Dr. Benjamin Bikman – ‘Insulin vs. Ketones – The Battle for Brown Fat’

Dr. Benjamin Bikman – ‘Insulin vs. Ketones – The Battle for Brown Fat’

July 22, 2019 100 By William Morgan


good morning I am delighted to be here rod Jeff thank you so much for the opportunity for the invitation to participate in the meeting and to speak this is a new type of meeting for me I normally at the purely academic meetings and I don’t mean that as an insult this has been a wonderful combination for me first time of academic Plus application I don’t have to hide this other side of me the secret low carb high fat advocate side like I find I have to do in other venues so I really am delighted to be here I am doubly delighted to share with you some of the research we’ve been doing from our lab so I’ve made an effort to make this very lucid and very accessible but it is in fact very recent data that I’ll be showing you as we are in fact these will be figures that we’ll be using to put together the publication that will soon submit for publication for review so as Marianne mentioned and Marion thank you for the introduction I we’ve been lately looking at the factors that go into modifying the way our body fat is acting and I think you’ll be surprised at what I’m about to show you I have nothing to disclose as a humble professor there’s not much for me to talk about in that regard many of you have seen this idea before or if you haven’t you have somewhat gotten the vague impressions of it there are two key theories with regards to why we are overweight on one hand and the one that certainly predominates our cultural psyche we are overweight because it is a strictly it is strictly a consequence of a caloric imbalance on the other hand it’s that there is an imbalance in hormones in particular the hormone insulin now both of these theories the caloric and the endocrine theory account for energy that comes in and both of them account for energy that comes out and on the caloric side however it’s just as simple as that you use it or you store it and if you’re taking in more than you’re using well then the outcome is as you’d expect the organism is taking in more energy and in the case of the human we’re getting fatter on the endocrine side it’s slightly more complicated it assumes that there it is not we are not perfect thermodynamic machines energy must be told what to do like a naughty little kid and in this case among many hormones insulin really does stand above the rest and when insulin is elevated over normal sort of baseline homeostatic levels insulin will tell the system till the adipocytes specifically expand the influx of energy and reduce the II flux of energy and as you would expect if you’re pouring more water into a sink and blocking up the drain the system gets bigger on that side as well so with these two specific series there is some overlap insofar as both of them account or have to account for calories so there’s some overlap and many people be willing to admit that degree of overlap and on the caloric side the story begins and ends with storing it or using it that is a purist when it comes to thermodynamics would say the energy has to be stored or used and thus there has to be a perfect accounting of it you can almost tally it up however what I’m going to show you and why this might be a little provocative is that the endocrine Theory actually encompasses I would say almost all of the caloric theory and that’s why you can be an endocrine theory advocate and really what I’m going to show you is have some wonderful defense against someone who tries to beat you in the over the head with the idea that it’s just an a pure numbers game it’s not really but as the kill as the caloric theory is somewhat in encompass in the endocrine theory that means the endocrine theory has to in and of itself account for some storage and usage of energy and it does as I’ll show you part of how it does that is the nature of our fat tissue we have fat tissue of course all over the body and most of it is will all introduce the characters in just a minute but the spoiler is they act they can act fat tissue can act a little differently in different environments so we’re going to talk about these two variables in particular and when we talk about the nature of fat tissue I’m going to show you how the endocrine Theory substantially changes how energy is used because of what it’s doing to our body fat and then going to talk about one last mechanism that we have to consider when we are insisting on counting calories but it’s too often overlooked so here are the players I’m telling you a story these are the characters in the story the liver is a very important character in anything metabolic and and beyond mind you and then two types of body fat that all humans have white adipose tissue and brown adipose tissue and in fact it actually looks like that it is really white or it is quite brown when you when you pull it out of a human or any other mammal and then the other two characters you’re all very familiar with the hormone insulin and then the molecule key I’m just going to call it t tone but then but the ketones now they’re not the same insulin is a hormone and ketone is a is a metabolite but they’re remarkably related and again this is an audience that’s very familiar with that so let’s look at adipose tissue first white adipose tissue is concerned with storing energy brown adipose tissue is interested in thermal regulation in other words if brown adipose tissue has its way it’s doing nothing but creating heat and this is something then when we look at them they’re quite contrasting on one hand white adipose tissue wants to store energy and then on the other hand we have this other adipose tissue brown adipose that