PointBotanicals Seminar With Isin Cakir, PhD (2024-06-19 14:03 GMT-4) - Transcript
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Arash Amini, Isin Cakir, Isin Cakir's Presentation
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Arash Amini: All thank you for everyone who is here not here seeing this live or the thousands watching live or in the recording? I'm a rosh amini. I'm a co-founder of a company called cellular farms and we have a product line called pointbotanicals where we're growing plant molecules for the health and wellness industry. Our first focus is a set of enzymes that produce this really interesting molecule called sulforaphane.
Arash Amini: sulforaphane is something that naturally is produced anytime you eat certain vegetables that have these two molecules in them glucoraphanin and miracinase and in our case, we're growing broccoli for glucoraphanin and radish for miracinase. We put them in a powder and when you mix them in a fruit juice, they hydrolyze and they form this sulforaphane compound and sulforaphane has all these amazing effects and complex chemistry and really interesting stuff. Addition here is a frontier researcher on some of what you call metabolic or obesity or related effects of this. I'm going to let him use his own language here. I'm just a Layman really and
Arash Amini: Basically sulforaphane is the reason broccoli is healthy. We consider it as a popular product because it makes this thing but the problem is most of us don't produce enough miracinase in our gut and we're not getting enough glucoraphanin and mirrors and miracinase from other plants to make a large amount of sulforaphane. So we're trying to make that easier for everyone to incorporate into their diet at pointbotanicals. So mission is not partnered with us. He's an independent researcher and he's here speaking about his latest research and What he's all excited about, so, can you tell everyone a little bit about your background and how you got here to this point? Sure.
Isin Cakir: Thanks for the invitation. I did my PhD at Brown University in I think my PhD in 2009. and I did a series of post talks in first and power medical school and Vanderbilt and I moved to University Michigan. I was there for about seven years.
Isin Cakir: And I recently started University of Pittsburgh months ago. Right now, I'm an assistant professor of medicine here and my main interest since my PhD has been on the regulation of body weight and food intake by a central nervous system. That's not exclusive what we work on. We also do Work on the peripheral tissues including other post issue and they were skeletal muscle but my main expertise is just the bulk of it is how the brain let's go to the hypothalamus. regulates feeding and energy expenditure. And today I'm going to mean to talk about some of the research we do…
Arash Amini: that's
Isin Cakir: but I want to give it a little bit of a historical perspective and without making it too boring for General audience.
Arash Amini: absolutely, and when you say adipose tissue on the Layman, I've seen it
Isin Cakir: Yeah, we store basic fat tissue.
Arash Amini: Got you. fantastic. So, if you could just show your first slide in case anyone wants to grab the paper with that title in it.
Isin Cakir: Sure.
Arash Amini: Really honestly rather mind blowing what is going on in the body how sulforaphane interacts the things that stuck out to me Were that it blocks the absorption of fat in lean mice it reduces. The adipose tissue in obese mice the more fat they are the more fat they have the more of this leptin they have and that somehow. makes the effect stronger and I thought it was really fascinating that it does not reduce.
Arash Amini: a liquid or lean muscle tissue only fat and…
Isin Cakir: All right.
Arash Amini: as the bodies like burning its own fat, it increases satiation or somehow you eat less because you're getting what you need elsewhere and I'm just blown away. The mechanisms are complicated for me, and I hope you can dive into that but Really fascinating stuff so with that take it away.
Isin Cakir: Thank you. And feel free to stop me whenever you like first questions if gets into a confusing or boring. Can jump forward backward?
Isin Cakir: so I want to study the video basic introduction to work on is I mentioned I study the revolution of energy or mist is and in the very simple terms this first to the regulation of food and taken energy expenses. So when we talk about energy homage, it's really the balance between two concept for intake and energy expenditure. and most of its regulated by the central nose system and the hypothalamus not exclusive about hypnosis in the center of this. And center of attention in terms of regulation of feeding as well as energy expenditure. So in the center nervous system, the hypothalamus receives from the circulation in terms of Adipose related signals repulsory release signals or hormonal signals and nutrient-related signs such as glucose or fatty acids.
00:05:00
Isin Cakir: And the hormonal signals or the related signals. From the periphery is pursued by a complex neuroscircuit in the hypothalamus that projects to other part of the brain. And I'm not going to go into this details here in the stock. But ultimately these neural populations interpret the signals that come from the periphery. And they basically send signals to the periphery intern to regulate food intake energy expenditures and also glucose metabolism. So a little bit about the history of how this. Sorry good.
Arash Amini: He said in that diagram with the three kind of. What did you call them as a group of neurons? It was called?
Isin Cakir: Yes, sir. Yeah.
Arash Amini: like a cluster that works together or is associated and it's
Isin Cakir: Yeah, so these are neurons that are intermingly to each other. They're basically located next to each other, but they do different things so some of them. Basically labeled as if I go back here this mpy slash AGR peninsula here in blue. These are a group of neurons that exogenically basically stimulate food intake. And there's another group of neurons called pomc or Palm seen neurons attack is located next to this. Mpya Jr. Pinods and they do the exact opposites thing the pumps, On our exogenic neurons that suppress feeling and increase energy expenditure so to speak.
Arash Amini: Interesting. okay.
Isin Cakir: Yeah, and interesting thing is in the human brain. Are billions of neurons in Mass printers like millions of neurons and the number of these for example employee agrp neurons. The mouse rodent plane is just a few thousands among all the tens of millions of neurons. Is a Japanese representative very small percentage of those entire neural population, but regardless of their number, they're major regular use of feeling they've been extensive study in our field. There are very important Regulators of food intake.
Arash Amini: fancy
Isin Cakir: just want to give it a little historical perspective of how the regulation of feeding by hypothalamus was discovered. This was done in part through basically recruit methods by Giving lesions to the brain and these were done in rodents in grads. what people did decades ago is they put little electrodes into part of the brain part of the hypothalamus to give lesions basically little electric currents to kill the tissue. And what they observe is if they damaged what's called a ventromedial hypothalamus labeled as vmh here and can you see my mouse cursor by the way? Is it visible when my okay awesome.
Arash Amini: Yes.
Isin Cakir: So when they lesion or killed the neurons in part of the hypothalms called vmh what happened was red started developing this hypophagic response. So they started eating a lot and they develop obesity. However, when they killed another little nuclear, I called the lateral hypothalamus. Then they people observed opposite Furniture. Basically the feeling of sitiation was there like mice or rats didn't feel hunger. And it is led to starvation died. they feel the urge to eat.
Arash Amini:
Isin Cakir: This was one of the findings about the hypothalamus being a very important part of the central nervous system that regulates feeding and body weight.
Isin Cakir: and again in early 50s the study came from our UK calling Kennedy proposed the idea of the adipostat and what he proposed was. He said there should be factors. It's a release from the adipose. You showed a fat tissue into the circulation that travels to the brain and tells the brain particularly the hypothalamus about energy storage of the body. So he proposes idea that there must be circulating factors that are factorized tires created from the fat tissue. That caused the brain to regulate free.
00:10:00
Arash Amini: That's some molecule that the cell creates.
Isin Cakir: Sorry, say it again.
Arash Amini: Factors, are they some kind of molecule that the cell creates for signaling something?
Isin Cakir: All Yes. Yes, so these are fat-drived. There was his hypothesis which turned out to be true, but it's about like 40 years for this to be discovered.
Arash Amini:
Isin Cakir: That's exactly what I'm going to talk about here and just another very brief historical perspective to some of the early studies. What New again, decades are good that there were a mouse models. They were meeting mice. And they were obese and one of them was called an Obama simply because they were obese. And there was another line Mouse line was labeled dvdb mice because they were diabetic. But also obese at the same time and people didn't know why these animals were getting massive hyperphagical busy. and one key experiment on was
Isin Cakir: When people stitched the circulation of these mice together, it's a method called parabiosis. What you seem to do is you make a very small incision along the side of the mouse and you basically Stitch the Skins together which leads to after about two weeks their blood circulation mix and whatever is present in one mouse goes into the circulation of And this is actually done in the Aging field too and they stitched a young and all mys together the young mice living shorter than they would and then the old mouse living a little longer than it would otherwise do.
