it's just fake advertising so that's gonna be right they're not lying about where the studies come from so these are gonna be genes which some of us may I may have talked about here they are misinterpreting the data because they don't understand the data okay so I'm gonna give you an example about risk versus predictability now this bit is given to first-year medical students so they're 18 years old then embryos I realize you guys are younger than 18 by saying could forgive me okay so they're embryos okay so at that stage I am talking about the risk of becoming pregnant okay speaking to an old audience maybe it's the likelihood of becoming pregnant but anyway I'm not judging right so but I think we will all understand that the younger you are the younger you are the more likely the higher the risk of becoming pregnant okay and that risk goes down to zero once you get into menopause and you get to zero okay now clearly we have understood this process forever okay but and given the you know trillions of women that have I've ever lived okay this is gonna be a very robust graph yet can I take a random 30 for your woman off the street without any biological intervention and predict if she's gonna become pregnant absolutely not okay she could have a hundred percent chance of becoming pregnant because she's currently ovulating she could have 0% chance because she's infertile for any number of myriad of different of different reasons I mean you'd be able to tell you biologically test them for this or that but based on a risk score you cannot predict but that doesn't change the fact that a 34 year old woman on a population level it's about 63% likely to become pregnant you have to take that same analogy and hold to these complex genetic curves so while the complex genetics is correct its productivity is very very very poor okay that's the difference ignore that bit and plus you can't get a little bit pregnancy while there are or not but anyway so just two or three more slides and then I'll shut up so let's go back to the question am I giving obese people an excuse okay and I'm gonna argue no look if you consider your your genetics your genes as a hand of cards now let's ignore the monogenic disorders because some some disorders when once you have you actually get the disease but let's we're talking about BMI here type-2 diabetes hypertension yeah that kind of stuff you got to consider your genetics like a hand of cards you can have good hands you can have bad hands and the only people you can brain are your folks right so you can't do anything about that there is however okay you can however win with a bad hand of cards it's more difficult and you can't lose with a good head of cards if you're silly with the way you actually play it I'm gonna give you another example I will never ever run as fast as Usain Bolt Gene's clearly genes yeah but it doesn't mean that if I train I won't run faster than I do now okay i I'm clearly nowhere near my genetic maximal potential about how fast I run in fact I would say that the only people that are close to their genetic maximum potential I probably professional athletes because that's all they do they only train okay in order to do that to try and get as close to their genetic potential as physically possible what do you genes do of course your genes indicate how you look what color you are whether or not I'm gonna commit I'm bald you know your likelihood of type 2 diabetes it gives you a bracket it gives you a maxim a maximum I don't know what a minimum but I certainly gives you a maximum range that you can actually go for but that doesn't mean that within that range you can't move that you can't do something about it if you actually understand your biology a little bit more so okay one last thought not to last words here the desert tummy is relevant so we know what the desert tummy is I think most of you do you understand it but for those of you just just let's recap desert tummy where if you go out for dinner three course dinner type the Thai place okay now I guarantee you unless you go to a Michelin star restaurant let's ignore that for a moment but if we go to a regular place by the time you reach your main course in the end you have achieved your metabolic requirements for the day in other words you had enough calories for the day yet when the pudding comes chocolate cake whatever it is you'll eat it okay so that's the putting stomach the question is why is it specific for puddings which is always an interesting question right so what do I mean well if you say you've had steak and chips for dinner or something okay now if you've had steak and chips for dinner and you're really full and the way their waitress comes along and says do you want more chips do a mistake you go I'm gonna puke right so we all have had that feeling but yet when the chocolate cake comes you'll eat it so why is it specific for the chocolate cake and we have to go back to we have to chuck back to evolution again so fifty thousand years ago on the Serengeti this is me okay this is me dragging back an antelope so let's assume that it's cost me two thousand calories to take down said antelope okay let's just let's just make that assumption what happens when you get back to the village you have to eat at least 2,000 calories right because that's what you spent but if you only eat 2,000 calories you don't buffer against the time there's no guarantee you get an antelope next time round so you need to eat more to make sure that just in case you don't get the antelope the next time around but so what when that happens a part of your brain known known as the hedonic pathway the element of food which you get with chocolate cake and not so with broccoli sorry parents right I like to find but anyway take takes over so you actually eat more than you actually need but how do you get past the mechanical problem of being filled with 2,000 calories of venison right all and it seems quite bulky stuff what your brain does is it begins to change the quality of the calories that you like to eat it begins to increase the caloric density which means that for every given gram of food you have you have more calories in it okay so you can stuff it in there as much as you can all right what what are high in caloric density free sugars now at the time 50,000 years ago this would have been honey this would have been fruit okay and fat ladies and gentlemen what is high and through a high in sugar and high in fat desserts the dessert tummy is a holdover from the Serengeti which to make sure you ate as much as possible even though you were so full that you needed to change the density of the calorie so you could stuff as much of it there it's physically possible so that we could live to today so that we could judge the people who have actually evolved to actually live so there we go that's that's the thing so are we all sinners I guess is the question note that the rehearse okay so like this is my last question you know where this is me eating a pizza am i sinner you know am i sinner um I I guess well what what do people who have our high propensity of becoming obese what is it like okay now I realize I'm not a beast yet but I I have worked with with a number of people to televisions or what have you and I've and I've asked them and simplistically put both from a biological perspective as well as an anecdotal perspective okay people who are who who are obese were overweight people who have a high genetic risk of becoming obese feel slightly hungrier all the time not ten times as hungry not twice as hungry but 5% hungrier all the time okay so as a result they eat more as a result they become obese people say there's always a choice you know they're annoying people skinny people with many many packs I have one pack right many packs okay yeah people always have a choice they always have a choice they can say no well okay yes they can say no okay but if you feel slightly hungry all the time it is always gonna be more difficult to say no all right so the one message I want you guys that actually take away from here obese people are not lazy they're not morally bereft they're not bad people they're fighting their biology okay they are feeling hungry I study all the time which is why they are the way they are and we're trying to fix the problem it doesn't mean that we can't actually help and getting people to actually lose weight but until we understand that this is not a moral failing ladies and gentlemen it is not a choice that we have full control over until we understand that we will never ever fix this or visit fix this obesity problem ladies and gentleman my name is Charles yo this is where I work thank you very much for listening to me [Applause] you

Channel: The Royal Institution

Views: 95,484

Keywords: lecture, obesity, fat, genetics, fat gene, weight, weight loss, dieting, giles yeo, metabolism, heatlhy weight, bmi, ri, royal institution

Id: pOJYTMe_bp4

Length: 57min 49sec (3469 seconds)

Published: Thu Apr 26 2018