wants to use it but appreciate that in the typical caloric model we typically consider energy use of something really that just the muscles are doing but I’m telling you there’s a type of fat tissue that we all have that actually is also interested in just using energy so why not opposed to storing it brown adipose is using it and babies have a lot of brown adipose tissue I have three little kids now and it’s been interesting for me to see over time when they get out of the bathtub when their brand-new little babies infants they don’t shiver have you noticed that little babies don’t shiver they don’t need to we need to shiver because we need to our muscles when they shiver they create heat that’s shivering induced thermogenesis when you have as a baby especially an infant has a lot of brown fat that brown fat is keeping them sufficiently warm that there’s no shivering required required but of course as they start to get a little older then round fat starts to diminish and sure enough by the time we become even your kids and aging up towards adulthood that shift there’s a shift happening and relatively less of our fat is brown fat and more of our fat is the storage white adipose tissue and thus if we’re cold we start to shiver there has been some debate in the field with regards to this relevance in adult humans but let me be clear we have brown fat tissue and it is relevant it is more active in some people it can be induced to be more active in some people regardless if you have more of it and it’s more active you’re going to be in a good place metabolically speaking and I’ll get into that in more detail in just a moment so with regards to brown fat I’m going to assume as a professor I assume my students don’t know too much about the topic I’ll assume that now so pardon the assumption if it’s offensive so brown adipose tissue is unique because it in fact it looks brown because it is enriched amoled with other things with mitochondria and as you know mitochondria is the site of as has been talked about several times at this meeting already oxidation of nutrients glucose or lipids what the medic Andreea are doing in brown adipose tissue though is unique but all mitochondria have a capacity to do two types of things and so on one hand the mitochondria will pull in glucose and it will only use as much glucose as it needs for the work that the cell is requiring the energy for does that make sense the cell has a certain energy for energy and then it will take in only as much nutrient and glucose in this case in the particular case of the brown adipocyte it’ll pull it only as much glucose into the mitochondria as it needs for the work to get done in contrast another mitochondria also have the ability to pull in glucose and use it to produce nothing but heat and it will just continue to produce heat and so it’s like you just keep throwing logs onto the fire what is producing this heat is something called the uncoupling protein or UCP one all mitochondria have to some degree this protein and if I had known that dr. Eve was going to go into the electron transport system while boy we could have really gone into that I didn’t think we were supposed to go to that level so I feel ripped off but that is it’s remarkably relevant the uncoupling protein is it has its place right there in the electron transport system so if the uncoupling protein has this way it’s starting to produce a lot of heat from the mitochondria but as you can see if we’re wanting to fire to get bigger and bigger and bigger the fuel is glucose so our glucose starts to come down because we’re using it all it’s like ours would stack as we’re throwing it more into the fire we’re going through that much more faster than normal and in a mammal in a human if glucose starts to come down that of course is going to affect insulin and what happens to insulin well of course it starts to come down you have less need to increase in some to try to bring it out of the blood the mitochondria are already doing it in this overall series of events more uncoupling protein in mitochondria resulting in this subtle increase in heat sometimes imperceptible mind you in the body it’s not like you’re trying to tear your clothes off you’re so hot but this results in a reduction in blood glucose because we have a sink we have a place to dump the glucose a reduction in insulin and overall creating a very metabolically favorable milieu the body is becoming less resistant to obesity and more resistant to diabetes and conditions of insulin resistance so back to the liver the liver is a site of of tremendous flux converting nutrients into other nutrients and at the heart of this is the molecule acetyl co a and again you’ve already seen this if you hadn’t seen it before acetyl co is at the branch point of many many nutrients nutrients turning into acetyl co a or acetyl co a turning into nutrients all of them amino acids glucose fatty acids in the case of what the liver is going to do with acetyl co a liver is going to dictate that in a large in a large way there are other hormones that come into play but insulin stands again above the rest now as a reminder a CoA is a metabolite of the breakdown of both fat and glucose so just keep that in mind if insulin is high it wants to turn acetyl co a into lipid so whatever source the acetyl co a was or whatever we got that from if insulin is up it’s activating an overall of events that is pushing acetyl co a into Lippo genesis creating new fats from the liver if in contrast insulin is low then we have a very different outcome and in this case we have this unique production of ketones insulin is a potent inhibitor of ketogenesis and let me be clear this is a pathway that is never resistant and never you can have