Keto Salt Lake 2019 - 08 - Dr. Benjamin Bikman: Insulin vs Ketones. The battle for the mitochondrion

um so for our next speaker Ben Benjamin Benny he likes to be called all of those things that I like being called them I'm okay being called them he told us he has a bunch of brothers and he's been called every version of Benjamin Hospital so dr. Beckmann earned his PhD in bioenergetics and was a postdoctoral fellow with the Duke National University of Singapore in metabolic disorders currently his professional focus as a scientist and professor at BYU is to better understand chronic modern-day diseases with a special emphasis on the origins and consequences of metabolic disorders including obesity and diabetes he frequently publishes his research in peer-reviewed journals and presents at international science meetings everyone welcome Benjamin thank you hey thanks guys thank you I thanks so much I'm delighted to be here it's fun to have a new bunch of students because the semester BYU just ended they get out earlier than everyone else because they don't have spring break because nothing good happens with college students it's pretty great so they got out early but now I'm missing teaching now I get to know I get another chance Chris and Miriam thanks for the introduction I remember when Chris in particular reached out to inquire with my ability and interest in participating I'm delighted that's Chris and Miriam with Keo ciao guys thanks so much I'm delighted to be here really is a fun opportunity to share some of what we do in my lab and I'm from right around here right do I use 30 miles away and I have an active research group there and it's it's a lot of fun it's a wonderful place to to be as a scientist in part because the students that I get to work with are really quite extraordinary when you get a bunch of early 20 year-olds who commit to not drinking and having premarital sex they're very very productive we get a lot done in the lab they're very productive so I have a very productive lab and I'm glad for that alright so by way of disclosures I I'm a co-owner and insulin IQ and best fats coaching and supplements and then I'm a consultant with an international supplement company called unicity now my focus on mitochondria is well in that fact that's the focus of my talk Chris I'm just gonna shift this a bit so I can see it and be a little more mobile hopefully I don't unplug anything your familiar if Amy's mentioned the mitochondria in fact Amy what a delightful talk I have just so enjoyed learning more about brain glucose hypometabolism and started with you I'm just delighted to hear that so we need mitochondria mitochondria are essential as Amy noted in energy production while it is true that there is the potential within the cell to produce energy for the body for the cell to to use and get done what it needs to do to work most outside of the mitochondria most of the energy production is in the cell the overwhelming majority will occur within the mitochondria for the cells that have it we know of documented instances pathologies and humans where disordered or disrupted mitochondria play a big part of the development or the etiology of that disease and I have them listed here and of course many of these are not inconsequential sarcopenia being the loss of muscle dementia loss of brain function kardama APPA the-- being the loss of the the functioning of the muscle of the heart so very distinct from just heart disease in a general sense so a lot of bad things can happen when the my talk on the mitochondria aren't quite up to snuff so we need healthy mitochondria for healthy function we have been several of the speakers and I'm delighted again to be here and it's a little sort of funny to be the concluding speaker I'm amazed that and not this many of you have stuck around all day but we've mentioned several have mentioned the word metabolism and as a person who active studies metabolism I'm always a little weary on how it's used not that it's been used incorrectly but essentially metabolism is the sum of two general processes it is the balance of the catabolic processes that are involved in breaking things down for example nutrients primary nutrients being lipid and glucose so the catabolic processes are taking something complex like nutrients and the anabolic processes are taking simpler things and building things out of them like glucose in the form of with via gluconeogenesis or glycogen glycogen ASIS lippo genesis and forming protein sorry lipid and then just even the synthesis of protein so we have here then catabolic processes breaking things down anabolic processes breaking things up now just as there is kind of a connection on the top of this metabolic circuit there's a connection on the bottom and that is now the actual production of energy I do kind of beg your pardon I hope this talk doesn't get too it won't get too technical you're gonna follow it wonderfully because you're all pretty informed and quite clever but it's definitely more of an applied talk but I promise it'll get interesting and it are more interesting in a second so ATP is the molecule when we speak about the cell making energy or the mitochondria making energy that's what we mean that is the energetic often we always call it the energetic currency it's what the cell is using to buy something to get something done when a muscle is contracting and relaxing that's the main work that's an obvious sign of cellular work ATP is what's literally what's allowing that to happen so that's cellular energy when we talk about that we're talking about ATP ATP is a product of catabolism and are breaking things down ATP can also be used and is used in anabolic processes and