Isin Cakir: And this is a method to show that there's a circulating factors in the blood that regulates whatever, that you're interested in and people did this experiment disobey and DB mice when it's just them together. And when did they did the power biosis experiment is mice what the observe is the old you will be my started eating less in some cases. They died of starvation. The DVD miles was again obese and intact And…
Arash Amini:
Isin Cakir: what this experiment concluded was there was something in the circulation of DB mice. That was present in their circulation that Rand is two mice were power bios together. whatever this Factor was in the DB mice mouse was going into the circulation of tall bmos. Resulting in the Obama's eating less and losing weight. And a concluded that problem or be Mass lacked is factor, and then when it was coming from the DB Mass he was working and inducing weight loss. Another hypothesis, they put forward at the time was DB Mouse had a lot of this Factor clearly, but it wasn't responding to it. So maybe the DB mouse was in Midland in the receptor that was pursuing the presence of this fact.
Arash Amini:
Isin Cakir: And long story short in mid-90s group of researchers led by Jeff Friedman at Rockefeller University identified this Factor as leptin and they call it leptin because the name comes from the Greek word laptop, which means A year later. It's receptor was also cloned lectin receptor. This hormone was in a rather simplified way. What it does. Is it secreted from the fat tissue into the circulation? And in the blood it goes to the hypothalamus X may not hypotherms other part of the brain too. But mainly it means side of action is diaphras and it tells the brain to decrease food intake and increase energy expenditure. And the mice we were talking about before the opioid mice were actually missing leptin. That's what we're getting obese.
Isin Cakir: And dvdb mice had actually a lot of leptin but they had a mutation and the receptor so they brain did not physically receive the signal. Clipton was present so both mice were getting obese.
Arash Amini: Okay.
Isin Cakir: And when you to the parabolouses experiment what was happening in the US this excess leptin from the DB mouse was going into or be my circulation be Mass was it's the brain of the hobby Mars was saying, okay. There's a lot of Lipton I should stop eating this week.
Arash Amini: They'll be small said the receptor, but didn't have the leptin enzyme.
Isin Cakir: All right. Yeah.
Arash Amini: So when our brain our hypothalamus absorbs, let's say receives leptin. when you say energy expenditure, is it What does that mean in real term? Is it just burning that are you getting?
00:15:00
Isin Cakir: Yeah. It's basically generate heat you dissipate it. Yeah.
Arash Amini: of course, which is really the
Isin Cakir: Yeah, and this circuit is really well studied in a biochemical context. can Go through details of it. It's gonna be a little I can't really think of a way to simplify that…
Arash Amini: No, I think.
Isin Cakir: but in the most important, it's basically you dissipate. Yeah. Yeah. Yeah.
Isin Cakir: Yeah.
Isin Cakir: That's it again. I don't think I quite understand.
Isin Cakir: This is not to say but I mean your butter temperature is not going to change because I in memos about the temperatures as well regulated when I say you generate here you basically dissipates it but this is not heat That You're Gonna Fill as a changing your body temperature. Basically, it's like radiating it in the rather simplified terms.
Arash Amini: So interesting passing.
Arash Amini: Sure.
Isin Cakir: Yeah, it's basically you lose energy and…
Isin Cakir: a mass is converted to energy you lose it. That's what energy expenditures they're in their ways to measure it and I'm going to talk about it in the context of what we published. Actually they're specific cages for mice and this is done in humans as well. And I'm gonna talk about it towards and yeah.
Arash Amini: Perfect.
Isin Cakir: Okay, so It was a fat Drive factor. It's called leptin because what it does and in the beginning it was taught. we identified the major hormone to use weight loss.
Isin Cakir: The deficiency of Lipton as I prefer mentioned in rodents as well as in humans leads to high profitical business. So obvious is a leptin Mouse. It is a mutation and leptin unit these mice cannot produce leptin and it leads to again is very obese phenotype shown here is 67 Grand miles and just for reference and normal Mouse. Comparable age would wear around 20 25 grams so you can tell the difference and if you let them back to this mice you can see Significant amount of weight so it goes in this cartoon from 67 to 35 grams,…
Arash Amini:
Isin Cakir: right? So given depth and back works. it's a reversible phenotype in this mice that are missing Lipton and soon after the humans clone several families identified with mutations in the left engine It Was Written receptor genes and in the same thing in humans, it leads to hypophagic obesity and giving Lipton back in this significant weight loss in humans as well. It's a pretty lifesaving treatment actually, but fair to say they're very few families identified that the mutation and Lipton. they can be treated with giving labs and So again after it's discovery of people thought okay, we found a major bullet to cure obesity. We can probably treat.
Isin Cakir: Obesity with Lipton and one of the initial thinkers was okay, maybe obesity represents leptin deficient State and by giving depth and back we can reduce our business. However, the fact was exact opposite soon after it's Discovery. We learned that serum Lipton levels are basically the amount of leptinia blood correlated very well with how much fat you have because it was a fat Drive Factor the more fact you had the more left here. And this led to the concept of leptin resistance and what it really meant is although in common obesity. We had a lot of leptin in the circulation. Our body was not responding to
00:20:00
Isin Cakir: I put a few cartoons from some books Etc Addressing this concept and there's a tor Piece again, one of the big pharmaceutical companies called Amgen actually licensed. Lipton hoping I was going to again it was gonna be a cure for obesity, but it's not to be not the case. And again this whole thing that the concept of Lipton resistance and what it really means is exemplified here.
Isin Cakir: this graph from paper again from Jeff Friedman group the group who discovered leptin 94 and what we are looking at here is On the left side is the part of it percent of lean Health to mice. Okay, so these are lean That consuming love at diet indicated here. And if you give leptin to this mice is here. They lose weight, right? By the way, it goes down around the time when you give them lift. So these are Lipton sensitive animals because they are Consuming normal love at tide. However, if you do the same experiment with my star fat high fat diet and that I obese. Leptin doesn't work. So giving Lipton does not induce weight loss.
Arash Amini: Use it or…
Isin Cakir: This is exactly what's called the leptin resistance.
Arash Amini: absorb it or…
Isin Cakir: So your brain doesn't respond to leptin.
Arash Amini: what would the term?
Isin Cakir: And this is also clinical trials we clipped into news great laws in large part fail wasn't a potent. Wait research. He wasn't inducing weight loss in humans.
Isin Cakir: exactly
Isin Cakir: Basically in some manner it's analogous to. What I would say insulin resistance, it's not exactly like Insurance resistance, but in some way. In terms of the word resistance one one maybe…
Arash Amini: because of leptin resistance
Isin Cakir: if you want to oversimplify it. I would say it's on the differences in human resistance. I don't careful here how I phrase because in even Severance is a specific give it excess amounts of instrument. You can still bring the plug glucose down. However, the same case is not true for leptin. So although you have a lot of Lipton and giving exertion of sleep and doesn't really bring your weight down.
Isin Cakir: that's the prevailing idea. the process here So we ask the question. Can we find a way to reverse lip to resistance and I'm going to skip through this part like the molecular biology of it how we Came to identify some of the dragly work on to reverse Lipton resistance. and again Capital discussed is in detail, too, but we found as one of the molecules of fun that we hypothesized and then show to be reversing their persistence was so far. And this is the structure of sulforaphane shown here. This is a simple structure and it's a natural compound. it's abundantly Fund in a group of vegetables. Including broccoli and Brussels sprouts, and I'm going to talk about in a bit
Isin Cakir: and so for a fan I was looking into again the literature is when It was isolated first from broccoli in 1992 by a group of scientists at Johns Hopkins, I believe. by the scientists named here Paul tellerized group And at what I understand from the historical perspective of it, the reason people were interested in so far pain initial was because of the correlation of lower cancer incidents and consumption of broccoli or other vegetables containing this molecules. so Farthing was isolated from broccoli extracts and
Isin Cakir: this is a review article from a group of scientists who were trained. Charles Hopkins, I believe and worked at some point. I think with the scientists. I was just mentioning before. And what they show here is something very ative the amount of activity of sulforaphane. This is an I would say indirect measure of how much of an active sulforaphane is In different stages of the plantage for broccoli and if you see here the seeds and the Sprouts of broccoli has way more actively compared to the adults.
