Lecture 11/12: Starting and Stopping Eating PDF

Starting and stopping eating 2" Based upon Logue Ch.2! Appetite: The psychology of eating and drinking! 1! So far…! • In the last lecture we looked at a variety of peripheral factors that go towards starting and stopping eating! • We now continue this line of enquiry by focusing first of all on th...

Starting and stopping eating 2" Based upon Logue Ch.2! Appetite: The psychology of eating and drinking! 1! So far…! • In the last lecture we looked at a variety of peripheral factors that go towards starting and stopping eating! • We now continue this line of enquiry by focusing first of all on the consequences of digestion! – Recall that digestion results in breakdown products of the food, the bodies response to those products and the chemicals that assist this process occurring in the blood! • What effect do these have on hunger and satiety?! • Can these contribute to short and/or long term energy regulation?! 2! Glucostatic theory 1! • An important theory of energy regulation was developed by Mayer in the 1950 s! • Glucose (blood sugar) is the primary source of energy used by the brain! • It also provides one (important) source of energy to all other cell types! • Blood sugar level drops before a meal! • Blood sugar level rises rapidly after a meal ! • It is logical therefore to presume that blood sugar level may relate to hunger (& satiety)! 3! Glucostatic theory 2! • Mayer claimed that:! – When BSL was high in Arteries but low in veins we were not hungry! – But when BSL was low in Arteries and low in veins, we were hungry! • Mayer found significant correlations between these differences in BSL and hunger! • We also know:! – If you give an injection of insulin during an inter-meal period (which lowers BSL) hunger ensues! – If you artificially reduce BSL by 50%, this increases caloric intake by 200% (over a control meal)! 4! OK, but…! • Glucostatic theory looks to be a good fit for how the body might maintain its short-term (i.e., daily) energy needs ! • But what about long term regulation of body weight?! • In humans and animals long term weight regulation is important for several reasons! – To maintain fat stores in case of short term food shortages! – Need to change body weight in advance for seasonal variations! • Hibernation! • Migration! • Winter! • How might this system work?! 5! Lipostatic theory! • Lipostatic theory was developed to deal with the need to maintain (or change) long term (strategic) body weight! • The bodies main store of energy for periods when food is not forthcoming is fat! • 1 kilo of body fat is equivalent to about 7800 Kcal! – We are (roughly) around 10% fat, which translates to around 20 or so days of energy! • The key idea here is that the body has what is called a set point…! 6! Set point! • If we move from this set point then the body works to restore things back to that set point! • This set point is not set in stone but may change due to environmental/genetic factors! – Shortening daylight predicting winter and hibernation! – Pregnancy and lactation! – Puberty (fat redistribution)! • This process of maintaining a particular set point is termed homeostasis! • Both lipostatic and glucostatic theories are homeostatic models! • The glucostatic theory is because:! – If BSL drops below the set point, we get hungry and eat which raises BSL! – If BSL rises above the set point, we start to feel full and so stop eating which then allows BSL to fall! 7! Back to fat! • The lipostatic model suggests the body has a set point for fat! • If we gain fat and thus exceed this set point then the body works (or not for various reasons that we will explore later) to reduce weight (fat) and vice versa! • The body appears to use various indicators which signal how much fat there is! • The most important identified so far is the hormone leptin! 8! Leptin 1! • The body has two types of fat cell! – Brown fat cells (used in thermogenesis)! – White fat cells (for storage of fat)! • White fat cell numbers appear to stay relatively static, but they can massively grow as they increase the amount fat stored in each cell! • White fat cells secrete leptin into the blood! • The bigger the fat cell the more leptin it secretes! • Thus leptin is a marker for fat store levels (see right)! 9! Leptin 2! • Increasing levels of leptin are associated with ! – Inhibition of hunger (you don’t feel hungry) ! – Stimulation of satiety (you feel full faster)! • During fasting/dieting leptin levels may drop markedly stimulating appetite! • Paradoxically, leptin levels may be elevated in the morbidly obese - but this no longer appears to moderate appetite (possibly leptin resistance?)! • Leptin receptors have been identified in the hypothalamus, which is a key brain area involved in regulating appetite! 