the most profoundly insulin resistant individual on the planet insulin will still act in this pathway and inhibit ketogenesis but in this case I’m saying insulin is low and an insulin sensitive individual insulin is low ketogenesis is happening so we start producing ketones and so let’s take these two key players and then put them in the spectrum of what it’s going to do or put them in perspective with regards to its actions on fat tissue and these are little little bubbles of adipocytes or fat cells if you will so the first question we asked in my lab what is the effect of insulin on the nature of adipose tissue and so the first and so in what I’m going to show you and on the first hand we increased insulin and if we increase in from what’s going to happen to ketogenesis and ketone levels of course it’s going to plummet good good students so the first study first study was insulin inducing hyperinsulinemia in a mouse model and what we found immediately so let me take you through this this is this figure is firstly just looking at the mass the growth of the fat pads over this four week of induced hyperinsulinemia and we it just like humans mice have very distinct Depot’s or places of fat tissue the peri renal is a typical visceral fat the inguinal on the mouse is a subcutaneous fat that’s right beneath the skin and then the inter scapular is the mouse’s site of true brown fat and in the humans as you could seen that one image I showed you earlier although I didn’t highlight it that’s sort of where we are tearing it in our thoracic cavity what you’ll see is that hyperinsulinemia and the animals increased the peri renal the visceral and the subcutaneous fat but it had no effect at expanding the overall mass of the typical brown fat that prototypical brown fat site in the animal just like in the human around the threat cavity and that in green I’ll cite in the animal as I said is comparable to the human subcutaneous and what’s so remarkable about that is our subcutaneous fat in most people is our greatest site of fat storage and in humans our subcutaneous fat as you can see from this study that subcutaneous fat that is classically considered white can in fact start to shift over to be more Brown and thus more metabolically active as it starts chewing through glucose to just produce heat and I didn’t mention it earlier but that’s called I indicated it on the arrow but that’s uncoupling so it’s increasing the degree to which the mitochondria are uncoupled it’s pulling apart the need to use energy just for the sake of getting work done now then we looked at what insulin was doing to the actual effect to the mitochondrial physiology and so in this case I’ll just simply state these two figures that you see on top and bottom in the middle of the screen this is us actually looking at the rate at which the mitochondria are using oxygen this is metabolism if you will in its purest form the degree to which mitochondria are using oxygen and so you’ll see that in the white adipose tissue insulin did nothing to the mitochondria there was very low rates of respiration the mitochondria and the white adipose tissue we’re already using very little oxygen and insulin didn’t do anything to it and then further to the right of that you’ll see you see p1 this is us actually measuring the amount of that you see p1 protein and you’ll see that it’s a big blank space all across there was no effect it was already very little or almost undetectable and insulin didn’t do anything to it good or bad from what we could tell in contrast when we looked at what insulin was doing to brown adipose tissue we saw as you can see the black bar is compared to the white bars in that bottom figure insulin brought down the degree to which the mitochondria are using oxygen and this was in brown fat tissue this is a tissue that wants to is designed to have a high rate of mitochondrial respiration and if you look a little further you’ll see the first two uncoupling of the UC p1 the animals that just got the PBS in Jack Shen’s that’s just a control a saline solution they had high levels of uncoupling protein they’re brown fat and then as you go over go over to the right a little bit you’ll see that is greatly dropped the uncoupling protein was just just plummeted in these in in the brown fat tissue in these hyperinsulinemic animals then we looked at the actual metabolic rate we put the animals in metabolic chambers and measured what’s called indirect calorimetry and we found that over four weeks that at the beginning both animals had comparable levels of respiration rates or in uh of metabolic rate then after four weeks the insulin brought that metabolic rate down significantly wait for the human evidence to support that I’ll show you that in the end or in in just a bit so overall this study and we have more data we’ll submit it soon this is overall suggesting a shift that the brown adipose tissue is starting to behave more like white adipose tissue thus we start to see an overall shift where we’re promoting an overrun environment a metabolic environment that is favoring storage and is inhibiting youth all because of insulin now we ask the flip side the other question we say what happens if we increase ketones and so if I want to increase ketones in a mammal what do I have to do the insulin I have to flip it around and we did this one in RAC and note as evidence of just how different rodents and humans are if you are wondering I mean to something we always do need to keep in mind and I of course keep in mind as a scientist look what we have to do to a rat to put it into ketosis 1% carbohydrate so is it appreciate that when we try to apply rodent studies and a high-fat diet in the mouse cause obesity yeah boy these mean different