New Insights on Fasting

The Lipid Energy Model: New Insights on Fasting and Cell Structure by Dave Feldman | #PHCvcon2021

New Insights on Fasting

Video Transcript

Want to know the best natural herbal remedy that grows wild in your own backyard? You'll be surprised as I was... take a look..

hi guys welcome to my talk this is the lipid energy model new insights and data on fasting in cell structure conflicts of interest i do have membership in patreon revenue and through cholesterol code and i also am a partner and managing director for own your labs so this first section is kind of a bit of review it’s the lipid energy model in a nutshell i’m definitely simplifying a lot but that’s so that we can build on it from there as you know for those going on a low-carb diet many observe their cholesterol levels rise and through a series of experiments myself and many others have helped find connections between metabolic changes and cholesterol levels i have and continue to hypothesize these cholesterol levels are highly influenced by the trafficking of fat around the body in lipoproteins i like this analogy to start with what what can this bag teach us about fat based storage and when you look at it of course we’re looking at golf balls in a mesh bag you have to ask what if we couldn’t open or close this bag what if we could break the balls apart to small enough pieces to get through the mesh holes that’s kind of the basis you want to think about when talking about fat storage so it all starts with triglycerides triglycerides are the storage form of fat based fuel they’re commonly found in adipocytes and lipoproteins and these are big they’re bulky so they stay within membranes really well with the help of some lipases one of which we’ll be talking about a lot in this talk we can break them apart and then ultimately bring them out easily through the membrane and you want to understand exactly what the constituent components are it’s glycerol which is a three carbon chain that connects these fatty acids together and they’re very soluble in the bloodstream they’re also commonly used by the liver to generate glucose and their counterparts which is free fatty acids also known as non-esterified fatty acids these are the free form of fat-based fuel and they’re commonly found in the bloodstream often carried by a prominent protein known as albumin in these small molecules they can easily slip through membranes once you what i want you to keep in mind are these two categories are constantly being converted back and forth to each other triglycerides are getting re-esterified into membranes and often they’re getting hydrolysized out into glycerol and free fatty acids so going top view now what we’re looking at is when particularly on a carb-centric or mixed diet and when healthy and going on a low-carb diet or fasting we hypothesize the following takes place that there’s a higher continual release of free fatty acids from adipocytes which are our fat cells and this also results in a higher uptake of free fatty acids by the liver so more going to tissues in need more also being picked up by the liver and this in turn results in a higher liver production of ketone bodies a process typically referred to as ketogenesis which the ketogenic community loves to talk about this is good because these can cross the blood-brain barrier so they’re very important for survival in all of this this isn’t controversial but it gets a little tricky into the next part see we hypothesize that there’s a greater re-esterification of triglycerides in the liver and this brings us a higher secretion of these triglycerides on board lipoproteins particularly vldl particles this in turn results in a greater direct supply of vldl to both adipose and non-adipose tissues and this part’s key we see a higher turnover of vldl and delivering triglycerides to these tissues at least this is what we’re hypothesizing resulting in more ldl particles and therefore more ldl cholesterol this is controversial in fact there’s a lot of spirited debate on many of the things in the bottom half of this graph both in and outside of the low-carb community and certainly a central point of my research but what i want to do now is go ahead and drill in deeper on body fat and not just body fat but also cell membranes as this is an important part of the story of course body fat is typically in science referred to as adipose tissue because they’re made up of these adipocytes and adipocytes as the fat cells they’re pretty interesting they kind of look like an eyeball the nucleus looks almost like an iris that’s just sort of squashed up against one side of the cell and it has many of the things you would expect in the cell mitochondria the golgi apparatus membrane cytoplasm etc but obviously the bulk of this is this fat reservoir that’s bloated with triglycerides it’s about 95 triglycerides with about five percent uh other lipids and what we’re usually looking at when we’re looking at the cell wall whether it’s adipocyte or anything else is we’re looking at what’s commonly referred to as the fluid mosaic model these different elements they’re kind of they’re floating but they kind of allow for