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Lecture 5

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University of Toronto St. George
David Lovejoy

Wednesday, November 25, 2009 BIO270 Lecture 5 - One of the points he wants to mention is that when he was a grad student & he started off as a reproduction biologist, & when he first went to see his professor, he decided well what he really wants to work on are steroids. Steroids are really cool, particularly the sex steroids. He said well yeah, they are really interesting, but he should work on peptides instead. He did & then when he finished his doctorates, he had the opportunity to do a post-doc in Texas to work on peptides & also steroid stuff as well. So when he got his PhD, he was really enthusiastic, piled everything into his truck & drove from Vancouver to Austin. & he got to the laboratory, & found it, the laboratory was really quite disappointing. There is a lesson in all of this – you should check where you’re going before you get there because it was a considerable investment & when he got there it wasn’t really what he wanted to do, didn’t really like the person, so after 3 days he went back, driving another 4500 km back to Vancouver. He was in a pretty depressed state about the whole thing, he thought his whole career had gone down the tube, he wasn’t really sure what he was going to do for the rest of his life. So he decided well maybe he’ll go back to Edmonton – they had a possible position there so he decided to cross the border from the US to Edmonton or to Alberta in the middle of January. Now there is a little border crossing where they have like one person crossing a day & these guys, they are really bored & so they pulled him over, so what’s going on? He said he went to Texas, didn’t like the job & came back. They said wait, you drove 4500 km to the south part of Texas, then turned around & came back? Prof said yeah, seems like the right thing to do. How long did it take you, they asked & he replied it took 3 days to drive there & 3 days to drive back. They said you drove 4500 km in 3 days? Yes I did, he replies His truck was loaded with every one of his belongings & it was absolutely full, he had a little canopy on the back of it, everything was full. So he goes, what’s all this stuff back there? He said those are his belongings & that he was planning to move down there. But you came back? Yeah I came back. He says well I don’t know, I think we’re going to have to search the truck & he gets on the radio & says ‘Hey Bob, we have 619 going on here, we’re going to have to search the truck’. Oh great. So he’s sitting there & the guy is going through the glove compartment & he pulls out this little brown file. What is this? He says it’s a chemical he needs for his experiments – it was estradiol. Now when a biologist seizes estradiol, they have this white powder, so the guy gets back on the radio again & he says we’re going to upgrade this to a 620. The prof gets impounded & so does the truck, got put in the interrogation cell & they searched the entire truck & said well we’re going to test this. Fine, test it. He goes away & the prof is in this cold interrogation room for hours, & he comes back & says well, it’s negative on all of our tests – well yeah it probably would be. He says well what is it? Prof says it’s a steroid. & this is right at the time when Ted Johnson was indicted for steroid abuse. He says well gee, that’s even worse right now especially with all the press everywhere. He gets all excited, he runs back & shouts Hey Bob, it’s a steroid. Another hour goes by, & then he comes back again, gee whiz it’s not on our list, he says, holding this vial, what is it exactly? He says it’s estradiol, it’s a sex steroid. He says ooh so if I wanted to get big muscles, I would take this? No, if you want big breasts you would take this. So the rule is here to be careful what you take across the border. He eventually got let go. He never went back to work on estradiol – maybe that’s because of that incident. - Now we have a series of lectures on 3 topics which are all kind of related. We’re going to start talking about glucose & energy, & then we’ll go into the stress system, & then after that we’ll be talking about digestion. So they form a nice little set & then in the last class we’re going to be going into dieresis – it’s complex so we have allotted 2 hours for dieresis. Hopefully we’ll have time for review & give us some intel. - One of the themes we will see, we spent a lot of time talking about the neuroendocrine circuits in reproduction, & he was talking to some students today about that little bit of detail, but one of the things that we may want to consider is that when we’re looking at these cycles, here’s going to be some pattern associated. - Many of the hormones that are released by the brain play a role in a lot of these actions tend to be peptides or small proteins, & then they tend to release things like steroids from the tissues & they can get that kind of feedback. But it’s frequently the case that you get these different classes & the different classes have a particular functional attribute based on the structural elements & some of the chemical properties we spoke about earlier. - Now we used reproduction as a model with a fair amount of detail because the endocrine loops, the neuroendocrine & endocrine loops which lead to reproduction, are fairly complex. Hopefully we have the understanding that it’s a loop, something communicates to something else that then goes back & we have this