00:25:00
Isin Cakir: Market stage broccoli suggesting that the Sprouts actually have way more active so far away the seeds also and adult plan and I also on this
Isin Cakir: Picture from I pulled us off internet which and I can't really watch what is the numbers to be precise but it gives a I think good indication of the relative level of sulforaphane in this different plants. vegetables and again, I guess basically shows suggests what we saw before in this graph that the Sprouts have way more so far and broccoli itself.
Isin Cakir: Yeah, yeah.
Arash Amini: what you need it's dependent on. You might call it exogenous or an alternative source of miracinase then. utilize reaction
Isin Cakir: Yeah, I see. Yeah. That's exactly what I'm gonna talk about right now. I was going to present a concept of cool car of Anan and My resume so as you actually very well mentions. So farfan in its active form is not present in this vegetables. It's present in the form of its precursor called the glucoraphenic and glucoraphanin. Prison all this different vegetables is actually get converted to so far from which is by active molecule and it's converted by this enzyme called my rosinase that's either present in the plant itself, but it's in a different compartment. That's why in the vegetables or the plants. It doesn't the enzyme Myers and it doesn't actually clear Google Chrome and so far off and they are because they are in different compartments.
Isin Cakir: But it does so when they get together and they get together when the animals start chewing the actual vegetable and the other source of myrogenase is the gut microbiota. So his glucorf and if the myosin is the enzyme as you were saying it it's not coming from.
Isin Cakir: The reasonable itself it's present in the gut microbiome. And I think it's worth the mention here is and…
Arash Amini: One thing I would love to see research done on is somehow sampling the population to measure just the amount of that bacteria.
Isin Cakir: again I'm not an expert in this cut microbiome feel at all based on my limited reading. My understanding is based on your microbiome composition the commercial so far away get affected so a certain extent Simply…
Arash Amini: Let alone how much miracinase it's producing because I've been going really deep around the science of endocrine disruptors and…
Isin Cakir: because you know how your microbiome is composed and…
Arash Amini: pesticides and…
Isin Cakir: are they producing more or…
Arash Amini: all the stuff in our and…
Isin Cakir: less active miterogeneous or…
Isin Cakir: not might affect…
Arash Amini: …
Arash Amini: we're all ingesting a little bit of pesticides and…
Isin Cakir: how much of the glucoraphene you get from diet. It's converts profit.
Arash Amini: herbicides and so on and it's affecting everyone's gut biome to what degree. Where did you start? How much pesticide do you intake? So, where are you now? It's a completely Variable, it's sad it's good. We're discovering all this but it is kind of interesting too.
Isin Cakir: Yeah.
Isin Cakir: Absolutely.
Isin Cakir: Yeah, so another thing to mention here a couple of important things. the sulforaphane itself is pretty unstable. So it's essentially Heat. I'm not sure if it's light sensitive too, but it's definitely heat sensitive. And our glucoraphanin is not so I think that part of the reason when I was looking into all the supplements around and again, I mean, thank you for mentioning in the beginning, but I wanted to repeat it. I'm not in any…
00:30:00
Arash Amini: I think the synthetic.
Arash Amini: Sulforaphane, I'm not sure it's an open-ended question. What?
Isin Cakir: Trying to advertise or disadvantage. Supplements it's up to the people to use it. But when I looked at the market for the available supplements,…
Arash Amini: right
Isin Cakir: most of them come in the form of glucorofinance combined with enzyme the myrogenase and I think there's a good reason for that and the reason is sulforaphane is Pretty hard to make it in a stable form. I think there are some companies who sells coffee in as well in some states.
Arash Amini: I was careful that is.
Isin Cakir: Ation, yeah.
Isin Cakir: Right, but my point is so far I've been itself is it's an unstable breath not stable molecule. That's why Google Chrome and that's actually call outs involved present in the Plants as well and…
Arash Amini: Yeah. Yeah.
Isin Cakir: there's a term I learned as relatively recently you might have heard of it the mustard oil bomb. I don't know if you hurt. So basically it's refers to the right little parking. unpleasant taste so far a fan has when they but people like who take this as so far from about certain they get this burning sensation at the back of their throat because of sulforaphane. and this is also true for
Isin Cakir: For the animals it actually feed on this. Plants that wants to eat My rosinase and glucoraphane and the direction before compartment get together. Once the chew on the plan. And then basically I think about my understanding is it depends The animals that assume them it's some sort of like defense mechanism.
Arash Amini: Yeah, yeah when I make it every so our product is this powder of the mixed broccoli and radish and you have to mix it in orange juice. That's great and you can smell it.
Isin Cakir: I think that's one of the reasons glucoraphene is used as a defense molecule by the plants against the animals that consume them.
Arash Amini: Hydrolyzing you have to give it a couple minutes and when you take that sip, I put it in orange juice, but you can smell a little bit of that sulfur.
Isin Cakir: And one way is this repelling pregnant? Taste of sulforaphane. It's called mustard oil bump.
Arash Amini: Sure.
Isin Cakir: Yeah.
Isin Cakir: Yeah, and I think there's a reason they called it a bomb is because I was reading about it is because basically two different components. That they become explosive basically generate so far. I've been on when my rosiness comes together with glucose.
Isin Cakir: so what does it do just a little bit very basic biology is to what sulforaphane does it's a natural and I have to activate it. And I put this very rather simplify cartoon here to explain this Nrf2 is what's called in biology long class of proteins transcription Factor a transcription factor is basically a protein. That's and they're tens or hundreds of different kinds of transcription factors, but in general what transcription factor is, is it supporting that can bind In a specific manner to different parts of the DNA called. genes to decrease their expression. It's basically turn it on or off.
Isin Cakir: And every transcription factors is its own Target gene pool. So different transcription factors actually have different Target genes. and in the case of Nrf2 the target genes fall into Brought the two categories one is the anti-inflammatory genes. So Nerf two once it's active it Is anti-inflammatory genes and the other pool which is probably what in earth is most well known for his detoxification or antioxidant defense genes. So if two once it's activated basically turns on this genes and…
Arash Amini:
Isin Cakir: activates them. And the important thing to the regulation of error of two is in a normal, I would say non-stressed or unstressed cell and if these capped inactive by another protein called kept one shown here in the dark green. So keep on in an unstressed cell keeps in Earth to inactive and what's sulforaphane does is it breaks this interaction? That separates the two protein. Set an earth to 3. And in this weight activate inert 2 and then once enough to is free from kf1. It painted migrate into the nucleus and does what it does. It turns on those genes that are important detoxification, which are also other sets of genes that are antiox a defense enzymes
00:35:00
Isin Cakir: and some other genes that are considered anti-inflammatory. Again, I skipped the part of the biochemistry to keep the simplified about so far. I've been actually Similar to what class of moleculegen species do react to oxygen species also activate Nrf2 in a similar Way by breaking these interaction.
Isin Cakir: So I wanted to give a few examples on some clinical trials people did in the past to study is detoxification properties of sulforaphane and one interesting study. That caught my attention was actually conducted by a group of scientists from actually University of Pittsburgh back then and together with people from I believe Johns Hopkins, I'm going to talk about this studying a bit, but just want to give a little background on something. That's really interesting Again, this is related to what sulforaphane does by activating nf2 is detoxification. pathway if you look at the tetris by that thought by risk factors and this is
Isin Cakir: Chart to play from 2019 and I think what I understand is the situation is way worse. if you look at here the air pollution was number two.