things as we go across the mammals and species but nonetheless we put the animals into ketosis with an incredibly high fat ketogenic diet now many of you probably know why a high fat low carb diet is ketogenic but let me just pretend some of you don’t being a good professor in this is a study looking at the consumption of these very extreme macron versions of macronutrients in humans pure lard pure carbohydrates pure protein and you’ll see what insulin is doing how the insulin response is in each of these instances proteins having a modest effect increasing and it would depend on the protein just like it would depend on the type of carbohydrate but whereas protein has a modest insulin effect carbohydrate has a substantial internal insulin effect and then you can’t even see the insulin effect to lard because it’s just humming along at zero so pure fat as it is ingested orally now mind you in nature we wouldn’t typically this crowd is different you wouldn’t typically be eating pure fat but if you eat pure some do and that’s great but if you eat pure fat there is not an insulin effect from that pure fat that’s why when it is a low car behind me to the body but not sufficient to increase insulin thus it is a so-called ketogenic diet so that’s what we did to these rats and this was a very very new data literally within the just within the past couple weeks we pulled the in green ole fat pads the subcutaneous fat from the rats and we looked at the mitochondria from the rats and you’ll notice the black bars with the ketogenic diet fed animals versus the standard Chow fed the white bars you’ll see that the mitochondria in these in this subcutaneous white fat from the rats shifted and you see that the mitochondria are acting they’re much more active they’re using much more oxygen and then if you’ll notice on the bottom with that Western blot it’s subtle it’s a little hard to see but you see p1 started to climb that it was almost undetectable in the white in the subcutaneous fat of the standard ciao fed rats and now all of a sudden we start to see it starts blossoming it’s growing the protein is starting to be expressed and that’s likely what’s driving this increased rate of respiration in this white fat tissue thus it’s shifting the white fat to be more like brown fat now we then went a little further and this is very recent we actually grew fat cells in Petri dishes in culture so we did a culture a cell culture of fat cells to just look is this happening just at the level of the fat cell or is it needing to happen in the whole organism do we need the interaction of other tissues so in this case we grew fat cells across the dish and we increase the Chi tones by simply feeding them beta-hydroxybutyrate now mind you something that’s interesting in any lab that has ever worked with adipocytes knows you actually can’t grow fat cells you can’t turn them into fat cells without insulin so you’re growing these sort of primordial early versions of cells the fibroblasts that can have the potential to turn into all kinds of different cells and we make them turn into fat cells by giving them insulin so we have to treat them with insulin for a period of time then we clear the insulin out and then we started treating them with ketones to see what would happen and then the control cells just would stay in the normal control medium and what we find the black bars you’ll see that we almost have and I don’t want to get into the details of what the conditions are but I certainly would love to if any are interested but just take it for now we’ll just say it’s mitochondrial function and respiration but you’ll see the overall trend the black bar is the adipocytes that were fed ketones not just the standard culture medium a substantial increase a doubling of the rate at which these cells are using oxygen in other words we are all together when ketones are up fat cells begin shifting their actions and they now are starting to use more energy in this uncoupled state and they’re less inclined to store energy so we’re shifting hormones because of instable because of ketones because insulin is low we’re starting to shift the use of energy how the body is using it and again this is important for when we are trying to account for calories so overall the overall conclusions from this to this point are that each of these molecules insulin versus ketones are having contrasting effect on the way our fat tissue is acting in particular if insulin has its way what does it want to do to the adipocytes it wants to shift it to be very very white and not very in not very storage mode and not using of energy wants to spare the energy and store it in contrast if ketones have its way of course then we’re shifting it more towards a brown phenotype it’s acting more in this wasting and again this is all because of what are doing to the mitochondria the mitochondria that were once very coupled that we’re only using as much energy as the cell is needing now all of a sudden it’s wasting it just to produce heat it’s like we just keep throwing logs on the fire because we want the fire just to get bigger and bigger if uncoupling protein has its way this is what’s happening and so again it’s a fundamental shift and how the Beretta and how the adipocytes are using their energy and in particular it’s an increase in energy and again just for the sake of producing heat so everything I’ve shown you up to this point is sort of encompassed in this message right here as we are shifting between insulin and ketones one being high one being low because they are not meant to be high at the same time in a human they’re not meant to be low at the same time these are contrasting and that’s relevant when it comes to supplements these days but