 I gotta tell you a story. I like to start off all of my lectures with a story even with my unfortunate biochem and physiology students. They have to listen to me. It's great. I have a captive audience. They can't reply back. I can just let them have the whole story and talk. So I get to do that with you, too. About three years ago, I was not the man you see before you. No, no. I was much more of a man than you saw before you. I went to the tune of about 235 pounds. About that time, I had appointment with my physician whereupon he got the results of my lipid profile. The lipid profile was, of course, as bad as it gets. High cholesterol, LDL is high, HDL is low. I was going to die. So he said, well, I'm putting you on statins. I said, no. I didn't really want to go on statins. Not sure I appreciate that particular drug. He said, well, then you're going to have to lose some weight. I said, okay, I guess I'll go lose the weight. So I got the phone and I called my family. I got a call from one of my family members, Karen Pendergrass, who some of you may actually know, who runs some Facebook blog sites. Yeah, thank you. Anyhow, Karen said, Dad, you have to go paleo. I said, what the hell is paleo? She said, well, Dad, you just got to go back and eat meat, vegetables, fruit, and nuts like they did back in 1500 BC or 15,000 BC. I went, hmm, it was interesting because immediately it struck me right away that there was something intuitively right about that, that it made sense on a sure, pure evolutionary viewpoint that the evidence for that kind of a diet made really good sense, that the idea that we would eat something that these folks ate that long ago because I would not have expected lots of genetic changes to have occurred in the last 15,000 years because it's a drop in the bucket relative to the other millions of years. So to me it kind of made sense and I now like to refer to the paleo diet and I hope you'll adopt this is, this is the default diet. We're going to reboot, right paleo authors? We're going to reboot. It's the default diet. And I am amazed. When I talk to dietitians, I'm constantly amazed that they're saying, well, your diet is just wacky. And I'm like, that cannot be. This is the diet we ate for millions of years. How can that be the wacky diet, right? You know, you've had this conversation yourselves, right? Particularly with your loved ones, my dad in particular, who can't manage to get over it. So 30 days later, after I started the diet, I was in the hospital because of course, right, I'm 235 pounds. My knees hurt. My hips hurt. I was taking ibuprofen and copious amounts. And of course I had a GI bleed, which sent me back into the hospital 30 days after I started my diet. Oh, and by the way, I had already lost 20 pounds in that short period of time, admittedly easily 10 to 12 of those water. So they did a lipid profile. Literally 30 days after I had started the paleo diet, I was already reversed and was under normal lipid profile. It had completely reversed in 30 days. Okay, so there is your end of one end of story, right guys? I got my end of one. It's a just so story. I'm solved. That must be the end of the story, right? Well, this is why I was hoping I might get a little bit of a background because I have this strange background. I'm not a researcher. I haven't I've done a little bit of research in allosteric regulation of an enzyme called pyruvate kinase, which is in the glycolytic pathway for those of you happen to know that. And but mostly what I am is I'm a teacher. I run a molecular biosciences program at KU Edwards in Kansas City, which I hope will be next year's site for AHS 13, not that I'm plugging. And you know, the whole thing turned around. I mean, it was really amazing that in 30 days this happened. So I just stayed with this diet and it made me think about what the heck is going on here. Because that was pretty remarkable. Something like that could actually happen that quickly from a biochemical standpoint, and from somebody who had been talking about genetically modified corns being a good thing. Yeah, because I said, well, there's no difference in the starches, which is actually a true statement. But oh no, we were taking out the ecology of it, right guys? So I started investigating was we do. And since I'm not a researcher that and because I'm a teacher, well, let me tell you what I teach. And this is what you needed to hear. On a regular year, I teach the following classes, a graduate biochemistry class, which I teach three times a year, 200 students, a graduate physiology course, a graduate neuro biology course, developmental biology, anatomy, brain dissection class, biochemistry lab, cell structure and function, and I'm forgetting what? Oh, immunology and occasional virology. So that was this is my weird background right coming into this right so I start reading and immediately I run into some neurons that were in the brain that I remember back when I was in grad school. It was pro opium melanocortin. Right back in my face, the opioid pharmacology stuff I'd been really well versed in was right there back in part of the hypothalamus that regulates food satiety. Cool, right? I've got