10! Leptin 3! • Leptin deficient mice (the ob/ob mouse) become very obese (see right)! • Humans with defective leptin signaling also become obese and this may be reversed with leptin injections! • There is also the db/db mouse, which lacks leptin receptors – this too is obese, but here leptin injections do not work! 11! Leptin 4! • Leptin secretion follows a circadian rhythm (see right) suggesting that it may also impact on short term energy intake! • It is highest at night and lowest during the day and early evening! • Note the relationship to diary studies of eating time and to Night Eating Disorder (where it is shifted rightwards)! 12! And how do these theories fair?! • Lipostatic theory has held up well! • As for the glucostatic theory, this has run into various problems…! – A/V BSL ratio does not always correlate well with hunger (the decline effect)! – Diabetics can have high BSL but still feel very hungry! – Alternate indicators (on which to base the set point) have been sought ! • Insulin has been suggested as one candidate! • Metabolism of glucose in hypothalamic cells is another! 13! Insulin 1! • Insulin is a hormone released by cells in the pancreas that primarily regulates carbohydrate (glucose) metabolism! • Insulin forces liver and muscle cells to store glucose in an inactive form called glycogen! – Clusters of around 20,000 glucose units (plant equivalent is starch)! • It also has a range of other metabolic effects such as promoting the uptake of blood lipids into fat cells! • BSL is closely regulated and insulin is of key importance in this process! • Abnormalities in BSL regulation (due to lack of insulin) can be both fatal and have long term adverse effects if not managed appropriately! 14! Insulin 2! • The absence of insulin produces a disorder called Type I diabetes, with high BSL and complications such as neuropathy, ulcers (amputation), blindness, renal failure and heart disease! • A second type of diabetes, which used to be relatively rare and is now very common, which can produce similar long term complications if not properly managed, is called Type II diabetes! • In this case there is plenty of insulin but cells become insensitive (i.e., resistant) to it! • The occurrence of Type II diabetes is strongly linked to body mass! 15! Insulin 3! • Insulin’s effects on appetite are quite complex! • Artificially raising insulin levels before a meal can trigger hunger ! – Here cues to food (e.g., smelling it) produce a preparatory response, in which the body prepares itself to receive an influx of nutrients! • This includes release of insulin and feelings of hunger! • It also leads to a transient fall then increase in BSL! • Artificially raising levels of insulin during a meal can reduce food intake! – This is seemingly paradoxical as lower BSL should trigger food intake! – However, rising insulin levels normally signal the body dealing with an influx of nutrients – thus indicating the need to end a meal! • Insulin may be one index of the bodies current energy needs (but equally insulin’s link to appetite could be learned…)! 16! Cellular glucose metabolism! • A further potential marker for short-term energy needs may be glucose metabolism within cells in the hypothalamus! – These cells are exposed to circulating glucose and to insulin! – If glucose metabolism is disrupted in these cells using 2DG this produces hunger! • It is plausible (indeed likely) that several biological systems monitor current energy needs, but whether they control shortterm food intake as the glucostatic theory states seems unlikely! • While biological systems may be crucial at the extremes, in normal day-to-day situations, it may be a combination of multiple psychological (as per the last lecture) and biological process that lead to eating, satiation and satiety! 17! Satiating agents! • One class of biological signals that may be important in satiation and satiety involve digestion! • Food moves from the stomach to the small intestine! • A proportion of this movement occurs during ingestion, suggesting that events in the small intestine could influence satiation! • For example, over the period in which one eats a liquid meal (soup) 40% leaves the stomach during the filling period (ingestion)! • Thus signals from the small intestine could contribute to satiation (i.e., ceasing eating)! 18! Satiating agents - CCK! • One such signal is Cholecystokinin (CCK)! • It is:! – Released by the gut (small intestine) as food moves in from the stomach and by tension in the stomach wall! • Physiologically CCK stimulates the gall-bladder to contract! – Its primary function is too contract the gall bladder! – The more CCK released the slower the stomach empties (affects the pyloric sphincter)! – Higher protein and fat levels increase CCK release! – Elevating CCK levels in rats reduces food intake suggesting a role in satiety! • This is true for both intact and sham feeding animals! 19! Satiating agents - CCK! • To establish whether CCK (or any other pharmacogenic agent) is involved in satiety under normal circumstances we need to meet 5 criteria:! – – – – – The agent must be released during feeding! Exogenous administration must affect feeding! Exogenous dose must match endogenous dose! The agent should act and clear rapidly! The effect should not be due to other causes (i.e. CTA)! • CCK in fact meets all of these criteria! 