nonetheless that’s the sort of takeaway right now and we’ll bring it all together again in just a minute but there’s still one other point I wanted to mention because I’d meant I’d mentioned earlier that energy the purists when it comes to thermodynamics will say well it has to be used or has to be stored but in fact in this state there’s one more that too often we’re overlooking that even we this community of low carb high fat advocates isn’t really appreciating I think many some might be but I don’t think it’s enough and that’s this idea of wasting which is I’m considering it distinct from using energy in this case wasting energy so what do I mean by that let’s go back to that initial paradigm where we looked at the two theories of ovc why why we get fat the caloric model and the endocrine model I’d already met I’ve already shown you now that in the endocrine model we have this unique use of energy in the form of brown fat where we are uncoupling the mitochondria just to produce heat to use glucose just to fuel the fire but in the case of the endocrine theory of obesity we have another idea where we have another outlet of energy and this is in fact in the form of ketones themselves and you already know this I imagine some of you already have come to this conclusion if you didn’t know it already and so if insulin is low in the human body we are then turning acetyl co a into ketones and then some of these can remember where the seed Okoye coming from appreciate this it’s coming from nutrients like predominantly lipid and and carbohydrate so we are literally taking pieces if we look at a fat molecule we’ve started cutting the fat molecule up into small pieces and these pieces are acetyl co a and then they convert them into ketones so we’re taking literally taking pieces of fat turning it into ketones and then what do we start doing it with it when we’re in ketosis we start breathing it out and what else do we do yes we start urinating it out and so we appreciate what that means in mind you this is happening this is happening in a person depending on the depth of ketosis five to twenty times more than the average individual so appreciate what that means we’re taking pieces of fat and we’re just wasting it to the environment can you appreciate what that means and it’s quite remarkable we’re breathing out fat and we’re urinating out little pieces of fat and I don’t mean that in the case of like nephritic syndrome or something the physicians are thinking well that’s waxy cats no that’s not what I mean I mean ketones these little teeny pieces of liquid that have turned into ketones we are wasting it from the body and this is again an a reckoning and accounting of energy that is quite unique to the endocrine theory and this is why you start to have some wiggle room when it comes to your a little in caloric excess and yet you can still lose more weight than someone else it’s because we have this wiggle room with wasting of energy not to mention the increased usage that I’ve already shown you now everything I’ve shown you all of my data from my lab has been from these models right now I very much appreciate the problem and the lingering question well what is the relevance to humans I appreciate that now I will let’s just look at the hints that already exist in the literature this study from just a few years ago from David Ludwig’s lab putting people on three diets differing in macronutrient content you’ll notice the y-axis is similar to the y-axis that I showed you and we measured metabolic rate in the mice they measured metabolic rate in the humans and you’ll see that metabolic rate was highest in the lowest carb group but this was isocaloric so they’re eating the exact same number of calories and yet their metabolic rate was the highest of all perhaps some evidence of increased usage increased uncoupling would account for increased oxygen use which is really what that’s measuring when they’re looking at metabolic rate this study is unique it’s interesting and the title says it all they put humans into two groups one was the classic low calorie so a calorie restricted low-fat diet the other was a calorie unrestricted low-carb diet in other words it was ad libitum eat however much you’d like now what’s interesting in the end they actually ended up eating about the same as you many of you know you end up just controlling your appetite anyway it’s you’re not going you know to a it’s not always Bonanza and you’re going crazy you end up just self-regulating and that’s what happened here the actual caloric consumption ended up being equal even the one group was told you can eat as much as you’d like what’s relevant here is that the group that was told eat as much as you’d like and they actually ate the same amount of calories it was not statistically different between them they lost over twice as much fat mass over the course of this study but that shouldn’t have happened and even the authors acknowledge this because they were eating the same amount of calories and yet one group lost two and a half times more fat mass they should have been eating less but they weren’t and more evidence of the fact that there’s some extra usage of energy or some degree of wasting perhaps now let’s flip it around those studies looked at lowering insulin what happens if we increase insulin so this study took equal body weight groups type 2 diabetics mat bodyweight matched with non diabetics and that in the original state the metabolic rate in the type 2 diabetics was higher than the non diabetics and that might be for any number of reasons but least of which could be that their insulin might have been lower than the other overweight non-diabetic but what happens and you start the type 2 diabetic on insulin therapy