it. I've got it in. And so I just started reading. Now I need to tell you, let me tell you about the problem I had. As soon as I started, it was like this. I just ran the search today on the word obesity and my PubMed, which I have access to 165,316 entries for obesity, 8,437 for the word appetite regulation. And of that, 1,437 were for appetite regulation review. How many papers do you think I've gotten through in as little as two years? Not 12 or whatever was 1400 papers. I don't have the ability to read 1400 papers in two years. And so I'm going to tell you a story today about appetite regulation. And I'm going to try to contrast to the differences in what I'll call paleolithic nutrition and what I'll call the standard American diet. I think that's a great comparison for us in particular. And the difference in the carbohydrates versus protein intake, I think may and fat intake in particular may be quite striking as we look at some of the appetite regulatory sides of this. And so that's what I started doing was trying to ask this question. So I will tell you right now, I haven't read the whole thing. So and I will also tell you that as you read reviews, and then you get into the primary papers to actually really figure out a single primary paper as to whether it's good or bad takes hours. I mean, literally it takes hours. And when you first start, it takes five hours for a single paper. So it was a pretty slow start like you would expect. So with that caveat, I need to say to you that I've done this research, it's a literature research, which actually is kind of fun to do. I even got my students to do it because I now have an Appetite Regulation Seminar that we have and I make my students write reviews so I get to read their reviews. So that's good. So I kind of keep up with it. So with that idea in mind, you'll understand that the information I'm giving you, right, is not vetted. It's good information. I've searched it out. What I have is good. But I will tell you already that there are discrepancies. And what I'm going to tell you as you look from one literature source to the next one from one review to the next, there were profound differences as you would read them. So you kind of go, okay, three out of the last seven reviews said, it's kind of like that. So I'm kind of pulling out the best I could. And then I also need to tell you this, that almost every paper that I ever read about the whole thing in the abstract at the bottom, the last sentence almost invariably said, and thus we can use these drugs to regulate obesity, which should tell you the mindset of the people writing the papers and why this is very difficult. So with that idea in mind, there are some things that we can pull out of it, and let's do that. Let's assume something. Anybody want to go with me on this assumption? Paleo nutrition works better than the other diets. Anybody in favor of that idea? Raise your hand. Oh, somebody didn't. Where are you? We've already seen already just in the conference already that there's pretty good anthropological evolutionary evidence. And of course, the millions of us who have had an N of one experience. That's something about all the people who are talking about their own diet to their friends and family. I personally have gotten five people on the Paleo diet at work, and they have done well. So I get to add N of six. And then of course, supported by all the bloggers that are out there who are awesome. Because it wasn't for you guys, we probably wouldn't be here. And that's the truth. So thank you. So if this is our assumption that this particular diet works in a positive way. And I think we are coming to the conclusion from these, from the other evidence that this is true, then this nutrition must in fact regulate brain signaling processes that moderate satiety and hunger in a way that makes it better to maintain a healthier lifestyle. Because in the end, your brain has to tell you to eat. And your brain has to tell you to stop. And if you recall from Lieberman's talk, 20% of the energy expenditures are where? They're up here. And so there was a cost to all that energy. So we must have, we need to make sure that we're doing something about it in terms of regulating. Because obviously we overeat, we get fat. What happens then? It's kind of hard to run after the cheetahs. Oh, yes. We ran after the cheetahs. Who's afraid of who here, people? They're afraid of us. We were because of this, and this, and the fact that we can stand and know where everybody was. That was our advantage. We were by far the most superior hunter out there because of this. So we move ahead. All right. So with these ideas of mine, I developed this for a nutrition program that I co-wrote with a regular dietitian who did not agree with anything I said. That's the truth. And this is what we came up with. Because I said I'm not writing unless I get to do this part. So, and actually we did come to the agreement with this. So I will tell you. The 12 Commandments of the Smartest Loser was the name of the program that we did at the Jewish Community Center in Kansas City. And these are just the 12 Commandments and you will recognize them all as being