Arash Amini:
Isin Cakir: Affected and I think as of last year or so this air pollution Comfort it's strength number two.
Arash Amini: And is that India?
Isin Cakir: it's actually a classified as a carcinogen now and…
Arash Amini:
Isin Cakir: This is a world map. showing His dad's by a country from air pollution out to air pollution.
Arash Amini: he
Isin Cakir: And as you see here, it's Markley higher in Asia predominantly in China
Arash Amini: that's
Isin Cakir: That's part of India.
Arash Amini: That's interesting…
Isin Cakir: I believe and most China.
Arash Amini: because that makes sense that India China massive population density industrialization all economic growth a lot of power output and…
Isin Cakir: And The resolution is a little bad. I couldn't. Find a better map for this but again, like something showing the air pollution.
Arash Amini: but then to see the pollution from a satellite feed in Saharan Africa.
Isin Cakir: This is well known I think if for those of us we've been following the news on this China is known to be really high in air pollution…
Arash Amini: Across the Sahara. Is that the Dust?
Isin Cakir: because of fine naturalization in the last two decades or so.
Arash Amini: was a Fighters and
Isin Cakir: It might be that actually got my attention to and…
Arash Amini: yeah.
Isin Cakir: I believe this is from NASA's celloide images. And I'm going to brought it up because I don't want to commit a wrong message here. It was some and…
Arash Amini: Yeah, absolutely.
Isin Cakir: again I'm not an expert in this but there was some reports saying that some of the satellite images might in some sense be misleading and it could be dust the small particles and what's measured here is the small dust particles I think and it could be as you said send but again I don't want to Speak for certainty and definitely the air pollution in Chinese measured in very different aspects. This is not on the evidence. That is airport. Yeah, so that site and well documented.
Isin Cakir: And the other thing I was gonna mention is I put this.
Isin Cakir: Part of this article here from 2013 when the international Agency for cancer research and cancer to the classified air pollutants as carcinogenic. And if you want more this is a short article one one and a half page. And if you look at the very last part of it, they clearly say they det increase the air pollutants had actually carcinogenic properties. This is probably one of the reasons that it's coming for increased death rate. Anyway, the interesting thing is this study was conducted and this is the paper the basically are connected this study in this China is around Shanghai and I believe Zedong. I might be very well mispronouncing this But the reason they conducted the study in.
00:40:00
Isin Cakir: Again, it's part of the China was precisely because of this significant increase air pollution. In this part of the country and what they did in again I tried to summarize this here. This is one figure from this paper and what they did is they conduct the study on the residents. Living in this area which is polluted and there's polluted air environment and the basic divided people. It's two groups one group will received the brockless proud beverage other group received the placebo. people didn't know what they were thinking and one of the measures they did was they looked at the detoxification products of this air pollutants in their urine.
Isin Cakir: So once these are pollutants get the toxified by mostly our liver the byproducts get secreted out in our urine what they observe is something actually. We're pretty remarkable. As you see here in the green that these are the samples there which value from the people were consuming the broccoli's broad beverage.
Arash Amini: I mean
Isin Cakir: Byprodct the toxication product Benzene was detected much higher in their urine.
Arash Amini: it looks like up to twice as much of the
Isin Cakir: Really? they were detoxifying is
Isin Cakir: Toxic air poison is much better because keep in mind these are people living in the same environment. They're reading the same air and on a difference here is that one group is receiving Placebo be Another group is receiving this brockless broad beverage and they were able to surprise their pollutants much better. Suggesting that this Bronco spot beverage they provided.
Arash Amini: and when it says durable,…
Arash Amini: I'm assuming that means long lasting effect or
Isin Cakir: was Helping them detoxify.
Isin Cakir: This compounds forms a much more efficiently.
Isin Cakir: Basically reading I think it was 60% increase. So this is one of the Graphs from the paper.
Arash Amini: right
Isin Cakir: They look at several different by products of detoxification and they have different values for some of them. And I think it's their conclusion to this is through activation of Nrf2 through sulforaphane.
Arash Amini: Yeah, It's still. considerably higher and it starts at the same spot and then you see immediately. the
Isin Cakir: It is level of detoxifying genes that in turn, breaks down and detoxifies. There's a pollutants that come from polluted air.
Isin Cakir: yeah, that's other thing they did so they did this study for about I think 12 weeks. So these are days at the bottom. I should have more clearly. one thing they wanted to also test here is this affect global? I guess this something temporary like But it's happened just for a few days and then disappear it was durable. So for about 12 weeks. I think if I'm not mistaken, they did this study and it was durable effect. Good thing that yeah.
Isin Cakir: Yeah.
Isin Cakir: And they emphasize also in this paper that the study was done at the same time with all the participants because they didn't want. I think there's a graph in the paper showing the air pollution amount in the indivion.
Arash Amini:
Isin Cakir: So it's blockchain. So what they showed it. The study was done at the same time. So people were actually getting exposed to this pollutants otherwise it would be hard to interpret the results, but it wasn't at the same time for all the participants.
Isin Cakir: So this is only one of the examples like showing, broccoli extracts or Rocco spot extracts or phoraphane was showing all this benefit and always, a lot of research is the screens to find.
Isin Cakir: Other natural occurring or synthetic and are activators and shown here's the structure of some of them. And one of these compounds shown here the cddl. Is also called pardoxylin methyl it's a very potent energy activity and these are synthetic compounds research and sulforaphane is shown here is along with other Natural Energy activators.
00:45:00
Isin Cakir: they differ in their potency of its in their Half-Life have stable they are and so forth and I put another slide showing from another paper. speaking to their hot potent of an activated they are so what we are seeing here that confusing people too much is the More to the left the courage. So for example
Isin Cakir: This one on the very left is bardoxal Method and the more to the left is curves means they're more active more potent of an actuator of an error of two. So what this graph is telling us is brought up some method is more potent and so forth and sulforaphane is more important than the metal fumerate demand and these two compounds the metal fumerate and paradoxical metal as a show before. These are synthetic energy activities where sulforaphane is a neutral activated but among the natural activities I have to say beforehand is one of the most important ones present. There was another clinical study conducted with this products were method the very proton and earthy actuator compound. and I also noted the Clinical study here.
Arash Amini: and is at 15 kilograms,…
Isin Cakir: This is called the beacon study.
Arash Amini: yeah over the course of your
Isin Cakir: It was conducted in patients with chronic kidney disease and type 2 diabetes and I put here for some data for our interests at the body weight…
Arash Amini: yes your paper.
Isin Cakir: because of these people and what this shows is like The course of this study that was conducted for about a 48 weeks. But Oxford methylene area after activator the synthetic and…
Arash Amini: Just real quick how I want people to understand…
Isin Cakir: I have to actually lead to significant weight loss in people.
Arash Amini: how complex this Sciences at this…
Isin Cakir: And this is shown here in kilogram.
Arash Amini: How long did this take you from planning to it hit the paper.
Isin Cakir: So people with very high. BMI over 40,…
Arash Amini: It was published.
Isin Cakir: they lost around 15 kilogram on average which is significant weight loss. And this clinical study I think. Failed at phase three because of Nrf2 unrelated cardiac side effects. What I understand is they followed up on it.
Arash Amini: in one year two years.
Isin Cakir: And what they found is. people with existing heart conditions were Actually getting this adverse effects and I think they started another study after that which might be still ongoing or…
Arash Amini:
Isin Cakir: it's completed. I'm not sure with when they selected the patient put more carefully excluding, people with existing heart and
Isin Cakir: but this is basically a proof of principles showing that energy activation in humans was also resulting in potent weight loss.
Arash Amini: Good. thing and with team members…
Isin Cakir: 15 programs…
Arash Amini: how many organizations were involved was it just
Isin Cakir: which is more than 30 pounds.