their metabolic rate starts to significantly drop and that’s what they found when the type 2 diabetics started insulin therapy metabolic rate dropped more evidence that there’s some shift going on and then the last study I want to show you just as hints that are supporting this overall effect in humans is this one I love this study so let’s just look at it don’t let it be daunting at first Glantz this took type 2 diabetics for month 0 when they were first beginning their insulin therapy and so let’s look at a few key things on this slide so what’s happening to their insulin dose over the six months do you see what’s happening the overall trend their insulin dose is climbing and that’s very much reflective of this biological phenomenon that it too much of something results in a desensitizing or a down regulation of the sensitivity to that something in other words hyperinsulinemia causing insulin resistance so these types of diabetics are becoming more and more insulin resistant throughout the course in just 6 months mind you now what’s happening to their body weight throughout the course this this is only six months and they gained about twenty pounds of fat and that’s actually quite common among type 2 diabetics who began insulin therapy so a 20 pound game now lastly that’s interesting so far but what happens to the amount of food they’re eating or at least reporting and I admit that’s a potential problem it’s going down so one of these variables insulin dose or caloric consumption is matching the overall change in body weight only one of them so in the end as we wrap this up and kind of bring this to a nice coat takeaway conclusion again there are two theories of why we get fat the caloric in the endocrine theory and very much among both of them there’s this insistence that energy must be stored or used but in the case of the endocrine theory which encompasses both of those there’s also that third option now that we have to consider which is energy can be wasted not wasted in a universal context but in the human context wasted from our bodies and in this state where insulin is low as evidence I showed you suggest that we have a shift in how our fat tissue is acting in particular fat tissues acting more uncoupled it’s acting more like brown adipose tissue and there’s relatively less overall activity of the white adipose tissue and then the takeaway from that is if there’s less of adipose tissues acting less like white adipose tissue and we’re less inclined to store it so there’s a reduced inclination to store energy and in contrast because of the shift in fat tissue acting more on couple or more like brown fat tissue there’s an increase in the usage but it’s not because we’re working more this doesn’t mean we’re exercising more because how what are we using that energy for it was for heat yeah so that’s a thermo regulation aspect of Browns fat and then lastly again but separate from these previous two separate from brown fat I just had to mention it whisp insulin is low ketogenesis is up and now we have these little pieces of nutrients that we are wasting from the body in the form of expired dress and urination so altogether these overall factors is what leads me to fairly comfortably conclude but the caloric theory is very much encompassed within the endocrine theory but you’ll notice I’m trying to be diplomatic and say well there may be some things I’m leaving a sliver that is outside of that circle and because as a scientist I am seeking truth and I acknowledge there may be some variables that I add there haven’t considered yet and I just haven’t seen it or or we just don’t know yet so I’m going to leave some of it on its own just to respect our neighbors overall this is what I believe this overall series of events a shift in how our fat tissue is behaving a shift in how we are using energy in the form of wasting it with it with lost ketones this is what I believe we had we should have in mind when we refer to the metabolic advantage that comes with a low-carb high-fat diet this overall environment metabolic environment within the body that allows us to not have to account for every individual calorie and just when we can tell people and tell ourselves eat when we’re full don’t eat when we’re not we don’t have to count calories because if we are a little excess the body appears to be prepared to cope with that and just because of this talk in the historic context we’ve seen I just also wanted to mention this isn’t a new idea we have known this and you’ve already many of you are already very familiar with this you are all familiar if you’ve seen the previous talks this is not a new idea this has been around from the very beginnings of our considering why we get fat so in the future right what we’re doing right now we’ve started collaborating with strick a bypass clinic and we are getting the first steps will be simply identifying correlation between fasting plasma levels or any other indices we can get of insulin sensitivity and the and the activities of subcutaneous and visceral fat tissue so we’ll measure just like we’ve been doing from the rodents will measure uncoupling protein will be measuring mitochondrial respiration in other words how is the fat acting is it acting like white fat in some people is it acting like brown fat in some people and then we will in fact get into in states of ketosis in humans and once again pull fat biopsy and see how is fat behaving so I acknowledge the human data is still lacking I believe there’s hints to support it there’s proof of concept but we’ll soon we’ll soon find out so in conclusion I hope you’ll have some questions for me during the break I love questions and again I’m thankful for the opportunity to be here thanks [Applause]