we're building things up it costs energy to build things up now on the kind of bollocks side I want to introduce this other concept and you've already heard me talk about some of this before we also have the production of metabolites and that could be something as obvious as say lactate remember humans ma'am animals don't make lactic acid okay anytime someone's saying my muscles my legs are sore I need to elevate them and clear out the lactic acid no no you may as well say that they're sore because unicorns are poking the muscle with their horn it's not happening we're not bacteria we don't we don't make lactic acid but lactate could be an example of a metabolite and then I have that little flame indicative of the production of heat which in fact is a consequence of any chemical reaction now one other distinction and we look at metabolism in this paradigm that I'm giving you is the location within the cell in particular the catabolic processes tend to occur within the mitochondria at least to a degree and in some instances to a large degree whereas the anabolic processes are occurring outside of the mitochondria in the area known as the cytosol and I'll come back to that concept in just a minute now as we look at this anabolic paradigm or I'm sorry metabolic paradigm this circuit including catabolic events in anabolic events you can see that we have created at least the way I presented it a circuit a circle and what's how does the cell prevent itself from going in this vicious cycle of building things up just to break things down could you see why that that's a problem that would be very inefficient and the cell would have horror that inefficiency and in fact wouldn't do it so I've created this circle and what actually determines which event is in charge is it catabolic catabolism or anab ilysm and it has everything to do with the hormone insulin insulin will determine which metabolic event is predominant in other words which metabolic event is actually happening are we catabolic or are we anabolic in general or at this at the level of the cell I would encourage you as time would allow to read some of these delightful studies from a man named George Cahill when I'm talking about insulin being this key controller of metabolism that's not my line I'm stealing this from George Cahill and he's referring to insulin not only as strolling metabolism but also being the hormone that indicates the Fed state what's important about that is of course if someone has high insulin it might be high even when they haven't eaten it's like their body is stuck in a Fed state in contrast if you can maintain a diet and lifestyle where insulin is low then it's like even when you're eating your body is in a fasted State and benefiting from that in all of the myriad ways so insulin is key here and it looks a little something like this as insulin is elevated it is promoting an AB ilysm if insulin is low it is promoting catabolism that's what I mean by the arrows being the way they are so high insulin is anabolic to the cell telling the cell to build things up or at least not break things down if insulin is low it's signaling to the cell hey you're free to start breaking things down like my kids after we've cleaned up the room it doesn't last long things get things get catabolic very quickly in my home and that's that's okay at least I tell myself it's okay that's my move man my kids joke just recently my daughter read a book where the protagonist has like a rally a war cry and so all my kids have made of their own little war cries in one time they were saying what what dad's be dad's war crime was pick it up that is absolutely true I say that probably more than anything else Dave Feldman says I love you the most I say pick it up the most okay then I'm a bi after that I say I love you after they pick it up okay now I introduce that other thing you couldn't notice because I was distracting you I put glucagon up there I've already spoken about insulin and glucagon and they are two halves of a coin or the yang to the yin glucagon to insulin they are both relevant to anabolic and catabolic processes if insulin is the main anabolic hormone you could say glucagon is the main catabolic hormone and some might make the case that there are others that are more reflective of catabolic in fact and I would disagree I'm not over and say prove me wrong so in this case let's now introduce ketogenesis ketogenesis of course is a really nice sounding name for just deliver being told to make ketones this is a catabolic process at its core where the liver the mitochondria within the liver are taking fatty acids and I just have indicated they're mentioned as lipid and it is breaking the lipid down and indeed it's breaking it down at such a high rate that there's almost as I often describe it here's the the cell's energy needs and the body because insulin is low the the mitochondria within the liver almost can't help but breaking down more fat than it needs for energy and then this little excess becomes an exhaust valve if you will there's a way to dump to spill that extra energy that's being created off and that's the production of ketones and that's reflective of what I've talked about previously with regards to ketones inducing the state of being able to waste energy and as dr. nalli mentioned it's it is allowing the person to be in a metabolic advantage and yet maintaining the integrity of the laws of thermodynamics but but I'm kind of getting a little distracted quit distracting me so here with catabolism I'm mentioning fatty acids being broken down that's they're broken down into this molecule acetyl co a in fact that's I think next whatever next talk I give somewhere else I think I'm