basically being paleo. Right? Eat meat. Eat eggs. Eat fish. Eat shellfish. But for our Jewish people that we said you didn't have to eat shellfish. Eat nothing from grains. Drink water, not liquid food. Don't eat table sugar or equivalents. Don't eat dairy products or at least limit them. Eat nuts, but don't eat legumes. Eat potatoes, sweet potatoes or other root vegetables. Tubers are great. Maybe not want to eat too many potatoes because they have a less starch. You shall eat vegetables and fruit, but eat more vegetables than fruit. Get some sleep, exercise, and cook with the following, you know, saturated and monounsaturated fats rather than polyunsaturated fats. Everybody with me? Can we have a consensus please that this is relatively a fairly close paleo diet with any caveat you want to add to it to make it your own? All right? I understand that there are slight differences and we'll go with that. So I'm giving you the warning now that the following figures that you're about to see may cause the following. All right, because of the part, how do you make neuroregulation sexy? I haven't figured it out. Okay, remember I said there are 8,000 articles. Okay, so trying to pull these things together right has been quite a fun process and it's very hard to do. And it's also why I'm sure I have made mistakes here and there. But let's go through some of this because it's actually quite interesting. All right, so let's talk about some friends that we all know about adipocytes, right? These are the tissue that are in fats, we in your fat, the stuff right here with which I used to have a lot more. Pancras which is kind of located in the sea of the duodenum. Really important, we know it's a site for some major players for hormones, insulin and glucagon. Also amylin and pancreatic polypeptide. And then the liver of course is the major metabolic organ through which we mediate a lot of the metabolic demands of the entire body. We see that we have some, the GI tract itself. And here I'll tell you the first brain we're going to talk about. Because the real first brain is not here. It's your digestive tract. Are you ready for this? There are more neurons in your GI tract than there are in your spinal cord. Is that surprise you? Does it tell you the importance of food to your body? Might kind of give you an indication. We spent that much energy with that many neurons. In addition, there was something in the neighborhood of 30, 30 genes and 100 peptides from those genes that are released from the GI tract and ancillary digestive organs. Okay, so that's a lot of them. That's a hundred of them. Now, I know we've seen out in the literature that leptin, nobody knows about leptin and insulin and these kind of things. And those are major players for sure. But there are all these others. And many of them aren't even, they've just been discovered. There was one called Resistant that I just found like in the last couple of years. It's not even in textbooks even, that kind of thing. So you can imagine that this is not an easy, imagine 100 peptides each exerting their own little tiny effect with their own little tiny receptor and anything can go wrong with any one of them. So, but let's kind of key in here on some key players, ghrelin, which is a gut peptide that's produced by the stomach when you haven't eaten. And this is one that will tell you to eat. And it'll make your stomach do that funny rumbling, fun sound that you get. And then we got some others and you'll notice that this ghrelin happens to be in green, right? So everybody see ghrelin right there. And then you see these ones in red that we see right here. There's a cholecysticinin, glucagon like peptide 1, and to pancreas, peptide YY or PYY, oxytomodulin. They're red because they are what I'm going to term anorexic. They tend to cause you to not eat. That's kind of the job. How do these guys work? Well, they work in a couple places and they interact with the brain rather directly because right next to all of the GI tract neurons is another neuron that does come from the brain, cranial nerve number 10. And an afferent or sensory loop makes its way along the entire digestive tract, some exceptions. And as it does that, it expresses receptors. Receptors are mediating the effects of these neurons. So for instance, cholecysticinin makes its way to a cholecysticinin 1 slash 2R receptor and there it goes to the vagus nerve and the vagus nerve makes its way into the brain. So that's the interaction to the brain, but the peptides are actually talking to other parts of the digestive tract. So cholecysticinin also makes its way back to the stomach and it says wait stomach slow down. Slow. Don't send me any food yet. Why? Because cholecysticinin is primarily released in response to increased fats. So if I have a fatty meal to apply this idea, if I have a fatty meal, the increased fats will activate cholecysticinin. The increased cholecysticinin will cause you to squirt your gallbladder to squirt in some detergent called the bile salt so that it will emulsify the fats that you just ate. But it takes a minute to do that, right? We need some time so it says stomach, don't send so much because I