big circle. - We’ll see with many of these cycles, all of these will follow that. The lectures today are going to reflect variations on that theme. - We will start with glucose & energy metabolism b/c this is really the key to many of the mechanisms that we talk about. So whatever you do, any type of activity you do involves glucose & energy metabolism & this basic mechanism has become under the control of the stress system as we call it. So we’ll be introduced to this first. - Chapter 3: Regulation of Glucose Metabolism. We’re going to kind of gloss over this so we have the basic rudiments for glucose metabolism – the reality is it’s a huge field, the regulation of glucose & its implications in diabetes for example is a major medical issue & a large chunk of the University of Toronto is engaged in this kind of research. Depending on which way you go you’ll have many opportunities to study this mechanism in detail. - Glucose follows a really wonderful homeostatic mechanism as we’ve seen, so clearly if blood glucose is too low, the brain can’t function. Glucose is one of the only molecules that the brain can use for energy; in some cases it can use fatty acids but for almost everything it’s only glucose it can use. If there is no glucose going into the brain then it causes severe disruptions in terms of how the brain works. Clearly if the brain doesn’t work, then nothing else works so low glucose is a big concern. - You may know some people who are hypoglycaemic in which case the glucose gets cleared very rapidly from their bloodstream & they go into a kind of low glucose situation. Some of this can be quite dramatic. The prof had a friend who he traveled through England & she gave him ten minutes warning that suddenly she was getting low on glucose & while they were looking for a sandwich for her to eat, she collapsed on the sidewalk so it can be a major concern. Then there are others of us who can go for 3 days without eating – it doesn’t affect us that much so there is an incredible amount of variability. - By the same token, if blood glucose is too high, then the osmotic balance of blood is disturbed as well & that throws a number of things out of kilter, including all of the water & ion homeostasis as well which we’ll talk about next class. - There are 2 principle hormones we’ll be looking at: insulin & glucagon. Insulin lowers blood glucose levels & glucagon increases blood glucose levels. These two are obviously in opposition to each other & much of the understanding of the homeostasis of this can be based around the homeostasis of these two hormones – obviously there are others but if we understand these basic components then we’re almost there. - Both of them are secreted by the pancreases & there is a direct feedback loop. Insulin will impinge on glucagon which will communicate back to insulin. - Now the pancreas, like all organs in the body, receives a number of neural signals. Remember the autonomic nervous system so it’s getting direct neural input & also it receives a number of hormonal signals. What’s going on in the pancreas is dependent on the day to day needs & the minute to minute needs. While you won’t necessarily be able to perceive a need for glucose at the moment, it might build up slowly over time so it won’t necessarily be a nervous stimulus you’re getting, it could be an endocrine stimulus you’re getting so the pancreas has to be associated with both – it has to have the ability to perceive both sets of signals. - This is what we call an antagonistic paring where the hormones have opposite effects. There are many cases where you have one hormone & there is another hormone that does what seems to be virtually the opposite. Neuropeptide Y & corticotrophin releasing factor in terms of stress like that too. For this one it is a wonderfully studied system. - So it looks kind of like this. So what happens when you eat, well several things will happen. One of the first things that will happen is a rise in blood glucose as everything gets broken down in the digestive system that, we’ll talk about later today, will eventually lead to the absorbance of glucose in the bloodstream & that will increase blood glucose. - And blood glucose going up is perceived by the pancreas. The pancreases then secretes insulin & insulin is the signal to say okay, now that we’ve got all that increase in glucose, we have to get it into the cells so insulin is associated with the transport of glucose into the cells. So insulin is a large peptide hormone, it goes into the bloodstream & travels throughout the body & it hits a number of target organs. They will eventually uptake the glucose & then this will cause a decrease in blood glucose & cause blood glucose levels to fall. When blood glucose levels fall to a certain degree, then insulin will also decrease. - It also does a couple of other things. Glucose receptors in the digestive tract will also perceive the glucose & this will cause the release of another hormone called cholecystokinin. CCK is also found in the brain – we used to called it pancreatic cholecystokinin but then we found that it was in the brain so now it’s the same peptide, the same hormone so we refer to it as CCK. & it will also make its way to the pancreas so here are our endocrine signals, this is our nervous signal here & metabolic pathway. - Okay, now at the same time when you’re eating, there is a bolus of food going through & there are a number of stretch receptors in there. That says ah hah you’re eating something, so even if you were to eat something else you