gonna focus a whole talk on just acetyl co a it really is at the it is a keystone molecule that represents this nexus of catabolic processes like for example the breaking down of lipid and then anabolic processes for example acetyl co a can go on to become cholesterol now what I'm about to say here is that if insulin is low there is so much product there's only two options to acetyl Kuwait it can go into this and I mean it they can go into the citrate cycle and or it can go into ketogenesis and so why doesn't it go into the citrate cycle it's because the citrate cycle gets so full that it stops allowing acetyl co a to go in basically the cell is saying I don't need any more ATP and the citrate cycle exists to create molecules to go on to make more ATP so the cell is saying and we've reached the energy load we don't need anymore the only other Avenue is the production of ketones even cholesterol everything else any other thing to do with the Segal Co a requires that insulin be elevated insulin is not it's either citrate cycle or it is ketogenesis so we take the ketogenic route because the citrate cycle gets full because there's plenty of energy I hope that's making sense if it's not it's not that important anyway at least all of this is introduction so I haven't even gotten into my real topic yet so the relevance of ketones any cell in the body that has mitochondria which essentially means every cell except the erythrocytes the red blood cells will greedily gobble up ketones and use them for fuel the liver in fact isn't that's also a bit of an exception it makes them and doesn't use them as mentioned a moment ago and Adam mentioned described ketones as kind of hormones almost where they are signaling molecules indeed they are signaling molecules and regardless of what else is happening in the body if a person is in ketosis they are in a fasted state there is no other way to me there are a few bed ways to define a fasted State than just measuring ketosis or not if someone's in ketosis they are fasted yes I would submit that even if the person has actually consumed calories if they're in ketosis insulin and glucagon ratio is still reflective of a fasted state they are still fasting albeit perhaps in a nutritional fast not necessarily a caloric fast if you can appreciate how I'm teasing those two apart now all of this has been kind of a story of what the mitochondria are within the cell me at least introducing them as a main character here in this story now how are the mitochondria regulated and that's actually the meat of my my talk and I want to look at mitochondrial regulation in the context of these kind of two opposites if you will no I'm saying that they're opposites and that's not entirely accurate one is a peptide based hormone in the form of insulin and the other is a little carbon-based nutrient as all nutrients are the ketones and insulin but I'm presenting them as opposites in a way because you won't normally physiologically have both of them elevated at the same time we've we can kind of beat that by now drinking ketones and eating a bagel at the same time so they both could be elevated but that is not a natural state normally ketones are up because insulin is low now what I want to spend the remaining time talking about then is how these two characters ketones and insulin influence these three aspects of mitochondrial physiology mitochondrial number the structure or the morphology and then the actual degree to which the mitochondria are working and I'm going to define that more when we get there okay now as a reminder of course as I mentioned earlier we have to have healthy mitochondria to work and then as a caveat I mentioned here with insulin we need normal insulin insulin is a necessary signaling molecule to the cell and it even plays a role in normal mitochondrial physiology so when I'm talking about insulin throughout the rest of my talk I want you to be thinking about this hand-in-hand event of hyperinsulinemia and insulin resistance which I'm not going to take the time to define you I suspect I'll know it so when I'm talking about insulin I really mean to say hyperinsulinemia and insulin resistance again which goes hand-in-hand I submit in every instance okay first one mitochondrial number hopefully you guys are doing all right and not getting too sleepy eyed but really for me the challenge as a professor is that I have to be provocative enough for my two-hour lecture to keep the students off of Instagram that's and I bet you know what I bet same things going for you guys some of you guys are flipping at Instagram so put your freaking phones away okay why'd you pay what you pay to come here for you know you don't have a parent paying your tuition you paid this yourself okay all right so with mitochondrial number the main event to talk about is mitochondrial biogenesis that's just the term for referring to the cell's ability to take what was say once one mitochondria and really start to expand the amount of mitochondria found within the cell that's mitochondrial biogenesis and there is one primary primary key player and that's this transcription factor P G c1 alpha P G c1 alpha is the key to promoting mitochondrial biogenesis in adam Nally mentioned um thyroid hormone promoting mitochondria in fact it does it because of T threes effects on activating P G C 1 alpha as insulin climbs to high insulin inhibits P G C 1 alpha so hyperinsulinemia starts to turn that transcription factor off toning down the cell's ability to produce mitochondria now remember when I'm focusing on mitochondria you have to remember why it's relevant and it's relevant for far beyond just ketogenesis which which understandably this group is interested