can't process it and so it slows the stomach down. We call that gastric emptying. So that means as you're eating, right, and especially if you eat a fatty meal, then that means your stomach will be told to slow down, which means the food stays in the stomach, which means the stretch receptors in the stomach which are making way to the brain will tell you your fuller. And that will happen for a long time. It takes a long time to get the fats out of the stomach and into the duodenum. There's a time domain there. And because of that, this is a pretty powerful mechanism all by itself, all on its own, to tell you maybe eat a little more fat, right? So we have some other ones that do that. How about if you ate a high protein diet? Well, that will activate PYY, preferentially PYY over glucose. And PYY also will tell the vagus to tell your brain, hey, slow down. So far so good? Okay. All right, so oxytomodulin responds to glucose. And it will also tell you to stop eating. It'll also tell insulin to increase while it's at it. So now we go to our pancreas and the increase in glucose caused the pancreas to get insulin to secrete. Where does insulin go? Well, now let's see where insulin finally makes its way. We see insulin receptors located all over the place. We see that there are a couple of areas here. This is a part of the brain that's located next to the brainstem, which is where my vagus nerve is going. And here's another part of the brain that's making its way or that that has an opening, if you will, to the blood. And so insulin can activate its insulin receptor in these neurons known as the arcuate nucleus neurons. And there are two subsets of these that we're most concerned about the NPY, a goody related protein, and the POMC cart neurons. Well, what do we care about those guys? Okay, well, I'm going to get into that. In turn, these neurons, if we activate those preferentially over the POMC cart neurons that we see here, then that will cause you, that'll cause you to eat more, or rexigenic pathways. So if we activate NPY, a goody related protein, we're going to eat more. Notice I got an insulin receptor there. I also have a leptin receptor there called OBR. They're located there, but they're also located on the other one, POMC cart neurons. And if I activate POMC cart neurons that you see here, if I activate that set of neurons, that set of neurons will tell you to stop eating. So here's what happens. In, for leptin and insulin, here's what they do. They'll go to these neurons and they'll say, slow down. Don't work so well. And then they'll go to these neurons and they'll say, work more. So the outcome is, you stop eating. So far, so good. Does that make sense to you? Yes, I do want your eyes and feedback here. Because I'm getting more complicated as we go. All right. So this is a really seeming moment. In fact, there's lots of studies where they cut out the parts of the brain. They would have laid it and they would show, oh, you start eating a lot or oh, you wouldn't eat at all, one or the other, depending on which part of the brain you did. Well, the way these guys are mediated is they also send projection neurons to a place called the pair of ventricular nucleus. And let me clear up my screen here. So here's my pair of ventricular nucleus right here. And ultimately, it's an N.4 and anorexic pathway. If I activate those neurons, I'm going to have, I'm going to not want to eat. On the other hand, the lateral hypothalamic area is an orexaginic pathway and we activate that pathway you will eat. So it happens, MPYAGRP activates the orexaginic pathway here in lateral hypothalamus. Palm C activates the pathway here. But inhibition of this pathway means then the opposite. So now let's talk about what other places in the brain we're going to talk about. So this is just the basic circuitry. And it's pretty basic. And I'm giving you a very simple version of it. OK? And the reason why I'm giving you a simple version of it is because inside every single one of those neurons and every one of the cells that are around them and the astrocytes, they all have this in them. And each one of the compounds in there can have its own effect on what's happening in those neurons. And so the metabolic changes that we see can affect anywhere in this pathway. Did it immediately get complicated? You see why this is so complicated? I only brought you the slide so I can tell you it's complicated. Why do we care about this? Because in the end, we're worried about this little bugger called ATP. The cells need the ATP. The only reason why neurons need glucose at all is because the mitochondria are too big to fit in a part of the neuron called the axon, which is this really long thing sometimes up to a full meter long. They don't fit in there. They're too big. If they were in there, they'd be in the way. You wouldn't be able to, again, electrical sun go. They're just in the way. So they rely on glucose to get the energy. Actually, the cell body is fine. It's got mitochondria. And the end of the neuron has mitochondria. So they're OK. They're doing fine. They can do just fine without the glucose because they can use other fuel sources. But the inside of