couldn’t digest, that causes the distension of your stomach, then it will still do this. - In fact, some groups, in order to ward off hunger, what they would do is they would tie really tight belts around their midsection & so if there was a small amount of distension, then they immediately get the signal that yeah, we’ve already got the food. - Okay so then that is hitting the various integrating sections of the brain & the mass communicating from the direct route to the pancreas & we have this loop. - That is essentially the main components of insulin. - Now the feedback mechanism so if we think of this as a passive feedback mechanism associated with blood glucose & insulin, then there is a second system in place as well that is a bit more active. - So if plasma glucose goes up, as we’ve already talked about, this causes an increase in insulin affecting the beta cells of the pancreas. Insulin comes up etc, glucose uptake is taken up & then we get a decrease in plasma glucose & that feeds back brings plasma glucose down. - Now if this system was the only one in place, & you stopped eating, then what would happen is then all the glucose would simply be taken up into the tissues & glucose levels in the bloodstream would fall precipitously. You need a constant supply of glucose in the bloodstream to feed the brain as well as some of the other energy-requiring mechanisms of the body. - So there is a second system that is in place & these are from the alpha cells of the pancreases & instead, what’s involved is the secretion of glucagon. If plasma glucose is up, then insulin goes up, glucagon goes down, glucagon goes down, stops the glucose going into the tissues. So it tends to have then the opposite effect so when we get this insulin increases, glucagon decreases, however when this falls too far, then what happens is you get the opposite situation, glucagon then gets turned on, you get an increase of glucose into the tissues or into the bloodstream rather & then this causes an increase in plasma glucose which then tells insulin to come on. - So when you look at a feeding situation, glucose comes up & then it comes down, it’s insulin getting turned on & then as insulin continues to be turned on, then glucose levels keep going down. When glucose levels get too low, then glucagon gets turned on, glucose comes up & then down & eventually comes down to some steady state. - The reality is that there is a certain amount of this going on all day long. - This is where our book wants to talk a little bit about a couple of elements of receptor ligand interaction & the effects they have on the cell & this is referred to as additivity & synergism. It would be really nice if there was a single hormone that did a single function but in fact, because of the complexity of the tissues & the organisms we’re dealing with, many different hormones have overlapping functions. So it’s not uncommon to have 2, 3, 4, 5 hormones that may have a similar function. So when these hormones all come together & they all impinge upon the same cell, they can have an additive or synergistic effect. - So these are hormones that have the same or similar response in the target cell but they don’t necessarily follow the same signalling pathway. So you’re getting all these different signalling pathways that will converge. So here is an example: glucagon, epinephrine & cortisol, we’ll talk about later in the lecture, all raise blood glucose by a different mechanism. Glucagon is used in feeding for example, epinephrine is involved in stress & emotional stress, sudden requirement & cortisol for more adaptive type of stressor mechanisms. Whereas epinephrine deals with an immediate need, cortisol deals with an anticipated need for example. But they will all do the same thing, they will all act to raise glucose – if they’re all released at the same time, then there will be a fair amount of glucose that can be released. However, the responses to the target cell of these is additive, so for example if glucagon causes a two fold increase & then epinephrine does a 2 fold increase & then cortisol does a two fold increase then you get a six fold increase, it’s just additive. - What we frequently see is a concept called synergism & this is where the hormones enhance the effect of other hormones, so for example, hormone A has an effect & raises glucose by 2 fold but when it’s in the presence of another hormone suddenly it might raise it 10 fold so this is where the total is greater than the sum of the parts, this is synergism & in many cases, this is the situation. Growth hormone works this way for example, when ghrelin & GRF are present, then ghrelin could really potentiate & synergise with growth hormone releasing factor & you get considerably more growth hormone that’s released. - So here is an example of how some of these things work. - If we just look at cortisol, we get a certain amount of increase of glucose over a period of time. Glucagon, these are static studies, you would inject glucagon, you get an increase & then it decreases over time & epinephrine, you get a certain amount. If you take glucagon & epinephrine, you can get well kind of an additive effect here. - But if you put all of these things in together, if you add each of these components up, this is considerably greater than all of those so you get synergism & the reason for this being that if all of these hormones are present then the body goes gee, there must be one heck of a need for glucose, let’s overcompensate & get this. - So what does this mean? This means that if you’re