20! Satiating agents - Glucagon! • A further satiating chemical is Glucagon! – Glucagon (a peptide) is released by the pancreas and acts to increase the level of blood glucose. It has been described as having the opposite effects to insulin! • Glucagon stimulates the breakdown of glycogen in the liver, releasing glucose! • Glucagon instigates the conversion of proteins into glucose! – Glucagon is released shortly after feeding starts (i.e. a conditioned reflex) and both people and animals reduce food intake when extra glucagon is injected! 21! CCK & Glucagon - mode of action! • CCK appears to work via several routes! – Plasma CCK -> Brain receptors! – CCK binding to vagus nerve (brain [hypothalamus])! – Plasma CCK -> Liver function! • Glucagon also appears to exercise its satiating effects via the liver! – Damage to the glucagon receptors in the liver eliminates its satiating effects! • I want to foreshadow here the link between peripheral and central controls of appetite, so notice how this applies to CCK! 22! Food as a satiating agent! • The type of food one eats also has an impact on feelings of hunger and fullness! • Foods vary in several ways:! – Caloric density! • 1 gram of fat = 9 Kcals vs 1 gram of sugar = 4 Kcals! – Nutrient type! • Fat, carbohydrate, protein and fibre! – Texture (solid [soft vs crunchy] or liquid)! • To what extent do these variables influence intake?! 23! Fatty food! • In the short term fatty food reduces intake! • However, with long term exposure to fatty diets this effect dissipates and may even lead to enhanced intake! • This may occur via! – Insensitivity to satiety signals in the gut/stomach! – Faster gastric emptying! – More rapid absorption of fat! • Thus the gut/stomach may adapt to such diets (think of the consequences) ! 24! Low calorie food! • People tend to eat more of a low calorie food! • After exposure to its consequences, they will tend to eat more still! • This may be mediated by associative learning! – That is a particular flavour becomes associated with low calories and thus that flavour comes to signal that more needs to be eaten! 25! Nutrient type! • Calorie for calorie, protein based food is more filling than carbohydrate food! • This effect appears to be mediated by the small intestine! – Filling the stomach with saline vs liquid food exerts the same effect on satiety, suggesting that the stomach is perhaps insensitive to nutrient type! – However, if the small intestine s vagus nerve connection is cut, then no nutrient type effect is observed, even when nutrients are directly injected into the gut! 26! Texture I! • Calorie for calorie, eating solid food is more satiating than liquid food! • This may result from! – Rate of gastric emptying (faster for liquids)! – Stomach stretch/tension receptors (less for liquids because of faster emptying)! – Speed of contact between nutrients and digestive processes (faster for liquids)! 27! Texture II! • The crunchiness of ones diet is associated with body weight! – Crunchier diets are linked to lower body weights, softer to higher! • Crunchier diets require more chewing, which generates a slower eating rate and this is associated with greater satiety! – This was taken to extremes by Horace Fletcher’s (see below) 1870’s fad diet, where each mouthful had to be chewed 100 times! 28! Summary and conclusion! • We have now completed our review of peripheral factors! • As I noted at the start there are a myriad of different peripheral factors governing intake! • What then should we conclude?! – Need to consider short (glucostatic type theories) vs long term (lipostatic type theories) effects - with lipostatic theory much better supported! – Predominance of psychological factors for short-term energy intake control! – Need to consider redundancy - a lot of it! – Need to consider interaction between peripheral and central systems! ! 29! Starting and stopping eating 3" Based upon Logue Ch.2! Appetite: The psychology of eating and drinking! 30! Central mechanisms! • The previous two lectures in this series have concentrated on peripheral factors, we now turn to look at the role of the brain! • We will examine five issues here:! – – – – – Putative hunger and satiety centers in the brain! Neurochemicals that modulate appetite! Interaction of peripheral & central mechanisms! The issue of conscious control of appetite! General models of appetite control! 31! The case of RD ! • Interest in central control of eating was initially triggered by cases such as RD! – RD was a 12 yr old boy who became rapidly obese! – His neurological condition started to deteriorate (blindness)! – Surgery was undertaken to remove a cyst! – The cyst had been pressing on his hypothalamus! – Once the cyst was excised he improved! 