in we're all interested in ketones and that of course requires mitochondria as we'll get to but please keep in mind the fact that the mitochondria are essential to normal cellular function so hyperinsulinemia inhibits mitochondrial biogenesis via the inhibition of P G c1 alpha or turning it off one thing that's kind of noteworthy about this is that earlier I'd mention that insulin is a main anabolic hormone yes it is absolutely true what's so interesting those anabolic processes that I have mentioned their lipid Genesis likes glycogen is's and then even cholesterol synthesis those are events that occur outside of the mitochondria they occur in the cytosol so the mitochondria rather insulin signaling anabolic processes it doesn't need the mitochondria anyway the mitochondria are involved in catabolism as we'll come to in a bit now I'll mention also I'm gonna show just very briefly a little data from a paper we just published last year and all those first authors are undergraduates remember and BYU undergraduates are remarkably productive whatever whatever thing else you want to say about BYU boy these undergraduates are there's something else they're not goofing off no spring break could be why you it's there in the lab okay so what happens on a Saturday night they go bowling for an hour and they get bored and because no one goes to the bar they go to the lab and get some experiments done so here we actually looked at what insulin is doing to mitochondrial function in fat tissue and there's a lot more to this story but I'm only I'm only gonna show this where we found in two different types of fat not in the classic white fat no effect on PG C U and alpha it maintain normal levels this is these are called Western blots when we actually get a picture of how much protein is there essentially we found that in the subcutaneous adipose tissue the adipose tissue of humans and rodents that can become brown that's the type of fat that of course is right beneath the skin that can jiggle and be pinched and or or the actual brown fat which in the animals is right between the scapula and in the humans it's generally around the thoracic cavity in the clavicle and collar bones so here we see that PG C 1 alpha in both instances is we have a quantified and figures this one and this one we see that there was a significant reduction in PG C when alpha protein just by inducing hyperinsulinemia in the animals and we aren't the only ones to show this there are several other papers that find hyperinsulinemia or chronic exposure to insulin also will turn down this mitochondrial biogenesis now that's insulin what about ketones ketones infective a very powerful activation of P G c1 alpha so what was once one lonely little mitochondrion becomes the whole population of mitochondria within the cell and this that in and of itself isn't particularly surprising insofar as even for a cell to use the ketone as I mentioned earlier it must have mitochondria the catabolic the main catabolic processes and in the case of ketone the entirety of the cat the catabolism of the ketone catalysis occurs within the mitochondria and that could be why multiple papers report this phenomenon where ketones beta-hydroxybutyrate particular induced mitochondrial biogenesis then the activation of P G c1 alpha is a big part of that so if we wrap up this first concept how insulin hyperinsulinemia and ketones influence mitochondrial number whereas insulin resistance in hyperinsulinemia tends to have a dampening effect it abhors the cell using the resources to produce more mitochondria remember because mitochondria exist to break things down but for the sake of the cell of course unlike my kids in the playroom which break things down just to break things down here the ketones are in contrast having a positive effect activating mitochondrial biogenesis if for no other reason then it has to have mitochondria the ketones do in order for the ketones to simply be used as an energy source next was mitochondrial morphology this is the classic way of presenting the mitochondria I mean the previous speakers have shown it any version anytime you see the mitochondria it's always this kind of circular kind of being shaped molecule a little oblong the reality is I still I will never forget the first time we imaged mitochondria within muscle cells I I big I hope you can kind of see that we stain it with a red dye called my toe tracker and what you can see it's these long little stringy things that's the reality of mitochondria at least when they're allowed to be dynamic and they are very dynamic moving around the cell changing all the time but what's relevant about even the name mitochondria is that my toast means thread when you look at the mitochondria they look like little threads and so rather than looking at the mitochondria as a small little distinct ball or oblong shape the reality is they're these big reticular structures connected throughout the cell now however they can exist in that very distinct shape and so mitochondria as I mentioned earlier are very dynamic they can flux between these two instances or these two scenarios and that's through these processes that refer that we refer to as Kandra fission which separates the mitochondria pulls them into distinct little balls or globules versus mitochondrial fusion which has those little distinctive globules start to come together and again it is dynamic the cell is allowed or it's expected it expect to be able to flux between the two in the case of hyperinsulinemia and insulin resistance it gets the cell stuck in a state of fission it promotes and locks in mitochondrial fission the problem with this and we published a paper about four years ago looking