Isin Cakir: So in the remaining amount of time, I want to talk about our paper that came out. I believe this was published. 2022
Isin Cakir: good question. So there are multiple factors that affect his process just not specific to our case, but in general it's a matter of hunting human power
Arash Amini: Three institutions five years. But it doesn't people.
Isin Cakir: the main driving started again …
Arash Amini: It's really wild. It's really wild. I'm sorry, so please please go ahead.
Isin Cakir: no way more it's usually I wish to point here we started working on this I believe. Doesn't Seventeen I might be wrong but around the time. 16 17 and then we published in 2022. So here's another thing publication process on its own might take years.
Arash Amini: Yeah. Yep.
Isin Cakir: I mean our papers that we mitted. To a journal and then from the time we submit to the publication takes sometimes I got two years and it's hiring and pretty much sooner.
00:50:00
Isin Cakir: In this particular study. We actually got a research funding from foundation called qnrf Qatar Research Foundation.
Isin Cakir: And there were also internal funds involved. But it was basically three different institutions in walls. I wasn't available at the time and we relocated to Michigan. So machine Universe was involved University of Michigan world and Qatar University. One of the collaborators was in Qatari University. So it was three different institutions.
Isin Cakir: About five failure for five years.
Isin Cakir: Yeah, I mean I'm glad you brought it up and it's something like that wound in most researchers limited funding and finding, driven researchers. The different everyone is suffering from I think. But I'm not going to talk about more. so I put some of the slides from the paper and again the paper is published and actually it's a Accessible Journal anyone can access for free to elife. This is a journal that started many years ago. It's one of the Open Access journals. So one of the first things we did was we treated obese mice wait so far away or vehicle. And here once you do this study is one thing you want to make sure is dozing and the
Isin Cakir: that those you administer is precise and in order for the study to be reproducible by other groups. Another thing is like
Isin Cakir: again, I'm saying this because a lot of extracts people can purchase and…
Arash Amini: So the faster it's detoxify or broken down the less time it has to do its thing
Isin Cakir: use and Their content and sulforaphane problem highly ways. In terms of this extra trip. I'm in Tech. They are so forth. So that's why we are not doing this is the extracts. Although he could we wanted to use sulforaphane…
Arash Amini: This is wild.
Isin Cakir: because we want to make sure what we are admission to the mice. and exactly how much we are administering.
Isin Cakir: right And we injected to my spy intraperitoneal injection. Basically, we are administering the compound into that abdominal cavity which is taken up by, circulation it goes through liver. And then gets distributed to the brain. So there's a lot of to close to the pharmacol kinetics of compounds here, which I'm not going to go anymore detail, but I just briefly mention is a lot of factors to be considered here one is certainly What the half-life of the compound is? Basically how stable it is in the body. So any form molecule including drugs determode administered to the body they are usually taken up by liver and they get decomposed to a certain extent. And how fast they are broken down most by delivered not exclusive but mostly by the lower. Determines how it's bioavailability to other tissues.
Isin Cakir: Exactly to make it in the most, layman terms. It's precise to what it is. So what we observed here is when we administered sulforaphane to obese.
Arash Amini: There we go. Yeah, perfect.
Arash Amini: And so do you remember because something I read and I don't know if was your paper or another paper when they were giving I think this might have been an obesian study when they were.
Isin Cakir: And these are mice Sorry by this mice just to give a little background to…
Isin Cakir: how we do. The bite is Mice from approved vendors. They're several vendors throughout the United States and…
Arash Amini: giving their inducing obesity with BPA And they gave them the high fat diet was like corn oil.
Isin Cakir: in other countries, too. So why type my eyes which are basically in Tech mice and not meeting mice but also meeting Milestones too. Everybody is basically non-metent wild mice so I Good, maybe hot corn syrup like…
Arash Amini: Do you?
Isin Cakir: I speak. how high fructose?
Arash Amini: You something like that?
Isin Cakir: With feed them special diet that's rich in fat composition.
Arash Amini: I can't remember. Do you remember what you fed your mice in the study to get them?
Isin Cakir: Okay, that induces just like it doesn't humans is to what we call the Western diet. so what we're feeding is Diet we purchase again from companies that sell rather than diet and this Is manage in my city induces or busy. So you take a normal mouse that weighs around 25 grams you fit a kind of diet where 60% of the calories come from fat that's called high fat die.
Isin Cakir:
Isin Cakir:
Arash Amini: Gotcha.
Isin Cakir: diet for 16 weeks in the mouth body weight of the most doubles comes to Say around 50 grams. So it is all the ingredients including carbohydrates protein And most of this weight is exercising excess fat. And once we inject this mice with other minerals and vitamins Are required but it's specifically designed to be high in fat composition that drives weight gain and…
Isin Cakir:
00:55:00
Arash Amini: Dodge
Isin Cakir: it's very popular. It's very highly used by research confusing studying obesity as well as diabetes.
Isin Cakir: and Mike's loudest food if you Expose them to this food.
Arash Amini: Who doesn't yeah.
Isin Cakir: They really like They studying way more and main reason they came with because they liked his food so it is this obese mice which we call the diet in disobey's e. He administered sulforaphane to this mice. What we observe was the food intake went down so they studying less. And they lost weight. So this is the body weight curve on the left here is obese my story they lose weight.
Isin Cakir: date less
Arash Amini: This is over two weeks only. This is over to 14 days only.
Isin Cakir: Yeah. Yeah, I think we've done studies longer term and the weight loss continues and then the body weight stabilizes after a while. Once they lose significant amount of fat. And one interesting thing we observe is if you do the same experiment with lean healthy mice. So these are same way they're not exposed to if it died so their body weight is about half double mice. So to give a very rough number the lean mice around 30 grams and then obese mice are like 50 grams or so. lean mice sulforaphane the same dose of farthing and Dean mice didn't affect feeding body weight and one take on message here is the weight loss of five and was not something averse non-specific because there are a lot of
Isin Cakir: Compounds that might decrease food intake just because it makes my sick just like,…
Arash Amini: mmm
Isin Cakir: just like causing nausea in humans same thing happening in in rodents. But It happens in lean mice or an obese mice. It wouldn't discriminate. So the fact that so farfan was inducing great for specific, bees mice not in lean mice told us this effect was specific busy and in the rest of the study actually question how that was working.
Isin Cakir: And we looked into the phenotype of this obese mice a little further in the next and next slide is what I'm showing. So if we looked at the lean mass and fatness of this mice after weight loss we saw that Almost exclusive weight loss was coming from the fat.
Arash Amini: That's crazy.
Isin Cakir: with mice was not losing lean mass most of fatness and this is important because if you try to like to dieting which I personally didn't pass and this is true for humans and as rodents If you lose weight by simply eating less by dieting you would lose most of those fat Mass, but you would lose a little bit of limestone. and if you followed the reason News or…
Arash Amini: mmm
Isin Cakir: literature on the very popular drug or zempeg. It's a very popular weight loss drug these days. that talks also leading to some degree of Lynn Mass which some people complain about and a certain extent is unavoidable again, once you decrease your feeling and important thing here with this sulforaphane although it was decreasing feeding significantly is obese much were eating less and losing weight. The Lynn Master didn't decrease which was actually something that it was very remarkable in terms of observation we made…
Arash Amini: Yeah.
Isin Cakir: and it ties very well to the mechanism of action of Orphan in this weight loss that I'm going to mention in a bit.
Arash Amini: And for just reference vehicle, I found out at the Google. This is the liquid that you would administer the sulforaphane, but without this all been and…
Isin Cakir: All right, so
Arash Amini: so it's kind of control versus sulforaphane.
Isin Cakir: All right. So it's in some sense again, simplified is we could considers vehicle. Is it like placebo? And just to make it like very we're here.
Arash Amini: Place sure Yeah.