32! Craniopharyngioma! • RD had a craniopharyngioma! • These constitute around 9% of all childhood brain tumours! • Children with such tumours typically present with either severe obesity or emaciation (along with other symptoms seizures etc)! • Following surgery to remove the tumour (typically around the hypothalamus) the hypothalamus may be permanently damaged! • Permanent damage is associated with lifelong problems with weight regulation! • If the hypothalamus is spared, then patients weight may return to normal! 33! Tumours continued…! • The inference from cases like RD’s was that the hypothalamus must be involved in weight regulation! • Moreover, the hypothalamus might be home to various ‘centers’! • In the case of RD, his tumour may have affected a satiety center’! • Damage it and the result is hyperphagia (i.e. over eating)! 34! Hypothalamic lesions! • Hetherington & Ranson (1940) were amongst the first to investigate what effect gross lesions of the hypothalamus had on rats eating behaviour! • Although such rats appeared to behave normally many demonstrated hyperphagia and became obese! 35! Was it the hypothalamus?! • By locating the lesion sites on p.m. they determined that lesions in the Ventro Medial Hypothalamus (VMH) were best at inducing hyperphagia (crudely – remove brake)! • Other groups then determined that electrical stimulation of the VMH (i.e. activating it) inhibited eating (crudely - apply brake)! • The imputation of this was that the VMH was a satiety center! 36! VMH as a satiety center! • Certain cells in the VMH are sensitive to blood sugar level (insulin/cellular metabolism) ! • If these cells are destroyed then the result is hyperphagia! • If the other parts of the VMH are destroyed then the impact on feeding is far less severe! • This appears to link in with the Glucostatic theory (and its descendants)! 37! A hunger center?! • Scientists then inferred that if there was a satiety center what about a center to initiate feeding?! • A candidate soon emerged, another nucleus of the hypothalamus called the Lateral Hypothalamus (LH)! • If this structure is lesioned rats die of starvation - they just do not eat (crudely – remove accelerator)! • Similarly if the LH is stimulated (i.e. made active) this induces rats to eat (crudely – apply accelerator)! • Recall also that some patients with tumours infiltrating or pressing on the hypothalamus present with severe emaciation! 38! Stellar s theory! • These findings led Elliot Stellar (1954) to propose…! – – – – The VMH is a satiety center (crudely – the brake)! The LH is a hunger center (crudely – the accelerator)! Both centers utilised BSL and body temperature! These centers worked in conjunction with other brain areas and with other peripheral factors to regulate ingestion! ! 39! And now…! • Whilst a lot of evidence has been accumulated that is favourable to this general model (e.g. vagus activity to VMH and LH) it is not without its problems! • These can be divided into three major issues! – Is only the target behaviour affected! – Are the lesions only affecting the VMH/LH! – The role of other brain areas! 40! Target behaviour! • If we lesioned the visual cortex (effectively blinding the animal) we would find that the animal could not navigate its way round a maze very well! • Would we then conclude that the visual cortex is the brain center for maze learning?! • Very similar issues are raised by lesions in the VMH and LH as these also clearly alter! – Arousal! – Sensory processing! – Motor behaviour! 41! Lesion location! • Early lesion techniques were crude! • We have to distinguish between at least two major effects that a specific lesion might have! – Site specific damage (what the investigator wants)! – Fibre s of passage damage (what they do not want)! • It turns out that lesions which are restricted solely to the VMH (excepting cells sensitive to BSL) are far less effective at producing hyperphagia than non-specific lesions! 42! Other brain areas! • Stellar never envisaged that the hypothalamus was the control center for eating behaviour! • Evidence from neuropsychology and neuroimaging confirm this! • Neuroimaging of feeding is very hard! – One procedure is to scan participants whilst hungry and then again when sated and ask them to imagine eating in each state! – When hungry, the scans indicate activation in the hypothalamus (as we might expect), but also in the amygdala and insula cortex! – When sated, activity is observed in the OFC and in the amygdala! • More recent studies show many additional brain areas are involved in feeding-related activities! – These include the hippocampus, the temporal lobes, the anterior cingulate cortex, amongst many others! 43! Neuropsychology! • Another way to explore the neural correlates of feeding is neuropsychology! • Damage to several other brain areas may produce very unusual patterns of eating behaviour! • • • • Dense amnesia (temporal/hippocampal origin) and over-eating! The amygdala (Kluver-Bucy syndrome)! The orbitofrontal cortex – rare to find specific lesions! Frontal lobe damage in general (disinhibition - over eating)! • The consequence of such lesions are worth examining ! – They can aid understanding the function of specific brain regions! – Damage to certain brain areas raise important issues biological models of eating (i.e., eating is controlled automatically by biological signals rather than consciously by exercise of will)! – Amongst these the effects of hippocampal damage are of special interest! 