the neuron, the axon, it requires glucose. So can you imagine if you're dependent on glucose to get something, to get your neurons to work? Do you think we might have evolved a way to get us to sense that we needed glucose? Sure enough. Now, what part of the body do you think we want to have do that? I'm guessing the hypothalamus. All right. So with the hypothalamus at work here, and its interaction here with these peptides. And by the way, this is just the same figure. I've just blown up parts of it. The peptides come back. And they're going to do there. I want you to be anorexagenic. And I want you to be. We're going to mediate through the vagus nerve. And we're going to make our way all the way over. And to tell you, oh, don't eat because we're inhibiting this pathway. If we inhibit this pathway, you're not going to eat. Those are the behaviors that we would end up with. So here is a list of the peptides that are coming from the brain, or coming from the gut, rather, that are making their way to the brain. I mentioned this one called ghrelin. We say it's anorexagenic signal. And the anorexagenic signals include insulin left in and the whole series of things. So now we need to worry about another part of the brain. So this is just the basic circuitry. And we're going to interact with the circuitry as we move ahead. And in this, we need to talk about the word resistance. We've been banding around a lot, the word insulin resistance and left in resistance. Well, let me draw you a picture of what this really means to what it really means. So here's an insulin receptor. And I draw two little things because that's what it kind of looks like. It's a called a tyrosine kinase receptor. It gets phosphorylated when insulin comes in, or left in. All right, when this happens, it initiates a series of things inside the cell. And it could tell that cell to make something. It could tell that cell to depolarize. It could tell that cell. And it could be a series. Well, this will cause this. And that'll cause that. And A will go to A active. And B will go to B active. And that will make A to go to. You see there's these cascades inside that more or less resemble that funny looking figure that I showed you that's going on inside the cell. So what is resistance? Well, if I inhibit anywhere along the path, any movement of one of these arrows from one kind of compound to the state of another compound, I've altered the resistance of the receptor. Or I could take that receptor located here. And I could go, mm, mm, and I could pull it into the interior of the cell so that I sequester it away. That also is resistance because the receptor is not there. In neurobiology, it is the most common thing in the world for a receptor to undergo this form of what we call downregulation. We pull the receptor away from the membrane, which means insulin can't get to it. Therefore, it can't be to the effects. This is so common that when Matt Lalon challenged me to find a positive feedback pathway, because I was trying to figure out what the seasonal, if there was a molecular basis for the seasonal affectation of maybe eating, glucose. This was his challenge to me, find this. I said, well, I don't even need to go any further than insulin resistance because any time you have XS hormone, the receptors down regulate, it is so common. It's the norm. Unfortunately, I can't tell you, based upon the literature that I thus far read, I cannot find a single paper that shows with excess hyperinsulinemia either of these mechanisms in brain. We did, however, Lustig's paper did identify one for fructose, where we did have insulin resistance, and he mediated that pathway, and that was good to see. But it's not the same one in brain. They use different mechanisms. So I don't know whether that is happening or not, or the mechanism for it. But I would be surprised if it wasn't. It doesn't make sense to me that it wouldn't be doing in a brain, which tends to do that. So I said insulin was a major what? Makes you stop eating, right? But if I have no receptor for the insulin to bind to, what happens? Oh, I'm not getting the signal. So therefore, you will begin to eat. Remember, if I don't do what it's supposed to do, then I'm going to do the opposite. Well, if it was supposed to stop you from eating, now you're going to eat. All right? So I needed you kind of feel, because at any one of these places, I could have this kind of resistance. And if you're overeating sugars, you're going to get hyperinsulinemia. And if it's there for any length of time, you're going to downregulate the receptors. In any form or fashion, whether intracellularly or sequestering the receptors away. So this would explain all by itself the effect of carbohydrate use on insulin and insulin receptors. Same thing for obesity. If we're obese and we're making too much leptin, and the leptin is supposed to tell you to stop eating, then you're leptin resistant, because I don't have the receptors located there, the behavior to eat now is in place. So the resistance idea is actually very important, not just metabolically in the liver, which is where most people have been talking about. But in appetite regulation, this