at some of this when when the cell in the mitochondria are stuck in fission their ability to produce ATP is compromised so less energy production for the cell it promotes insulin resistance exacerbating what was already causing the problem it produces more reactive oxygen species which will we call oxidative stress and it promotes fat gain and that could just simply be a consequence of the insulin resistance and the compromised energy production one cell type that is particularly susceptible to this event are neurons and we see that within the nervous system how insulin resistance is promoting the state of fission in addition to the work that we published from my lab looking in muscle cells now back to this paradigm of displaying the mitochondria being dynamic going through fission versus fusion ketones in fact as you can already guess have a different effect now this has not long been known this study mentioned that we really don't have a great deal of understanding on how in this case they're talking about ketogenic diet but how ketones influence this mitochondrial dynamic whether it's more fusion or fission and so being a scientist one of the great beauties and I mean it of being a scientist is we just get paid to ask questions that's a wonderful thing to be paid to be curious and then to try to find a way to pay to answer your question of course but we did this in cheap ways and in less cheap ways but the first process was to just treat muscle cells in culture with beta hydroxy butyrate just supplementing the growth medium with the ketones and then next step was putting the rodents into a ketogenic diet and I will never forget when first time I ever met amber O'Hearn her mentioning to me this advantage of humans being able to get any ketosis quite readily and I didn't even really appreciate it and yet in hindsight looked back and realized what you have to do to get inroad into ketosis other than fast them which works is 1% carbohydrate diet yeah it's pretty remarkable that's what I mean that's what that's that's reflected there the macros have to be extraordinarily low carb to put a rodent in this case a rat into ketosis without fasting them so that was the the model that we used now this was the study we published just last year once again an undergraduate who's actually a medical school here at the you remarkable student once again has nothing else to do on a Saturday night so come into the lab and get some work done so what we found in treating the muscle cells of ketones we well firstly to lay out the experiments it was in fact very very simple and we did this we always start with cells to try to get proof of concept because it's so cheap to do we just try to get proof of concept in the cells and then we kind of graduate the project to the more expensive model which will usually be rodent and then maybe human at the end so in this case treating the cells of BHP versus normal just glue coasts rich medium we found a significant difference in the expression of two relevant proteins my diffuse in two which promotes fusion and then a protein dynamin related protein dr p1 which promotes fission and we see here the general trend is that there's a greater expression of my diffuse and two that was quite obvious and then more subtle because of the variety here but a general trend well this was beyond trend this was very significant this was a trend of a reduction in dr p1 then we actually quantified the amount of fission vs fusion via confocal microscopy again we put on a dye that will fluoresce when it hits the mitochondria and then we can get pictures of that under these very high-powered microscopes I can focal microscope we got those images and then we had a student who laborious Lee actually took fields and then quanta fied the degree to which there was fusion versus fission and you can see that in the cells treated with beta hydroxy butyrate the black bar dropped significantly and there was much less fission much more fusion but still both present which you need then in the rodent aspect of this study who simply put them onto the ketogenic diet or the standard lab now from muscle this was gastrocnemius which is a mixed muscle it has both fast twitch and slow twitch and I bet you guys have heard of those before we see here much much more my defusing too and no insignificant differences of therapy one but nevertheless still creating suggesting this overall scenario where fusion is enhanced in muscle so to wrap this topic up then with mitochondrial morphology hyperinsulinemia and with insulin resistance is promoting the state of distinct separate dysfunctional mitochondria not to say that fission is bad but the hyperinsulinemia is locking in the fission it's a forced and sustained mitochondrial fission that is in fact pathogenic whereas ketones are allowing this mitochondria to maintain this dynamic effect and in particular have fusion occurring now lastly mitochondrial function by I'm going to define my deconned really as oxidative stress so the production or the defense against reactive oxygen species and then coupling status mitochondria coupling versus uncoupling coupling status sounds like something else and we could be talking about a BYU and so far as so many couples get engaged and need marital advice on this I'm not talking about that kind of coupling here so with oxidative stress we will again as I mentioned will split this up into two subtopics the production of reactive oxygen species that's the R OS and the efficacy or presence or amount of antioxidant enzymes now as mentioned I think Amy mentioned we have to have oxidative stress it is absolutely essential to normal cellular cellular survival it's essential to normal immune