Isin Cakir: What we do is so far away in itself is At room temperature. It's an oil. It's actually good itself.
Arash Amini: mmm
Isin Cakir: So what we did is but it's not water soluble. So it cannot administer it in aqueous Solutions. So what we do is that we dissolve it in some organic solvents called the MSO, which is very commonly used in this kind of studies. And to basically I can't for that organic solid called DMS. So we should administer just the MSO to what we call the vehicle group. vehicle is actually the MSO. And sulforaphane group is administered so forth and dissolved in the Amazon. It's basically just The chemical property of the compound. It's not at soluble necklace solvents. one which administer it
01:00:00
Isin Cakir: and the other important thing to mention here is the mice after the loss rate their glucose metabolism significant improve. So what we are seeing here in this graph is what we call the glucose tolerance test. What you do here is you take mice you fast for a bit And then you administer them it's certain amount of glucose. And then you follow how fast they can clear glucose their blood circulation. So this is a very common to use method in rodent research, but also in humans as well. in the clinic
Isin Cakir: It's very common to use glucose tolerance test again in humans. It's typically done by an oral administration of a certain amount of glucose Suite solution you drink it and then they follow how much glucose you have left in your blood after a certain amount of time and we are doing something similar here and what we observe here is the mice Who are treated with sulforaphane they were able to clear this excess glucose from their bloods to much faster? Means the glucose metabolism was improved they were more glucose tolerant?
Arash Amini: And that looks at the effect mean you tracked it for over 120 days. And it's I'm sorry.
Isin Cakir: This is just a glucose monitoring down. This study is typically done over two hours. But similarly,…
Arash Amini: So in that same window the glucose.
Isin Cakir: it's very acute study. Yeah, but if you follow the blood glucose of this mice or several days during this so far off enchantment. You see a very significant decrease in Baseline blood glucose meaning there is a remission of the diabetics phenotype and
Arash Amini: interesting
Isin Cakir: Takes you something that's very important to mention here. The majority of diabetes are already obese and I'm talking about humans here. and this is a pretty reversible phenotypes. So the diabetes remission happens with weight loss. So if you lose weight Regards how we do it by dieting by drugs Etc. The diabetic phenotypic gets much better. Your glucose improves.
Arash Amini: but
Isin Cakir: And I think what the reasons for fourth entry is obese. Mice are Displaying is an improved glucose tolerance is because they're losing the most seconds to the weight loss not exclusively in this case secondary weight loss and…
Arash Amini: interest
Isin Cakir: there is a clinical trial done with glucorofen and again the precursor of glucose in humans. and what they observe is it was. Very good in management of insulin resistant diabetes. And again,…
Arash Amini:
Isin Cakir: this is a clinical study conducted in humans published in I believe science translational medicine. It's a very important study showing that the precursion of sulforaph An administered oral to diabetics. It was very effective in managing glucose and I think their conclusion that study was and again this is study published by another group not us. And it completely was pretty effective and comparable to metformin which is the most highly a medication for diabetics
Arash Amini:
Isin Cakir: so I think just summarize this point on the blood glucose management. it goes to fall. I think it foreign is a direct effect on liver to manage to block glucose production from the liver, which is Probably the biggest problem in diabetes. And the second thing is it induces weight loss and coming from is second. There's weight loss. It also helps manage blood glucosals.
Arash Amini: And what is AUC that last chart? I couldn't figure.
Isin Cakir: Yeah, I'm sorry. I didn't make it more clear AUC stands for area under the curve and basically this graph. Is a calculation of the area under this cures one accepted and…
Arash Amini: I see.
Isin Cakir: way to interpret There's good glucose tolerance test courses you calculate the area on the discourse. And then you do the statistical analysis saying is the area under this curve significant differently. That's why it shows the area under the curve foreign is smaller. Which means their improve glucose metabolism. Thanks for bringing up.
Isin Cakir: Yeah.
Isin Cakir: statistics is very important and it's I would say.
01:05:00
Isin Cakir: I would say it's on their appreciated in biology. There's a lot of wrong statistics applied.
Isin Cakir: it's not addressed enough. But again, I'm not gonna go into this here. But I said it's something very important to point out in life science lately. Yeah. Okay, the other thing I think it's very important to point out is be something we talked about in the past. I think in the beginning, was
Isin Cakir: There's a energy expenditure concept So how do we measure it? So specifications called metabolic cages that Do something very simple. It measures how much oxygen is consumed? and how much CO2 is produced but what is devices seem to do is that They sample the air within this cage. It's a semi-closed cage. So the example there in this cage. And they measure oxygen and CO2 amounts. So over time it calculates how much if there's a mouse inside. It's going to be done then on the thing. That's utimer oxygen and producing carbon dioxide stages is metabolic cages. Basically tells you how much oxygen is consumed…
Arash Amini: Okay.
Isin Cakir: how much CO2 is produced and from this it calculates what we call the energy expenditure. You recall energy expenditures,…
Arash Amini: of course.
Isin Cakir: you basically utilize the nutrients you oxidize a burn down. if High terms and then you produce energy right this energy could be used. to do anything we could think of. to survive to live and other form of energy is basically heat that dissipated. So if you dissipate this energy in the form of heat.
Isin Cakir: dissipated as energy you lose weight or you can use it in the form of energy called ATP to do any activated can think of it's important for survival.
Isin Cakir: this one energy is for the energy expenditures and what we see in this graphs is We put again mice in this metabolic occasions or metabolic Chambers, and we follow that over several days or dark and light cycles. And each one of these light and dark Cycles is basically 12 hour time periods,…
Arash Amini: mmm
Isin Cakir: And something also I guess important to point out is ents mice and rats are nocturnal animals. So they live in the opposite cycle to humans. So they are active in the dark cycle, but they are called nocturnal. So they consume most of their food in the dark cycle and they tend to sleep during the light cycle. And what we show here is again the sulforaphane administration led to significant decrease in the food intake of the animals. And if you do this without drug interaction, so if you fast yourself or if you voluntarily decrease your food intake and if you do this in Broadlands as well what you see is what you would observe is a compensatory decreasing your energy expenditure.
Arash Amini: plus food in less energy
Isin Cakir: Yeah, so that's one reason like dieting when you start dieting if you follow your body weight and again the same thing happens in Orleans. You lose weight much faster in the beginning, but then Your weight loss starts going down. That's because your energy expenditure is not going down.
Arash Amini:
Isin Cakir: So our body has Very efficiently, I would say to preserve energy. So once you start decreasing your foot intake your body adapts to it pretty well. To preserve energy and your energy expenditure goes down. That's why it's not the only reason always but it's one reason losing weight is not that easy. Even with dieting when you're satiety. And again, the reason I wanted to give is little background is because when we did this that was so far off into treated mice, although they were eating significantly less when we follow their energy expenditure throughout. Their energy experience did not go down. Really significant. I think that also adds to the effect of the compounds so far away in terms of inducing weight loss not only decreases.
Isin Cakir: Couldn't take but I'll say block that compensator decrease with otherwise see in energy expendition which didn't see when we traded my so far off and it's pretty important. And another reading you get out of this metabolic Chambers is what we call the rer or respiratory exchange ratio. and it's simply the amount of CO2 production, which is consumption and if you look at the ratio of these two things CO2 to O2 oxygen this ratio tells you. How much carbohydrate versus fat you're utilizing as your source of energy? So this ratio probably abbreviate Is a number between 0.7 and 1? so in a hypothetical situation where you're
01:10:00
Isin Cakir: Burning on the carbohydrates. Let's say glucose and if you remember even from your high school years Glucose is a six carbon molecule. You use six oxygen to burn it and you produce six CO2. so the O2 ratio divided by 6 is 1 so if you're not oxidizing anything else if you're utilizing on the glucose is a source of energy or rer ratio is going to be 1 However, the same calculation with a fat molecule you get a number very close to 0.7. and to survive we always utilize a mixture of glucose basically carbohydrates and…
Arash Amini:
Isin Cakir: fat and depending on if you're using more carbohydrate versus more fat is a ratio changes and the lower RAR is means more fat or utilizing as a source of energy and this is exactly so when we put this mice again into the chambers and we treated them so far away. There values were lower compared to the vehicle tree Group, which means that they are burning more fat as a source of energy and this makes total sense. Because it might start losing weight. They are losing fat Mass not lean mass. They're losing fat masses we discussed before earlier. And they have to oxidize this fat is the source of energy, right?