is a major mechanism why obesity may be responsible for its own continued existence. Because if you're eating, then what are you eating? If you're on the standard American diet, you're eating more 60. I mean, even if you go to an ADA diet, it's 60% if you're on a standard American diet, it's probably higher than that in terms of the carbohydrate intake. So you're spike insulin anyhow, and you're doing it with very highly processed foods, which in particular make the insulin level spike ever higher. I mean, if you eat a fruit, at least the insulin is only like this, whereas if you eat a data chip, it's like this or a candy bar. So far so good. You with me? All right, so right away, do you agree that if we remove the carbohydrates that we've taken care of at least the insulin side of it and maybe those receptors, because here's the other part, if you remove the stimulus, the hormone, then the receptors will go, where did it go? And they'll come back. So you can reset the receptors. And one of the things that you see with resetting the receptors is for insulin is the formation of ketones. Ketones will help insulin resistance to resolve back to being more sensitive. Now, when do we get ketones, gang? It isn't for eating carbohydrates. I can tell you that. Because the second you eat the carbohydrates, the whole biochemistry changes. The physiology changes. And you start making, you don't make ketones. As soon as you eat the sugar, you're not going to make ketones. So this is one explanation as to why this stuff might have happened. All right, now let's go to, I'm going to go here. Now we're going to add another caveat. This is one I was so happy when I saw Robert Lustig on 60 Minutes. I was cheering because my dietician friend was with me. I was like, yes. When you eat something sweet, tastes good, right guys? I like sweet things. This activates, this will activate the rexigenic pathway. If you eat something sweet, it's a reward. It's pleasurable. We like to eat sweet things. We really do. We're hardwired to eat sweet things. I think at some point we were supposed to be eating sweet things. The problem is, is that the sweet things weren't around very long. Today they're around pretty much all the time and they're the cheapest source of energy that we can get to. So unfortunately, that reward is all pervasive. And here's what it does to you. When we start this pathway, there are projections from this lateral hypothalamic area to an area in the brain also called the ventral tegmental area. Oh, those of you who have smoked cigarettes know all about the ventral tegmental area. Or if you're a drug addict, you might have known about the ventral tegmental area. Or if you're schizophrenic, you might know about the ventral tegmental area. Because the ventral tegmental area makes its way back to the brain all over the place. And in particular, it makes its way back to the hippocampus, makes its way back to the preorbital frontal cortex, where we do executive function. And these are dopamine neurons. And these dopamine neurons mediate what we now call the saliency pathway, what's important. It used to be called the rewards pathway. So this is the yin and yang of I got a pleasure point because I got a taste of something sweet. Activating the neurons in the VTA and the dopamine levels go up. When that happens, that feels quite nice. You have now managed to take care of your craving for a carbohydrate. The problem is, is that those neurons don't disappear quite so quickly. They'll last for years. So once you've gotten this addiction, which I managed to get at the ripe age of 14 when I would come home from school and watch Gilligan's Island and to make frosting. Thanks, mom. So I have this in spades. And like any addiction, you have to use addiction parameters to deal with it. So one of the first things to do behaviorally is to get rid of the stuff around your house. Because if there's a chocolate chip cookie anywhere near me, I want it. So I know Emily is following me. And she actually knows more about addiction pathways than I do because she's been dealing with clinical patients that deal with this kind of stuff. And I'll let her tell you more about it, I think. And I'll leave it just there if that's OK with you. But there's the neurobiology of it. When you aren't eating, then the dopamine levels go down. You are highly motivated. It's important you get those dopamine levels up. And to do it, you'll eat. So another positive feedback pathway at work here. Yes, by all means, smoke while you're drinking works every time. I was waiting for it to see if there was going to be a bowl of chips there. I was expecting there to be one. That would have been the tri-emvirate of addiction. So this gets me to a third part of the brain. This is the one that's so damn sneaky. That's why you're lovingly, or not so lovingly, referred to as the obesogenic environment. Let me tell you about this in place. In the obesogenic environment, I have these parts of the brain, the insula, the oral frontal cortex, triadema, and hippocampus, amygdalae area. These are the areas that when your brain gets signals, visual signals, auditory signals, olfactory signals. Here