function one of the main mechanisms a phagocyte like the macrophage can kill a pathogen is by doing something called an oxidative burst that basically just blasts the pathogen to smithereens with this production of reactive oxygen species so thank heavens for oxidative stress we need it we certainly the system was designed to have it there however of course it can go too far now when when I when I'm talking about the production of reactive oxygen species it essentially happens at the same level where we're producing ATP which of course is the consequence of catabolic reactions and of course is necessary for anabolic processes so here rather than producing ATP the cell ends up using the oxygen to produce the very first of the reactive oxygen species the superoxide radical I'm losing some of you as I see nodding off and I don't have a way to spice it up this topic is just heavy I'm not gonna apologize for it so so wake wake up for heaven's sakes ok so anyway here we have the production of the react the reactive oxygen species and because too much isn't good for these reasons here we have mechanisms in place to it to a deal with them to squelch these reactive oxygen species so that's this you know the kind of the pac-man eating up these reactive oxygen species dealing with the oxidative stress and of course we need that we need the balance here so let's look at what happens when insulin is elevated suffice it to say oxidative stress itself gets worse the insulin resistance itself can drive the oxidative stress in fact it can also go back round full circle oxidative stress is known you can induce oxidative stress in insulin sensitive cells and every cell is in fact but that you can create insulin resistance in that case as well but let's look firstly at the production of the reactive oxygen species themselves this was a very neat study they took these cells and induced they had elevated levels going up in higher higher and levels of insulin treated with these Ella levels of insulin over time and this is in minutes so just in one hour then looking at the production of reactive oxygen species in the hotter the cells are the more they're fluorescing in this case with the green since the more they're producing reactive oxygen species in other words the greener the cells are the more oxidative stress they're experiencing and you could see look at this spike in oxidative stress and these are pretty physiological dose a little elevated on this end but it's still the insulin the the chronic will not chronic 40 minutes for heaven's sakes exposure to insulin was significantly increasing the oxidative stress now on the antioxidant side of things the main enzymes I'm not going to take the time here are just the key players that are considered antioxidant enzymes or are within the cell so these are the molecules that are trying to deal with it multiple studies suggest that insulin resistance hyperinsulinemia is reducing the presence and the efficacy of antioxidant enzymes and the general theme when we start to increase ketones is the opposite not surprisingly in more evidence from our study that I just mentioned from last year we found in muscle cells we actually looked at after after the cell has made the oxygen radical that was the o2 - and I showed you a second ago the way the cell deals with it is to turn it into h2o - yes the very hydrogen peroxide we're putting on our little scrapes it's because it kills the stuff that's trying to get into the body it also can kill our own cells if it gets too high so we looked at how much h2o to our muscle cells producing as it's consuming oxygen in other words how much of the oxygen the cell is consuming is being used to just simply turn into h2o - and you could see when the muscle cells were fed beta-hydroxybutyrate as opposed to strictly glucose a significant reduction it was a p-value of about point zero one less than point zero one so very significant reduction in the production of h2 o2 per oxygen consumed in other words the muscle cell is cleaner with the oxygen that it's taking in and using it's producing less of this bad exhaust in the form of h2 o2 and more studies here now in looking on the antioxidant side of things that agree to which ketones are influencing these enzyme that try to keep oxidative stress in check one of the main the main one is the glutathione peroxidase this middle enzyme and indeed ketones have long been known to increase among all of those glutathione peroxidase in particular so presenting a very effective way for a cell to deal with oxidative stress I've spoken in fact the very first talk I ever gave in the realm of in the low-carb community was looking at how ketones and insulin affect coupling and when I talk about coupling what I mean by that is the degree to which here's this paradigm again the anabolic the sorry the catabolic processes are either producing ATP and in that case it's coupled in other words you're only using as much new treant you're only breaking down as much lipid and glucose for example as you need energy so basically the cell is saying alright I need this much ATP I'm gonna use that much glucose and lipid for fuel in contrast you can separate that process and now you're chewing through say lipid and glucose but it's uncoupled it's not because you need energy in the form of ATP you're just chewing through for no good reason in other words it's creating heat that is at its mitochondria that are more uncoupled or mitochondrial uncoupling now this event occurs here along the inner mitochondrial membrane through the electron transport system and I'm not going to get into that but both of these instances can be useful uncoupled mitochondria that's good if you want to