passage past each other and yeah there’s all sorts of functions there’s protection of course transportation and communication but we’re not going to focus on any of those what i want to focus on is the components that make this up that are the most predominant and that’s the phospholipid bilayer so if we look first at the phospholipids we find that they have this hydrophilic head hydro as in water and philic as in loving and then they have these fatty acids these uh long fatty acids that are part of their hydrophobic tails hydro being water and phobic being hating but i like to call them lipid loving and what’s great is if you put them in an aqueous environment something water-based what you’ll find is they almost kind of magically snap together and that’s because these polar heads they’ll face outward into the water-based environment while their tails will face inward towards each other so they can kind of create this layer that’s uh lipophilic inside it’s pretty cool but then on top of that we need cholesterol cholesterol is i like to jokingly call it the the intellectual property of the animal kingdom this actually gives a special level of structural composure and control it can allow us to shape things a little bit better gives it just about the right amount of flexibility to do a lot of the things we want so here’s an example of a lipid bilayer if we’re taking kind of like a cross section and this isn’t the scale at all but this is the structure as we would expect it to look these phospholipid tails are pointing towards each other with the phosphate head pointing outward along with these free cholesterol helping to maintain its structure it’s water based on the outside with the blood and cytoplasm for the inside also water-based and if you compare this to a lipoprotein we now see that we don’t have a bilayer we have a monolayer and that’s because while there is an aqueous outside with the blood there’s a lipid inside a lipid core these are primarily lipids and this is important to keep in mind because now when you look at a model it’s not going to be so intimidating you can expect that we’re looking at a lipid core these are not just the triglycerides but also other lipids that are found inside and this here on the outside that is the phospholipids and cholesterol but now let’s go with a little bit more of a complex 3d model what we’re looking at now is the lipid bilayer of a cell this is gigantic because the cell is gigantic relative to what it’s being attached to the inside of the cell this is the cytoplasm the outside is up here this is going to be the bloodstream and what it’s docked to is a lipoprotein and i know this is a kylomicron given its size even though this cell is going to be like you know way way way larger than the lipoprotein these are measured in nanometers whereas these are measured in microns several times larger it’s docked with the help of an apolipoprotein and a receptor but we’re not going to focus on that what matters is that we note that what’s happening here is a process called hydrolysis as i talked about earlier it’s providing lipids providing lipids from this kylomicron into the cell so we’re now going to apply some glasses so that we can focus just on three elements on the triglycerides in their counterpart when separated glycerol and free fatty acids phospholipids and cholesterol and so while there are many other elements that are going to be part of this lipoprotein and the cells that we’re about to talk about i want to mainly focus on these structural components because they’ll be very relevant in a second starting first with what happens when they’re relieved if hydrolysis is taking off these triglycerides and releasing them into the cell down below what happens to it as it loses them well as these lipoproteins release a little bit cargo it gets smaller but how does it get smaller i mean we’re not leaving air so here’s here’s the thing that i guarantee it’s not doing it’s not just squishing together it’s not these these monolayers are not just tightening the gaps in between the phospholipids and cholesterol that’s not what’s happening rather in order for it to get smaller it has to release these phospholipids and cholesterol to remodel to a smaller size and so it ends up with actually roughly close to the same gaps in between that’s an important rule and it’s important when you’re thinking about this in terms of it providing these lipids particularly to adipocytes because as these are coming off if this needs to shrink from releasing then this needs to grow to take them into storage full stop so how can it do that well we come back to this 3d model which is a bit more complex further still and we have lots of lipoproteins you see that are docked but you see this one’s kind of like a little bit submerged into the bilayer and this one up front it’s especially getting submerged you can even see these kind of complexes that are forming because it’s about to invaginate it it’s literally going to take these up in a process known as lipoprotein endocytosis and that’s great because by completely taking up the lipoprotein the cell can incorporate its phospholipids and cholesterol to this bilayer