studying for an exam & if you’re attacked by a bear, then it’s probably not the time to be eating a Mars bar because it will do some funny things. - Okay we’re not going to be talking about arthropods & insects at all in this class so we’re going to ignore this. - & that’s all he wanted to say about additivity & synergism. - Now feeding directly off this, because we’re going to be talking it, about these hormones, is stress. Now what does stress have to do with energy metabolism? Well he alluded to in earlier classes, when you're confronted with a stressor, then that indicates that your survival is being challenged – that is what your body thinks about: ‘if I’m being stressed, the reason I’m feeling stressed is because there is something out there that is noxious to the health of my body’ & all organisms will do this whether they’re humans or paramecium. That means that there is a challenge, this challenge has come that is going to require a metabolic response that is greater than what I need at the moment. In order to deal with that stress & challenge, we obviously need a fair amount of extra energy so depending on how that comes, you can get that energy in a number of different ways. - If it’s a low level energy, you might simply get hungry even though you may have eaten not too long ago. If on the other hand you get chased by a bear, then you need a lot of energy to run like crazy & even if you have an emotional stressor, this is one of those things that is really interesting, with a certain low level amount of emotional stress, many people respond & many animals will respond by a certain amount of food craving, so you might know a number of your friends that when you get stressed out or around exam time, you start eating like crazy. On the other hand, individuals that have a huge amount of stressors coming in, who are particularly sensitive to these stresses, may stop eating completely. - Understanding that & those differences between individuals has been a bit of a challenge so let’s take a look at some of these systems. - There are a couple of pages in Chapter Three on the Vertebrate Stress Response, so it’s a nice easy overview of this. - Everything possess a stress response, every organism. - & as he mentioned it is an adaptive mechanism – it may not feel that pleasant to you & you're going why do I need it? It feels so bad & if I’m stressed out, I can’t function properly, I can’t eat properly, I fight with my spouse, I can’t study, I can’t do anything, how can this possibly be good? Well in small doses, it’s a very effective adaptive mechanism & protect animals from a lot of different things & if we think in terms of animals, infection & predation, they really are major issues, injury, bad things might occur if there's a predator out there & you can’t leave the nest for a certain period of time, but also under temperature extremes, radiation, almost anything you can think of that is in a high enough concentration. - & the goal of this stress response is to take energy where it’s stored & shunt it to where it’s needed. So as he mentioned previously, things like reproduction, growth & immune responses, you don’t need them right now, you can use them later. - Now there are 2 parts to this. There is the fight or flight response, & this is where part of the blood flow is diverted from the core regions & shunted to the limbs & muscles – you don’t need to be digesting things. - & this is part of the immediate response – once you’re under attack you either fight them or you run like mad to escape from them. Now whether you are a rabbit being chased by a hawk or whether you’re an undergraduate & has to deal with the exam from hell, it’s the same mechanism. The difference is with the rabbit, oh you can run & you can hide, when you’re a student, the professor says you can run, but you can’t hide, sooner or later you’re going to have to write that exam so you fight for that & that’s the equivalent of fighting. Okay I’m going to study like mad & deal with this & show the professor. - The neuroendocrine axis that we’re going to be talking about is referred to as the HPA axis (in slide). We’ve already been talking about the HPG axis, the hypothalamic pituitary gonadal axis, this is now the HPA axis. Now in fishes sure it’s referred to as the HPI axis because they don’t really have an adrenal gland in fish. The fishes, what we think normally are adrenal glands, is divided up in fishes so they’re actually referred to as the interregnal gland in fish so we call it the HPA axis in terrestrial animals & the HPI axis in fishes. - There does not seem to be a clear similarity in invertebrates – some of the hormones are present but a lot of them are not & it’s just not really clear. Clearly they have some way of perceiving stress, but the reality is we really don’t know how they do that even though the organism is so simple in comparison to say us or vertebrates. - Well what goes into stress? Everything you can think of: infections, injuries will cause stress response. We always have some infection in our body at some time – if it’s below the threshold, we never perceive it; if however that infection increases beyond the threshold & starts to impinge on the organism then the HPA axis gets involved & you start getting stressed out – you might not even know why you’re stressed out, you’re just anxious. - A couple years ago, he came in northern Europe & contracted limes disease & they didn't know he had it – all they could tell was that he was suffering from incredible anxiety & once he found out