just waste energy like if you have too much energy in the form of too much body fat that would be very helpful ATP and it's more tightly coupled like at the muscle cell you want it to be very tightly coupled because then you're only the muscles never wasting energy it's only using the lipid and the glucose to make the energy that the muscle needs so it's pretty smart now which process is better uncoupled or coupled well it really just depends and then let's look at the big overview version of what I've been spending the last four years studying so it pains me to cover this so quickly because it's been so painful to answer all these questions but for you I'm gonna give you the cliff notes for version insulin is making the fat cells be more tightly coupled it is telling fat cells don't waste energy and this is reflected in that paper that I showed you earlier that we published last year and more to come in the context of in the case of ketones very very soon whereas insulin appears to have no general effect uncoupling or uncoupling at the muscle cell at all the muscle just continues to work as normal overall though this is promoting a general situation in the body where insulin is telling the body to store energy don't waste it remember insulin abhors wasting now ketones this is more of what we're doing again in the lab actively muscle there's no effect that was the paper we just published ketones have no effect on mitochondrial coupling or uncoupling they maintain perfect efficiency muscle cells do when they're fueled with ketones in fact maybe in fact they're better because they're producing less oxidative stress and then when you look at the edifice sites they're more uncoupled and this is the research we're doing actively where ketones are promoting the uncoupling allowing the cells to waste energy we have gotten now to the point of human research so we have humans coming in in normal non ketosis States versus ketosis States and we do two things we put them under this big space helmet and and measure their resting energy expenditure basically their resting metabolic rate and then we pull a little piece of fat from right beside their belly button we numb it with a teeny bit of lidocaine and indeed that is the worst part I can tell you from experience I was the first subject for this very procedure because we've never done it before so we did it on me and we that's what you can do right in science whatever you want not quite as long as you have IRB and I cook approval so we we numb it with lidocaine and then we make a little incision and then use a hollow little needle and pop out a piece of fat and then we measure the mitochondrial function so let's look firstly at the adipose biopsy we see we saw immediately the people that are in ketosis have significantly higher metabolic rates and it's basically what we're looking at here they're using much more oxygen that means they're busy your ATP production intended to go down a trend but when we looked at the amount of ATP or phosphorylation peak to oxygen used oh the pto ratio we found that these cells were making much less ATP as they were consuming the same amount of oxygen or if we said these are consuming the same amount of oxygen they're making much less energy out of it in other words the fat has become significantly more uncoupled so the fat tissue from people in ketosis is wasting energy to create heat pretty interesting adaptation and in fact even cold exposure can increase ketogenesis and it could be because the ketones then activate the fat to become hot when we looked at resting energy expenditure we found no significant difference across the group in general however only split it up among those college aged kids and then those of us that are not college aged kids we saw a slight it is always slight but a significant difference the older people that were in ketosis had higher metabolic rates indeed not significantly different from those young college kids we basically were bringing in a bollock right back up to that higher level take that your 20 year old ok so in summary yeah thanks for staying awake you guys have really been troopers here if we look at what mitochondria are doing as insulin tries to have its way with the mitochondria and ketones try to have their way with the mitochondria first the conclusion was that insulin is reducing mitochondrial biogenesis it does not want the cell to expend that kind of energy ketones in contrast are promoting mitochondrial biogenesis if for no other reason than it needs the mitochondria in order for the ketones to be catabolized and be useful at all in the sake of for the sake of energy at least the second in hyperinsulinemia is promoting and sustaining that's important sustained mitochondrial fission it's not allowing the mitochondria to be dynamic anymore whereas the ketones are just generally promoting fusion which is enhancing medaka ATP production for example and then lastly with regards to mitochondrial function i'm just generally saying the hyperinsulinemia it's just corrupting the mitochondria general more oxidative stress compromised ability to enhanced production of reactive oxygen species compromised ability to deal with those oxygen reactive oxygen species and in contrast when fueled or exposed to ketones the mitochondria within the cell appear to be working a little better reduced oxidative stress enhanced ATP production and this kind of odd unique differential effect where you have uncoupling at the adipose tissue or the fat tissue and yet perfectly maintained coupling at the muscle cell so pretty fascinating and almost intuitive event that's it and I look forward to any questions any at all thank you thanks guys thank you