there’s a lot of parts of this like uh the lysosomes and so forth that i’m not going to talk about but i will say it’s important because these lipoproteins because they’re made of the same components are part of this bilayer it makes this possible and that’s very relevant because we’re not just growing the contents of the container not just the lipids we’re growing the container itself so now let’s talk about lipoprotein lipase and hdl i love this study even though it’s really old it’s extremely instructive to kind of set it up you need to understand these two types hdl2 which is a bit larger versus hdl3 and smaller size and they say this in the early text that hdl can be divided into at least these two subfractions so alpha 1 is the biggest alpha 2 the next biggest and so on and remember hdl typically starts deliberated it starts small and becomes big as it takes on more lipids so here’s what they did this is an in vitro study they had vldl particles bloated with triglycerides and they saw substantial hydrolysis over 80 percent of the vldl triglycerides and it occurred during a four-hour incubation with lipoprotein lipase approximately 45 percent of both the vldl protein and phospholipid and 15 to 20 percent of the vldl cholesterol disappeared during this lipolysis meanwhile they likewise included this smaller species of hdl3 these nascene hdls hdl3 and they saw substantial changes also occurred in these hdl3 with the lipolysis of vldl during the four hour incubation without the enzyme no changes to these hdl3 but when lipase was present the hdl3 disappeared completely and at the end of the incubation was replaced by a less dense slip of protein which exhibited the flotation characteristics of hdl2 so don’t miss this last part during lipolysis apoproteins phospholipids and cholesterol were transferred from the ldl to the hdl3 resulting in a 50 increase in the total mass of the lipoprotein i can’t emphasize this enough we’re seeing with just the addition of the lipoprotein lipase a bunch of lipids that are hydraulicizing off of the vldl and being picked up by the hdl without any engagement in tissues or anything else just the addition of the lipoprotein lipase this was kind of a big deal to me because it really jumped on my radar in a new way because i was saying wait a sec this isn’t this isn’t lip isn’t lipoprotein lipase provided as needed from cells that’s what we typically call it in engineering is pad well like many i read in libidology the focus is predominantly on the receptors not so much on the lipases including lpl also like many i presumed lpo was provided as needed in other words there is very little regulatory influence on its production and supply wrong there’s enormous regulation into the transcription translation and activation of lpl this is from a study uh or actually a review adipose tissue lpl activity is high in fed animals and low when animals are fasted but most studies have shown that the opposite is true in the heart and skeletal muscle so this is smart even with the things we’re about to talk about on the endocrine side we see that in the fed state adipose lpl activity is going up during the fed state it’s going down in heart and skeletal muscle but yet the reverse is true in the fasted state lpl activity is going down so it’s going to be taking up less of those lipids while lpl activity is going up for the heart skeletal muscle and while we’re talking about the heart let’s talk about lpl in the heart the heart is a major site of lpl synthesis and fatty acids provide over 70 percent of the energy needs for the cardiac muscle not surprisingly cardiac muscle is the tissue with the greatest expression of lpl and thus lpl is likely to be an important enzyme and cardiac lipid uptake and metabolism i really i really have a great appreciation for this last line and its relevance neither non-esterified fatty acids nor compensatory increase in cardiac glucose metabolism can entirely replace the fatty acids not provided by lpl in the heart so in a lot of these animal models they would delete the lpl expression by cardiac cells and what they found was it was too much it’s too big of a deal in short to put it rather plainly in these animal models they found that the heart is not just preferentially seeking out fatty acids but it specifically likes fatty acids coming off of lipoproteins in particular so getting us back to lpl and adipose in mature adipocytes or adipose tissue insulin not only increases the level of lpl mrna but also regulates lpl activity through post-transcriptional and post-translational mechanisms likewise glucose also increases adipose tissue lpl activity the glucose stimulatory effect appears to be mostly through glycosylation of lpl which is essential for lpl catalytic activity and secretion glucose also stimulates lpl synthetic rate and potentiates the stimulatory effect of insulin naturally in the presence of a lot of insulin and a lot of glucose we’re going to expect an increase in lpl activity by adipose tissue and take that in combination with this is this is actually still a study i love this is fatty acid metabolism and adipose tissue muscle and liver in the heart in health