that he had lime’s disease did he realize what was going on. When you get the infection & it goes up to a certain level, he just thought that he had troubles with the wife which was interesting looking back on it & it’s kind of funny. They then gave him those anti-malaria drugs in massive doses & then after a month of these drugs, suddenly he had so much energy, he was bouncing all over the place, it was fantastic. He wishes he could do that but he doesn’t recommend going out & getting Lime’s disease & experiencing that. - Okay, unpleasant thoughts – he’s sure that everyone can think of something that is unpleasant, that makes us say oh god I feel awful. The more complex we are, the situation, the more effect it has. - If you’re really hungry & you didn’t have food for a long time, it activates stress. - If there are predators & that’s spelled incorrectly. - Unexplained sensory experiences – you see something, you just don’t understand. He was hiking in British Columbia many years ago & one of the cool things in BC was that you can hike anywhere & you can set up a camp anywhere in certain areas & they were doing that. Then around 2 in the morning, he’s in the middle of nowhere, he hadn’t seen anyone for 3 days, just him & his spaniel, & around 2 o’clock what happened was that there was a sound that was sound like a baseball bat hitting a flagpole & he heard it 3 times, & not only did he go into a stress response, his dog went into a stress response – they both frizzed out, sitting there scared of each other because they couldn’t explain it. Next morning, he got out & circumnavigated all around the campsite in about 200m in every direction & found nothing to explain what that was – it remains a mystery to this day, but not the perception of the stress. - Fluid in the ion level – these are one of the really great things: if you drink too much or not enough, you have too much salt, too little salt, it’ll do that. - Novel environments, & he used to think it was a really great thing & moved on a regular basis – he’s moved around 37 times in his life, living in 13 different cities & 3 countries & it’s really stimulating but then you’re stressed out for the first couple of years you're in the place. - Temperature extremes. Okay another wonderful example of being in California & spending too much time on the beach, he’s got a Celtic personality for god’s sake, he doesn’t do well in the sun & you get the same effect – you feel nauseous you feel depressed, it’s all the same mechanism. - The season & the time of the day – there are times in the day where we’re more sensitive to stress. - Security – how safe are we? If your security is compromised, you go into a stress response. - Sex & reproduction – too much of it, too little of it will generate this. - All of these things, you & every other organism is dealing with this on a regular basis & then this will lead to an activation of the stress response. - We’re going to be talking about a number of these things but he hopes that by showing us this figure here is that we’re going to be talking about a number of these different physiological systems & the stress circuit will affect every single physiological system in your body & every single physiological system in your body will & can impinge upon on the HPA axis. So there is this exquisite balance that we try to maintain. - Okay now we already talked about the autonomic nervous system. He put it in here as a bit of a reminder for us to indicate that it’s complementary to the endocrine system, & as he told us, we don’t need to memorize all of these different nerves & such, just know that the autonomic nervous system is complementary to the endocrine system – it plays a role with the nervous response. - Two main divisions. - The sympathetic nervous system, which is the arousal & fight & flight response. - So you’re at the campsite, you’re enjoying your meal & suddenly a wolverine leaps out behind a tree & attacks you. You go bam, suddenly get really nervous & you feel that pit in your stomach & you start shaking & you start to run. That is the first element of it. The second element will be if that’s your campsite for the next month & it keeps terrorizing you at various times, so suddenly you’re walking around thinking god is that wolverine going to be around? & then after a while, you get really nervous. You hear something or you can’t even enjoy your food because you know that wolverine is going to come out at some point & steal your sandwich – this is an example of the second stage. - Now he just wanted to indicate how that is complementary to the endocrine system. - The other part of the autonomic nervous system is the parasympathetic nervous system. - Finally after a month, you chase the wolverine away, it migrated, you haven’t seen it for a little while & you can finally enjoy your sandwich, you can now grow & sleep & get better. - There are a number of very common mechanisms. There was a really wonderful book that was written around 1951 called Stress by Han Seelig & although he wasn’t the first person to understand the mechanisms of stress, & this goes all the way back to antiquity when the Greeks were talking about what stress could do to the body although they didn’t call it stress, they called it something else, but one of the things that Seelig pointed out regarding stress was that you could get the same mechanism, the same physiological things, occurred all the time so this is what lead to understanding the stress response & he was the one who came up with the word stress though he