Arash Amini: It's just another verification that's actually what's happening.
Isin Cakir: exactly so just to go back to something we discussed before, something that was very important discovered in 94. In terms of how fatness was sensed by the brain. we talked about this hormone called leptin there was screwed from the fat that act on the brain. And we also talked about the concept of leptin resistance. Although in common. Obesity there is a lot of leptin in the blood. Is this phenomenon called leptin resistance? It develops that our body doesn't. Respond to it anymore. The reason I wanted to mention it again is because the next set of data from the paper wise. precisely on this topic far we
Isin Cakir: I discovered that the sulforaphane was inducing weight loss and died in his obese. So we wanted to test some other obese Mouse models and we turned to the commonly used genetic Mouse models this lein leptin receptor metal mice. So shown on the top are dvdb mice.
Arash Amini: And they're the ones that can't absorb.
Isin Cakir: right, so did he Have a mutation in the leptin receptor Gene,…
Arash Amini: and absorb it
Arash Amini: receptors of
Isin Cakir: so they have a lot of leptin. But they don't have the receptive to recognize or…
Arash Amini: touch
Isin Cakir: sense yet tonight. And if it gives farther into this mice. Basically, nothing happened. They couldn't take it and change Their body weight didn't go down. And we did the same experiment with all the Tried mice. they have the normal receptor, but they don't produce Lipton they lack leptin so they are very hyperphagic and they gain Body weight very quickly. They get obese fast. And I guess forfeit. Didn't decrease their put intake or body weight. So this basically told us something very important is the mechanism of action of sulforaphane. That was that. Sulforaphane in order for us having to decrease food intake or…
Arash Amini: mmm
Isin Cakir: body weight it required an intake lecture signal. And if you recall one of the earlier data's I showed. This so far I think did not alter by the way of intake of lean mice either and lean mice. Have very low circulating amount of Lipton. They have much less bad.
Arash Amini: Because they have less fat. It's
Isin Cakir: They're really low levels of lift. And I skipped those data that's in the paper from this presentation, but we did series of studies. To show that sulforaphane actually increased leptin sensitivity. And it reverse the Lipton resistant phenotype. It exists in dieting is obese. So reverse the leptin resistance. Made this mice more leptiness sensitive. And then therefore just by giving sulforaphane to have died in this obese, which already has. very high elevated level of circulating leptin My study responding to this endogenous existing leptin in their blood they start eating less and they lose weight. And basically they are take on message of this. Study that forfeit in Reverse is leptin resistance and induces weight loss.
01:15:00
Arash Amini: And leptin resistance is a natural phenomenon.
Isin Cakir: It nature leptiness develops all the course of obesity initially and it's mostly in the brain in the high profiles. right
Arash Amini: the interesting and the
Arash Amini: what do we know how affects leptin resistance
Isin Cakir: Very good question. So yes, and no we don't know the details, but the last piece of data is going to show is exactly. on that
Arash Amini: because this is putting Edge. This is a few steps beyond the known here.
Isin Cakir: so again, leptin resistance mean it develops in the brain and I want to be very transparent here. I don't want to present a very biased side of this story. There are a lot of scientists who think that Lipton resistance doesn't really exist. proposed this idea that the reason our body doesn't respond to. is excess amount of Lipton, business because the workable condition of the concentration of leptin reaches its maximum level and no matter how much you push it. It's not going to do anything else. So this there data to support that opinion as well.
Isin Cakir: I think again this is my personal opinion and shared by a lot of other scientists as well. That I do not agree with that. View, I think there's sufficient number of data. comes from a biology by a chemistry and animal studies that Leptin resistant does exist. but I would say irrespective of it whether the respect of the molecular biology of it the fact remains that There's sulforaphane what it does it sensitizes. the brain to existing hypolymic state Whether there's Lipton resistance or is not really important in the sense that it does really induce. I lift independent weight loss.
Arash Amini: sensitive interesting,…
Arash Amini: of course
Isin Cakir: Center I'm emphasizing this because The weight loss is here. I mean we see and several other groups have observe this it's another thing I think worth mentioning that it's not only our group that you pull it is it's reproduced by several other groups.
Arash Amini: mmm
Isin Cakir: Either it's five another like Nrf2 activated this weight loss. Has been observed in rodents as well as in humans in the clinical study as I mentioned.
Arash Amini: And so irrespective of the mechanism the results are well documented and clear.
Isin Cakir: I think that's good point out. But as researchers working in this field, if not more we are interested in the mechanism of action as well.
Arash Amini: Sure.
Isin Cakir: So what I was gonna say was Lipton resistance is mostly in the brain. It's in the hypothalamus. So one of the things We thought so far offend probably X in the brain to reverse Lipton resistance and we did some studies to the extent and there is a very relative crude and simple. Experiment you could do if you want to understand if a drug extent Central or peripheral? And that you infuse the drug directly into the brain.
Isin Cakir: Yeah. Yeah, so does a drug acts primarily in let's say liver or other post issue or muscle or in the central nervous system. And again a little bit about the pharmacology here. We administered this compound by. IP interoperitoneal injection
Isin Cakir: That doesn't mean that this drug has access to the brain. and that's mostly Because of What's called the The blood vessels that innervate it going to the brain. Have a special structure blood brain barrier and this is evolved primarily because brain is pretty selfish in its energy needs. So for example brain kidney depends on glucose and it's glucose uptake as opposed to for example.
01:20:00
Isin Cakir: skeletal muscle it's insulin independent. So brain relies heavily on glucose is an energy source. And that's one main reason fast and again this is true for rodents and humans. When you start fasting your livers that producing glucose, it's called hepatic glucose production and one main reason is to basically feed. That break the glucose need of the brain.
Arash Amini: Okay.
Isin Cakir: In his a particular cause production again, I don't want to jump from one thing to another but it's a particular course production is one main. Problem in diabetes, there's uncontrolled. tic glucose production In diabetes that your liver starts dumping glucose into the circulation that keeps the glucose levels High.
Arash Amini: interesting.
Isin Cakir: so the reason I was mentioning is because when we come to the Question of pharmacology, we administered drugs peripherally, which means if you swallow a drug if you take it orally or by injection. These drugs may not access the brain.
Isin Cakir: So we wanted to test the sulforaphane ACT directly in the brain or not. And I emitted a simple experiment we infused the drug directly into the brain of the mice. So in this case, we give much lower those of sulforaphane. And it doesn't go to the peripheral organs. It doesn't hit, muscle or liver or fat. and when we did this experiment it did not induce weight loss.
Arash Amini: and interesting
Isin Cakir: And there are more sophisticated ways of doing it. We did it with other studies. Where you can delete or all or activate its targeting In this particular study. We haven't done it. But one thing we did to sort of find out where it's acting was again. I'm not going to go into the biology of it in detail, but one thing we found is
Isin Cakir: we mapped its side of action most of the skeletal muscle. so we think that so farfane by activating its Target Nrf2 or nerve in the skeletal muscle induces weight loss. The precise mechanism of reaction. We don't really know and that something like we're very curious about but I want to yes
Arash Amini: Can I ask you you say skeletal muscle? Is that bicep? These are like them around.
Isin Cakir: After your skin, it's the largest tissue in the body most of our energy demanding tissue.
Arash Amini: and so
Isin Cakir: In this case. We looked at question almost. Car stroke muscle in the mice. It's a large muscle group. Easier to excise it easier to work with it's large size,…
Arash Amini: Okay.