we go. Ready? Favorite cookie? Chocolate chip? Should I put one out? You want to see it? I'm activating this. This particular part of your brain will tell you to eat even if you are already full. And this is the kind of thing that happens when you go to the restaurant. And you've eaten the big giant pasta meal. And at the end of the meal, the waiter brings you what? Dessert. And for some reason, you left room for dessert, didn't you? The reason why is because you've just activated your obesogenic environment. You do have some control in this environment, because this area, the prefrontal cortex, this part right here, is the part that's known as willpower. And so you can't exert some control over that. And in fact, to deal with the obesogenic environment, you will have to activate this particular area. You'll have to develop ways to deal with whatever addiction you have or with this whole pathway. This is the input that you'll use. So for me, because there's always chocolate chip cookies next to the coffee every day at work, because the very nice ladies bring chocolate chip cookies every day, I have to actually have a conversation with myself like, OK, there's going to be chocolate chip cookies around the other side. And like David Kessler, I'm going to know it's going to be there. And I will hit it. And I go in, get my coffee, look at the cookie, and say, I don't eat cookies. And now I go. All right. So this obesity-engined environment, well, the obesity-engined environment can come in a whole lot of ways. How about with a commercial at 7 o'clock in the morning? Tony, the tiger, at work here. So this is the reason why advertising works, because it's activating this particular part of you. So all those commercials for Taco Bell at 4 in the morning, they work. You're going to go out and eat fourth meal. In addition, you have stressful, busy lives. You have a chronic stress condition. Your cortisol levels go up. Stress is also part of the obesity-engined environment. And it goes right to this pair of intracular nucleus. And it inhibits the pair of intracular nucleus. And therefore, you'll eat. And we all know that, because that's the comfort food side of things, right? Oh, I'm going to eat, because I need some comfort food. That feeds your addiction and reduces this area. So what do you need to do? The recommendation is get some sleep, right? Because sleep will activate, lack of sleep activates cortisol. It's a big one for it. All right, so that's the whole bit of it. There's more. I'll be back next time, I hope, to talk about it some more. We'll get into some other areas as I vent some of this stuff out. And so with that idea in mind, we'll summarize by, say, paleontrition is supported by the purported change. And I say purported, because there's so much work to be done here, by hypothalamic circuitry and the brain and gut, that the regulation needs work in terms of understanding how it works. I will add that the physiology of this appetite regulation and the accompanying pathology that occurs when, because of it, is taken advantage of by several large corporate interests. Because every place in that physiology that I described to you is something in the neighborhood of maybe a trillion dollar a year in business that's involved, advertising, food production, pharmaceuticals, diet, that kind of thing. And I'll also add that this physiology, because the overall availability of carbohydrates, is also responsible for our increase in fitness, if I can coin the phrase, and that this is to the point where we are now probably overpopulated and can't sustain the culture. So I'll finalize by singing you a little song, and I hope you'll help me out. You'll hope you'll recognize it. Who's the folks who eat so right? Oh, oh my god. Gotta train them. Who's the folks who eat so right? Let's sing it, guys. Who thinks grain products are the blight? Paleo people do. We think legumes are bad, the American diet's sad. Us paleo people are just ditching for a fight. Thank you very much. We can take one or two questions while we're getting set up for the next presentation. Question? Yeah, yeah. Well, hey, I remember you. I was wondering if in any of these papers they talked about how the psychological problems with eating, as well, when children are told to finish their plates and are told to eat when they're not hungry and how that controls our eating into adulthood. Yeah, those papers exist. It was kind of out of my, I didn't get into childhood obesity issues yet. That might be where I go next. It's a great question and there's tons of literature on it, but I have not looked at it. Yes, sir. Now that we all understand how our brains work, what makes one cookie lead to two and three and four? Well, because there's these feedback pathways that cause you to eat more of it. There's this one weird one that goes in the hypothalamic circuitry that literally says eat more. And when you eat more, it comes back out. The sugar increases your, the glucose ascents by those same neurons and it tells you to eat more and inhibits the neurons that tell you to stop eating. So you eat more. Pretty straightforward there. I'll show you the circuitry. Thank you.