said later that it was his poor understanding of English that led him to use the word stress since he was Hungarian & immigrated to Canada. He thought that strain was a better word, but nevertheless, there are a couple of things that occur. - There is an interaction that occurs between the nervous & the endocrine systems – a number of sense organs detect stressors. What a stressor is will be dependent upon the experience to a certain degree, genetics – some odours for example are genetically encoded. - You get activation of the sympathetic nervous system here & this is associated with increased heart rate, respiration, dilation of airways so you’ll immediately recognize why this is occurring – you need that extra oxygen flow to be able to move. Now you’ll also get a decreased secretion of insulin from the pancreas – keep that blood glucose level to a certain degree & because of that, an increase secretion of glucagon from the pancreas. Because you're under stress, you’re going beyond what the metabolic requirements are for that time. You get an increased secretion of epinephrine form the adrenal medulla & all of these act to increase your blood glucose level. - That was the first stage that occurs. If that stress continues then you get the stimulation of the HPA axis. So the presence of epinephrine & the presence of stressors will all impinge upon the brain, if it hasn’t done it already, to turn this system on. This is a wonderfully synergistic system. When the HPA system is turned on, you’ll get a certain amount of adrenal epinephrine turned on, in some cases norepinephrine. On the other hand, if you get an epinephrine response, you’ll get an HPA response guaranteed unless it’s very fast. - So the hypothalamus secretes CRH – he has a tendency to call it CRF so corticotrophin releasing factor. That communicates with the anterior pituitary the same way that GnRH did & secretes adrenocorticotropic hormone or ACTH. ACTH goes into the bloodstream where it eventually impinges in tetrapods on the adrenal cortex & that secretes cortisol & in some cases, it will be corticosterone, depending on the species. Rats for example secretes corticosterone – similar to cortisol but slightly different. That will stimulate the target cells to increase blood glucose levels. - So you get the initial flight or fight response coming on first. When it’s through, the stressors first perceived, if the stressors continue then you get activation of the HPAaxis. - Now this cortisol will feed back to inhibit ACTH & CRF if necessary. As long as the stressor continues, however, this pathway will continue to go. - Now in a number of patients who suffer from say chronic depression or anxiety, what happens is this feedback mechanism becomes disrupted so it doesn’t turn it off as well as it should & it stays quite a bit. - This looks like an awful figure, but it’s just a summary of what he just said. So if we haven't been able to follow all those notes, here we have the same situation. - Stressful situation impinges upon the brain, we get the integration & we get an effect on the hypothalamus, this is our neuroendocrine response, here is our nervous response on the sympathetic nervous system & we will also have direct input into the muscles. - So for example, we put our finger into the flame, perhaps a Bunsen burner, you don’t know you put your finger is in it, you immediately pull it back due to the reflex loop before you realize hey, there is a Bunsen burner turned on. - In the hypothalamus, CRF is released from the anterior pituitary, the ACTH is released into the bloodstream, goes to adrenal cortex, out comes cortisol, it goes to target tissue, cortisol feeds back here (he wishes they showed that). - The same time, we’re getting sympathetic nervous system activity – inhibits insulin, increases glucagon, that’s also acting on the target tissues. The adrenal medulla is acting to release epinephrine that is acting on the target tissues & there is also a whole variety of different target tissues that will be involved depending on the nature of the stressor & you get a series of effects here & that is in its simplicity. - So he just wanted to give us an overview of the adrenal gland here. - Adrenal gland in tetrapods looks something like this. There is a cortex around the outside, the medulla in the middle. We already mentioned that the medulla is nervous tissue & it’s associated with the synthesis & production of epinephrine & norepinephrine, all the steroids are produced in the cortex, so cortisol & corticosterone is the principle steroid that is associated with the HPA axis. He will refer to these as glucocorticoids, corticoids because they’re from the cortex & gluco because they’re associated with glucose metabolism & we’ll be talking about another one next week called aldosterone but also estradiol & testosterone are also produced there as well though we’re not going to talk about that – there are some pathologies that implicate those hormones. - Now just when we’re feeling comfortable of what the adrenal looks like, no it looks a little different in every species. - This is what we’re used to looking at, this pyramidal shaped structure up here. We’ve just talked about the inside, that is referred to as the chromaffin cells. Here we have the interrenal cells out here. - In shark & boney fish for example, this is quite variable here, but often times depending on the species, they can be divided into 2 different groups, we can have an interrenal gland & sometimes what is called a head kidney which is our chromaffin