Channel: Keto Chow

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Keywords: keto, ketogenic, keto diet, hflc

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Length: 42min 52sec (2572 seconds)

Published: Thu May 02 2019

Reddit Comments

[u/Ricosss]

What I found really interesting is the comment that the abundance of acetyl-Coa is actually what causes ketone production. In theory this would mean that people who are lean, so low body fat, who tend to have a decreased metabolism due to lower free t3 and therefore reduced triglycerides catabolism from adipocytes, will not be able to produce as much ketones as a person with normal amount of fat or definitely compared to an obese person going keto. That could explain why lean people have a harder time fasting for longer periods of time, even when they are on a ketogenic diet. They'll have a higher reliance on fatty acids for energy which at the same time creates a higher glucose sparing effect which is needed because the ketone production remains low.

[u/[deleted]]

This was a really great lecture. Thanks for sharing.

[u/e0k2i4m]

Wondering what Jillian Michaels rebuttal would be

[u/Mrpoopypoopholepoops]

The mitochondria is the powerhouse of the cell.

[u/halpmeh_fit]

Thanks actually watched the whole thing- really cool research

[u/yodamuppet]

I live in SLC and had no idea there had been a keto conference, let alone Leto bakeries in town. I need to get out more.

[u/Benforman]

I heard Marvels next movie features a mitochondria protagonist