and disease and it’s a great kinetic study because what they’re tracking here is both in adipose tissue skeletal muscle also liver but let’s look at adipose tissue basically if you were to ask adipocytes hey where did you get most of your fat throughout the day in this case it’s about 90 percent 45 grams per day specifically off of lipoproteins from triglycerides and only five grams per day from non-esterified fatty acids so it’s not picking up that many free fatty acids it’s getting from the wholesaler if you will meanwhile for skeletal muscle it’s 10 grams per day out of 30. this is at rest are coming off of triglycerides from lipoproteins yet non-esterified fatty acids account for two-thirds where is it getting these free fatty acids obviously a large portion of these are coming from adipose tissue but an important takeaway here is that the bottom line is adipose is the major consumer of triglycerides on board lipoproteins in the serum and i like this next slide because it kind of ties it all together pretty well if we’re looking at triglyceride rich lipoproteins in its relationship with adipose tissue you can kind of call it or at least i like to call it the global distributor it’s sort of like the large freight trains or you know the the giant planes or the the barges that bring lots and lots of cargo and adipose tissue is a little bit more like the local distributor it’s locally distributing especially free fatty acids to adjacent cells and even to some degree neighboring adipocytes to be re-esterified again so take this in the context of fed versus fastid in the fed state we would absolutely expect that chylomicrons and vldls these are all apob containing lipoproteins that are bloated with triglycerides yes they’re going to provide some amount of free fatty acids to muscle tissue but in large part they’re repleting adipose tissue after all it’s a state of abundance now we’re into the fed state conversely in the fasted state now we’re going to primarily a release we’re releasing free fatty acids from adipose tissue especially to nearby tissues and the ldl to some degree will also provide some amount of this particularly i think that the proportion obviously is going to change a lot more the more fasted you are now there is going to be some amount of repletion by vldl but again this this is going to depend a great deal on just how low your insulin is how low your leptin is etc so let’s put our glasses back on and let’s look at the context of these three elements apob containing lipoproteins particularly bloated with triglycerides hdl lipoproteins and adipocytes and especially in this context of adipose lpl activity so if lipoprotein lipase activity is increased at adipocytes under healthy conditions and all else being equal we should generally see greater uptake of triglycerides from maple b lipoproteins like chylomicrons and vldls higher turnover of vldl triglycerides which means more vldl phospholipids and cholesterol being transferred to hdls that’s why i’m showing it here right you’re seeing turnover resulting in more of these fatty acids going into adipocytes you’re seeing also as part of this turnover more and more of these phospholipids and free cholesterol going into hdl species this means more remodeling of vldl to ldl and of course a greater growth of adipocytes requires more endocytosis of lipoproteins like ldl you could flip this script and look at it from the other direction again we’re seeing adipocytes are now releasing primarily free fatty acids and apob is not putting in as much and it’s not providing as much to the hdl side of the of the ledger so less uptake of triglycerides from apob lipoproteins like chylomicrons and bldl lower turnover of vldl triglycerides which means less vldl phospholipids and cholesterol transfer to hdl less remodeling of the ldl to ldl reduced growth of adipocytes requires less endocytosis of lipoproteins like ldl i have a recent experiment and really i have lots of data before this that i just don’t have time to fit into this talk but this recent experiment gave me a lot of robust data specific to what i was just describing it’s called the replication experiment because there’s really two of them one that i did two years ago and another that i did six months ago that is identical to the one i did two years ago so i’m not going to get into the deep details but here’s the thing you need to look at the most which is the first one is maintenance phase it’s about five days long and it was at a maintenance calorie level on a ketogenic ratio then there was a hypocaloric phase low calories for five days in fact it’s exactly half of what i ate in the maintenance phase and then lastly there’s a hyper caloric phase which was high calories for five days and at the end of each of these phases each of these five day phases i got wide spectrum blood tests so body weight goes pretty much as you would expect as i was at baseline maintenance levels here not surprisingly i kept a pretty much baseline at uh version two sorry i should mention we see both columns weight in version one which was the two year ago experiment wait in version 2 which was the six month ago experiment and note that i