cells. - In amphibians you have a different arrangement & again in birds. - So really an astonishing array of different morphologies so you don’t get the sense that they all look like this – they really vary considerable & even if you look at the 24 thousand species of bony fish, you will find a fair amount of variability even among the bony fish as well. - Again he just put this in to remind us about this. We talked about this earlier when we talked about the sympathetic nervous system. - What he tried to do was to intercalate some of these slides in here so when we’re flipping through this even though we covered this in an earlier lecture, we can go ah yes that earlier lecture is relevant to this material as well – this is the problem with doing this in a linear fashion. - If you’re really interested you can take a look at the histology. We don’t need to know this, he won’t ask us about it, but when we take a look at the histology, we can see very clearly a difference between the medulla & the adrenal cortex & the type of cells present are fundamentally different. - The key thing to remember is that the cortex is non-nervous tissue & the medulla is nervous tissue. - This is just another figure to show us the loop because the book doesn’t like showing us the loop. - Here we have CRF or CRH, ACTH comes out & then you get the negative feedback. The key thing to remember here is that unlike the reproductive system where the primary feedback mechanisms are acting on GnRH, you do get substantial feedback mechanisms that are acting on the ACTH so cortisol will have quite a strong negative input here & as well as at the CRF level as well. Here is our loop & think about these loops – this is key to all of these. - One of the things he wants to mention: this was a recent definition of stress that came out in the 90s where stress either real or perceived. So stress does not have to be present per se, as long as you think stress is present or you think a stressor is present, that is enough to drive this system. - Okay now that we’ve talked about stress & glucose, we’ll talk about digestion now which is where you get the glucose, well one of the places where you get glucose, & what gets shut down during stress. - He wants to indicate that glucose metabolism during times of stress can be very complex. We didn’t talk about it because we’re supposed to get a fair amount of this in our third year but he’ll just mention it in passing. Glucose could potentially come from free sources. It can come in from ingestion obviously but it can also come from the breakdown of glycogen primarily in the liver. But a third choice is for muscle breakdown & protein breakdown, so muscles, & what that does is to create amino acids & then glucose can be synthesized from amino acids & other such things through a process called glucose neogenesis (new synthesis from other sources). All of those will be regulated really quite differently during that. We’re not talking about that in this class, but there is a fair amount of discussion in 325, the third year course & endocrinology & we’ll probably get it in a number of physiology courses offered through medicine. - Okay we will now move on to digestion. - We can look ahead to chapter 11, & we’ve got a number of pages we can look at. There’s the introduction & things. & a little bit just on the type & acquisition of nutrients. & then integration of digestion with metabolism, we’ll talk a bit about that. So we’re going to be doing a truncated version of this, just to kind of go through the major issues of digestion. - Now there are a number of processes associated with digestion. We might just think yeah, okay so we have a pizza, we digest it or we don’t digest it. But in fact there is a number of processes that are associated with the digestive tract, the gastrointestinal (GI) tract. The mechanisms for these things can be regulated very differently. - So we’ll go through some of these things here. Assimilation is referred to as the process of nutrient acquisition, digestion & absorption. Now one of the interesting things about digestion is food represents an energy source – in fact we all agree with that otherwise why would we eat it? The process of digestion doesn’t seem obvious but it’s to extract that energy from all that food source – the more efficiently we can extract energy from that food, the better off we are. So as we become more complex & as our digestive systems become more specialized & more complex, there becomes a number of different ways to extract that energy in different forms. If we just take a look at this, the gastrointestinal tract is the organ system that is involved with this, as he mentioned it, is contiguous with the external environment & that we’re just modified doughnuts – we’re objects with a hole in the middle so the GI tract is associated with the outside – we can close it off to a certain degree but the reality of it is not every organism is based that way but we are for example. - There are a number of different cell types. We will talk about secretory cells, cells that secrete things; absorptive cells, so cells that are bringing things in; muscle cells because we have to crunch that stuff up, push it along this tube so there are a number of muscle systems associated with it & neurons obviously b/c it is regulated by the nervous system, primarily the autonomic nervous system. - Once assimilation takes place, then we have egestion & this is the excretion of undigested food & other things that get produced down there. - Let’s take a look at