Isin Cakir: but it's basically skeletal muscle.
Arash Amini: And so it's being absorbed through the muscle or…
Isin Cakir: so I think so for a thing goes to its bi distribution as well studied.
Arash Amini: what is it when it's acting through the muscle.
Isin Cakir: We haven't done studying our own but it's done by other groups. I think it's by distribution showed it goes to multiple tissues. It's not selected going to muscle. in this case again, it might be The reason we see the activation of and so what we have. Let me take a step back. What we're measuring here is not the amount of sulforaphane in tissues. What I wanted to always simplify this but what we looked at here was an earth to activity often. So for a pain it dissect the different tissues listed here.
Isin Cakir: We looked at Nrf2 activity in an indirect way. To put it in simple terms.
Arash Amini:
Isin Cakir: and the highest activity we saw was in the muscle among all the six tissues we analyzed And we looked at hypothalamus epidemal wider post issue.
Arash Amini: I see.
Isin Cakir: I read is in Google the subcutaneous water the post issue Brown adipose. You should liver and muscle And on its own this piece of data. May not be to be perfectly on a super commencing in terms of muscle being there side effects, but I put other graph at the bottom from another group This is it another. study conducted by group in Japan It's very well known in this Nrf2 system. The genetically activated nf2 in the skills almost and again, I'm not going to go into the political biology of it. But basically what they do is without using sulforaphane by using genetic tools, they activated enough to
01:25:00
Isin Cakir: In the skeletal muscle and they observed similar phenotype. They observe that these mice were protected from diet in this weight gain. And this was in another study. They also show that this was leptin dependent. So basically looking at Collective of this leg pieces of data suggest that muscle activating Nrf2 in the muscle leads to protection from obesity.
Arash Amini: so it's
Arash Amini: interesting
Isin Cakir: And this is a leptin dependent. Protection and I don't think anyone knows how so one. at this point is a complete hypothetical but one mechanism is probably Apostle for affin administration muscle secretes something that sensitizes the brain to let them forget again. This is complete hypothetical. I'm this point.
Arash Amini: Yeah, interesting fascinating really. is it fair to say perhaps that okay sulforaphane goes and…
Isin Cakir: Yeah.
Arash Amini: and it acts on different muscle different organs different tissue, but though the leptin sensitivity comes from it. Potentially you believe it comes from an acting on the muscle tissue.
Isin Cakir: I think so basically all the data we have suggested that and again in full fairness. I was always trying to keep this presentation as simple and understandable as possible, but I want to say that there are studies that show that in the brain activating enough to is beneficial for body weight regulation and…
Arash Amini: Sure.
Isin Cakir: for a number of neurodegenerative diseases so
Arash Amini: Right, right.
Isin Cakir: I think the important thing here is to finding is to find out what is the main driving? To you for this effect.
Arash Amini: right
Isin Cakir: I think ultimately it's a combination of effects. For example for detoxification things we talked about before for glucose metabolism liver And so far offense action in the liver is very important for those things. And these are drugs that act systemically, which means Doesn't know one target tissue was as you said to multiple organs.
Arash Amini: right
Isin Cakir: Which makes it a little hard to find Target tissue sometimes but that's why we use the genetic tools combined with pharmacology to map these things and
Arash Amini: I need a PhD just to read the genetic analysis in your paper. It was very very thorough, and I'm just blown away by all the different things sulforaphane does and when you just pick one, it's immensely complicated and not just
Isin Cakir: Yeah, absolutely. And that's the reason this study take. Longer than we want.
Arash Amini: Absolutely. Yeah,…
Arash Amini: absolutely. Right good science takes time.
Isin Cakir: There's always the case. Yeah. people who finish towards the end of the PHD, they look back And they say I could have done all these things in less than a year, but it's never the case. It's usually takes five six years sometimes even longer. because part of the biggest thing is in part of the Joy about it is also
Arash Amini: Absolutely, absolutely.
Isin Cakir: is following the problems that you face. It's just troubleshooting. It takes most of the time.
Arash Amini: Sure, you're discovering Uncharted terrain by the very nature of your inquiry. You wouldn't study something that's been, very well studied previously or else you want to find something new and so you're going into uncharted waters So what can you tell us about next up? Sorry if you have more slot.
Isin Cakir: yeah, I just wanted to finish with thanking the people who did the work.
Isin Cakir: and I'm always happy to mention at the time they were an undergrad one was a recent graduate, but Colleen Hadley and Pauline and They were very brilliant scientists who did lots for this project and they're both in colonies in a MD PhD program right now, and I believe she has her qualifying exam today. And Pauline is at Yale.
Arash Amini: Who?
Isin Cakir: She's in a PhD program there. and All of his work, not most of it was done in Roger Quan's lab. He's at Michigan right now. And we work with mustard Kumari and Dr. Risk from Qatar University. That is work. And as I mentioned briefly before significant part of the research was also supported from multiple different funding agencies. I tried to list them here.
01:30:00
Isin Cakir: Yeah.
Arash Amini: suitable manner that also Washes, the noise and finds the signal and presents it. Looks like you have one or two more slides. Did you want to
Isin Cakir: This is my last slide. I put some extra things…
Arash Amini: Happy to stop the recording on this Mark.
Isin Cakir: then just in case. Yeah, but
Arash Amini: Is there anything?
Isin Cakir: Yeah, and I forgot to say thank you presentation was a lot of fun and…
Arash Amini: my gosh, are you this is most yeah.
Isin Cakir: this is the first time I was doing as a, webinar to a public audience.
Arash Amini: absolutely, and honestly people have to see what you're doing and
Isin Cakir: It's in trouble. I hope it was less confusing than quickly.
Arash Amini: No, no, it was super fascinating. I think people are going to absolutely love it. Is there a place that you want people to follow your work? Are you working on something that you want to tease what's going on in the future for years?
Isin Cakir: So again, our main interest is in regulation of how the brain regulates feelings so different is some of the questions you were asking that what is the se mechanism of? Lipton resistance and how some of these compounds including sulforaphane reverse them is something one of our main area of research. And there's other cost of compounds we work with that induces similar phenotyping mice by reversing leptin resistance. So we are focusing on that as well as sulforaphane. That's definitely one actuary of research. and admittedly might be a biased view of is but studying. Neurons is a little harder. I would say than doing work in the periphery. This is a statement that could be misunderstood in so many different ways, but it's a little hard to work with the brain.
Isin Cakir: I would say…
Arash Amini: Sure.
Isin Cakir: then working with the peripheral tissues because of bunch of different reasons.
Isin Cakir: And that also makes it more interesting and in a more challenging and more interesting. So that's definitely one of the things we work on another area is again related to not this drugs but in general again related to finding novel Regulators of body weight and feeling Is there's a lot we know.
Arash Amini: mmm
Isin Cakir: In this field and there is problem more. We don't know. Which is always going to be the…
Arash Amini: Sure.
Isin Cakir: I guess in science.
Arash Amini: and where do you have a public facing a page or
Isin Cakir: Yeah, I'm in the process of building it. So as I said I recently started here and most Junior faculty to do I've been Spending most of my time just setting up the lab recruiting people writing grants. I've been busy sitting in front of a computer most of the time. And just getting a little bit of a breathing time to look at other things including building a web page. Yeah. It's gonna be up and running hopefully soon. yeah.
Arash Amini: As soon as you get I will add it to the addition for this seminar.
Isin Cakir: Thank you.
Arash Amini: I'm calling it a seminar because that was awesome brings me back to my own academic days.
Isin Cakir: Yeah, absolutely.
Arash Amini: Thank you so much. absolutely fascinating Can't wait to find out more about your next research project.
Isin Cakir: Thanks so much. Yeah this one.
Arash Amini: Hopefully before five years from now.
Isin Cakir: that's
Meeting ended after 01:34:09 👋