did weigh a little bit more in version one 196 pounds whereas i weighed 192 pounds in version two but the maintenance level seems to precipitously go down for version one in other words i probably have a set point closer to 192. as i’m hypocaloric not surprisingly i lose weight as i’m hypercaloric in the last phase i gain weight no surprise there also no surprise with glucose generally my glucose goes lower when i’m hypocaloric higher when i’m hyper caloric and not surprisingly it’s inverse for my ketone bodies particularly beta hydroxybutyrate at baseline it’s down here but when i go hypocaloric my glucose is going down my ketones are going up and then vice versa when i go hyper caloric ldl cholesterol followed the inversion pattern so here’s the baseline and now you see it’s going up when it’s hypochloric down when it’s hyper caloric and hdl cholesterol i kind of want to draw your attention to because we’ll talk about this a little bit more when it when it comes back to turnover we see baseline we see it’s going it’s tracking with calories as it goes down as fat goes down it’s going it’s going down itself and then it starts going back up but worth noting it hits its nader its floor after a full day of high calories so it hits it at the bottom of day two again these tests were taken on the morning of the day noted so on the morning of day two was when it was at its lowest at 38. and at 46 and note that five days later it’s up at 65 and 64. triglycerides should be coupled with that because guess what we also see something dramatic on the morning of day two while baseline i’m holding at hypochloric it starts to go up and then we have this huge spike that happen in both versions of the experiment so what do i think is happening here well getting back to the model i think that there’s a greater amount of chylomicrons coming in and this is again in the context of the shift from hypo to hypercaloric because i’m bringing in more fat and glucose we can expect higher insulin higher leptin and higher and sorry lower lipolysis overall on top of that there’s a bit more energy competition between the state of change going from release to storage but i want to draw attention again to glucose remember on this day with the glucose it had hardly risen at all it’s an energy substrate but so too is triglycerides triglycerides went to such an enormous spike but there’s a big difference between glucose and triglycerides again triglycerides have a major carrier in lipoproteins but lipoproteins aren’t the end of the story it also needs lipoprotein lipase activity so i speculate on day one i was capped out on the amount of lipoprotein lipase activity and by day two lipoprotein lipase activity was much much higher and continued as such and at that point we could see it would drop and continue um continue forth from there really it’s it’s outcomes razor in my opinion adipose lipoprotein lipase production may need to catch up to its activity demand in this context so here’s here’s kind of my layperson way of explaining this my body fat really my whole system is being told for five days in that hypocaloric phase hey we are in a state of scarcity please prioritize all the proteins you’re synthesizing towards all kinds of enzymes and hormones that reflect to that context oh all of a sudden now we’re switching from this hypochloric phase to this hyper caloric phase and my body and i suspect particularly my body fat is going whoa okay we need to do a gear shift toward prioritizing a different proportion of these enzymes particularly enzymes like lipoprotein lipase and that’s not overnight but it’s about two overnights i actually will get to those proportions closer to the morning of day two so now let’s look at phase completion of these replication experiments and how they look well again uh here’s the sort of summary on what the calories were for maintenance hypo hypocaloric and hypercaloric and also the the breakdown of the macros and we have some great data as far as hormones these pretty much go as we would expect insulin leptin free t3 they all go down during the hypophase they go all up during the hyper same thing with the energy substrates they go as we kind of expect which is the free fatty acids triglycerides they go up during the hypo whereas glucose is going inversely and then they flip again on the hyper but of more interest is non-hdl cholesterol versus hdl cholesterol this is a relative comparison where we’re starting it from 120 going up to 370 and same thing with the hdl cluster on the other side but you can see there’s a very clean inverse pattern between these two you also see it when you compare apo b versus apo a1 so we’re not only seeing it on the cargo of the cholesterol for both of these categories of lipoproteins we’re seeing it in the actual count of the apo lipoprotein that’s associated with that lipoprotein itself what i also loved was i was getting boston heart data for the second time i did the replication experiment and they have one called the cholesterol balance assay and this provide very powerful data when looking at it against the model because lathysterol and dysmosterol are markers for cholesterol synthesis so if