energy. - Now the energy content of the diet must match the metabolic demands of an animal – that makes sense right b/c if you eat whatever your budget is, your financial budget for the month, it (income) must equal at least or be greater than the amount of money that you’re spending – certain amount of money that comes in & goes out. If you’re anything like he was when he was an undergrad, he always had less money at the end, he was always spending more than what he was actually making. Now that’s called a debt. By the same token, if you were taking in less food than what you need, then you lose weight that is your debt. We don’t think of it that way, we think of it as a good thing don’t we? - If we take a look at different types of food, we have different energy components to it. For example, proteins & carbohydrates have an energy budget or amount of 4 kcal/gram & fats on the other hand have 9 kcal/gram. We need all of these things – we need carbohydrates, we need proteins & fats. We need all of them. There was a big push when he was in California in the early 90s & everybody was going on these fat-free diets & if you get fat-free everything, like fat-free hotdogs & potato chips, & friend of the Prof put their cats on fat-free cat food. This was really a big thing but what they found was that people were gaining more weight on these fat-free diets & then what was happening when they looked into this was that the feedback was not happening – if you take in a certain amount of fat, you get feedback to the brain saying look, we’ve exceeded our fat intake, we don’t need any more so then you don’t get hungry & there is a series of hormones (we won’t get into it) that regulate fat intake & fat foods, there are hormones that regulate proteinacious foods, & there are hormones that relate to carbohydrates, & each one of those appetites can be controlled independently. What people were doing is they were eating all these fat-free food, but they weren’t getting negative stimulus to the brain that said ‘hey, I’m sated now’ so people kept eating & people were eating more. In terms of his friends’ cats, they looked like little beach balls. - Some food is indigestible or unmetabolizable & energy is lost in the feces or urine. Now some food, indigestible or metabolizable, there is a certain amount, you can eat a certain amount of food & it can be digested to the best of your body’s ability. If you eat too much & you overload your system, a lot of it simply won’t get digested b/c there is just too much & your body can’t cope with it. On the other hand, if you go to places like MacDonald's & you’re having one of their thick shakes, they load it with a thickener, back in the old days it was called carboxymethylcelluloids & they make this milkshake thick, but you can’t digest it so there is a number of things in there. Any kind of plants will have a certain amount of cellulose that we can’t digest. - So there is a certain amount of energy lost in feces & urine & also a certain amount of energy is spent digesting the food because it takes energy to capture the food & it takes energy to chew the food up & grind it up & then digest it so there is a huge chunk of energy associated with attaining energy. & this is referred to as a specific dynamic action (SDA) or heat increment & this is the increase in the metabolic rate during digestion & this is an important source of thermal energy so we need a certain amount of that heat, it’s been argued that this is one of the reasons that the dinosaurs were able to do some of the things they could do, they were thought to be homoeothermic & it’s possible that they had these big digestive systems & some of them had huge stomachs that were very inefficient, but during this release of this heat energy was enough to increase their body temperature – that’s one theory. - Now if we were to break that down, we start off with our gross energy, it’s like our income taxes, this is what he thinks about when he does income tax, we start off with our gross energy, like how much did you grossly get paid? Well I got paid this much. - Okay here's feces, that’s your bills. - A certain amount is lost, we just can’t use it, then this leaves us with the digestible energy & then out of the digestible energy, a certain amount is lost in urine & this is unmetabolizable energy. Now we’re left without metabolizable energy & then a certain amount is lost in heat – heat is really just low graded energy & this is our net energy & this is the energy that is available for use in the body to meet all of our needs. - Now if we look at the digestion, there is a number of different molecular systems, different enzymes, that are associated with breaking down all of these different macromolecular complexes. Now we haven’t spent too much time talking about enzymes – we talked a little bit about kinases & phosphatases but let’s talk about a few other enzymes. - Lipases, we remember phospholipase C right, so lipases in general are things that break down fatty acids, fats & such so the triglycerides & phospholipids & they break them down into shorter chain fatty acids. - Protein & proteases, so lipases for lipids, proteases break down proteins obviously & you take a large protein & chop it up into smaller polypeptides & peptides. - & amylases, this breaks down polysaccharides, so starch for example, into smaller sugar chains, into oligosaccharides. - Here is our carbohydrates, proteins & lipids & then DNA nucleases so there are a series of nucleases tha
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