you’re watching your total cholesterol in this experiment or mine in this case starting here at maintenance level and then it’s going up during the hypocaloric and it’s going down during the hypercaloric following the inversion pattern it’d be understandable if you might start from the assumption that synthesis must be following the same that there must be a higher synthesis bringing in and then a drop in synthesis bringing it out but it’s exactly the opposite latiss sterile and dysmostral start a bit higher before then dropping at their lowest level of the hypocaloric and then both spiking at the hypercaloric and again occam’s razor in spite of the lower total and ldl cholesterol detected in the bloodstream production of cholesterol has increased substantially presumably to meat trafficking and tissue demands clearly i think one of the major tissue demands if not the biggest tissue demand is specifically at adipose tissue so the boston heart also had an hdl map which is extremely important when looking at what we were looking at before with the in vitro study they break out the alphas one through four and the pre-beta again this is from a size comparison largest to smallest and they have these reference ranges because they’re based on studies that sure enough if you’re getting one of these tests you typically want the biggest ones because they tend to associate with the best outcomes and that’s why these just can go up to infinity but downside is you usually don’t want anything above 20 in the case of the milligrams per deciliter four alphas three four and below these are all the hdl3 species so i’ll overlay it over here to make it a little bit easier but these are the numbers that i got in this last experiment you can see in the maintenance phase what my alpha 1 alpha 2 alpha 3 alpha 4 etcetera breakdowns were what it was in the hypocaloric and what it was in the hypercaloric and not surprising to me as it would meet the hypothesis for decreased adipose lpl activity for the hypocaloric this seems to reflect lpl turnover moving less cholesterol and phospholipids to hdl lipoproteins thus hdl species would be smaller well yeah we have more of the alpha 3 4 and pre-beta in this phase relative to both maintenance and hyper caloric when taken together and we have less of them in the a1 and a2 species total yet we see the opposite within with the hypercaloric which is why i speculate it’s increased adipose lpl activity we see that there’s more cholesterol and phospholipids that seem to have been moved over to these hdl species so we have more that are in the alpha 1 and alpha 2 and less that are in the alpha 3 4 and pre-beta lastly i just want to mention the lean mass hyper responder that we have coming uh and this question does need to be asked i mean why are low carb hyper responders receiving so little research in lipidology i mean in spite of many years of reaching out to former libertologists in the interest of expanding this research progress has just been slow to gather interest and one possible reason for this reluctance is the extraordinary high levels of total and ldl cholesterol common within our community within the low carb community and thus it’s been an issue but this is a phenotype that’s been incredibly ubiquitous and extremely common the lean mass hyper responders of course they have a very pronounced triad they have very high ldl very high hdl cholesterol and very low triglycerides our lee our facebook group now sports around 7 000 members and at a minimum i want to say probably a quarter of them are bona fide lean mass hyper responders that’s that’s an extraordinary amount given that each of these the ldl the hdl the triglycerides if you look at population data each of these by themselves are already so rare so the three of these coming together i think are of enormous importance i really do hope more research will come but as i just mentioned the last slide i think because it’s so high the conversation hardly gets started and that’s why we’re putting together a study on lean mass hyper responders in particular we want to look at their risk so over the last half year i need to update this has been a year and a half we’ve raised about a quarter of a million dollars towards a study on lean mass hype responders we’re going to be capturing ct angiograms at the beginning and at follow-up one year later along with wide spectrum blood testing and our team includes people of differing expectations for outcome conflicting hypotheses for risk level i’m a bit more optimistic my colleague spencer nadowski is a bit more pessimistic as to what the outcome is ultimately going to be and what it shows us in plaque volume progression but again i feel like we have to answer this question before we can really get a lot of research moving towards understanding the energy model or for that matter any other emerging model that can help better help better give us insight into this phenotype and really what we’re seeing in the low-carb community lastly i just want to say thanks to members and patrons that make this research possible and thank you that’s my talk [Music]

You May Also Like

About the Author: healthyhq

- - - - - - - - -