44! Eating & Memory I! • Recall that HM had a dense anterograde amnesia (i.e., an inability to encode new episodic memories post-injury) resulting from experimental surgery for epilepsy! • HM was reported to have eaten a second meal only 1 min after finishing a first! • He even started on a third, before commenting that perhaps he was a ‘little of his food today’! • HM showed no change in self-reports of hunger or fullness, although his hypothalamus and bodily appetitive control systems were completely intact! 45! Eating & Memory II! • These findings from HM raise some important issues! – They suggest that the control of eating may be under far greater cognitive (i.e., voluntary or conscious) control than scientists believed! • Indeed - as noted before - ALL of his biological systems to regulate food intake were working – so why didn’t they stop him eating a second full meal?! • This would imply that short term eating may not be under strong biological control, a conclusion we were edging towards after reviewing the periperhal factors affecting food intake! – They suggest that cognition may be important for:! • Calibrating how much to eat now based upon what we know we have eaten before! • Basing our sense of hunger and fullness on what we recall having eaten (or not)! 46! Eating and memory III! • Recognising the importance of these findings from HM, a number of groups have further explored the effects of hippocampal damage on eating! – Two amnesiac patients readily ate a second full meal 10-30 minutes after the first! • There reasons for stopping eating never included any explicit mention of having eaten just before! • They typically indicated that they just did not want anymore food! – Control participants (who were brain injured, but not amnesiac) never consumed a second meal and reacted with incredulity when offered the same meal again! 47! Eating and memory IV! • Memory is clearly important in normal individuals, when it comes to food intake! – Getting people to recall what they have eaten reduces food intake! – Distracting people so that they can not fully recall what was being eaten can increase food intake on a later meal! – The amount you believe you have eaten is more important in determining how hungry/full you will feel later than the amount you actually ate! – The hippocampus can also exhibit state-dependent inhibition! • This means when you are full the hippocampus inhibits retrieval of pleasant food related memories (if you see or smell food), reducing the desire to eat! 48! Eating and memory V! • Unfortunately we do not know exactly what the hippocampus does in regards to regulating food intake, although the material on the preceding page suggests some possible roles! – This is not simply an academic problem as diets that are rich in saturated fat and added sugar (Western style diets) selectively damage the hippocampus! • Years of animal data support this view (and indicate causality)! • Human data also support it! – Neuroimaging in elderly participants! – Hippocampal dependent learning and memory in healthy young adults and children! 49! Neurochemicals! • Another significant focus of research has been on neurochemical modulation of appetite! • This is a very important area of research because of its potential for drug development in the treatment of obesity and anorexia! • We will look at two classes of neurochemical! – Neurotransmitters (which affect single neurons)! – Neuromodulators (which affect groups of neurons)! 50! Neurotransmitters! • Several lines of evidence suggest that raising levels of Serotonin (SE) and/or Dopamine (DA) inhibits eating! • In particular raising levels of SE & DA in the LH reduces meal size! • Raising levels of SE & DA in the VMH reduces meal frequency! • Many drugs used in psychiatry affect DA (neuroleptics) and SE (antidepressants), so it is no wonder that weight disturbances are a common side effect of their use! • Serotonin is of special interest as many of the more recent weight-loss drugs have targeted this neurotransmitter system! 51! Serotonin! • Serotonin (increases) may induce satiation and satiety both centrally and peripherally (e.g., gut receptors)! • It exerts its effect in at least three ways:! – By reducing meal size! – By reducing meal frequency! – By reducing eating rate! • It may accomplish this via retarding motor behaviour connected with ingestion as well as affecting feelings of fullness! • Serotonergic agonists were recently used as effective dieting drugs (fenfluromine & phentamine), but had to be withdrawn because of problematic side-effects! 52! Neuromodulators I! • Neuropeptide Y (NY)! – Increase in the Hypothalamus increases eating! – Protracted increases lead to obesity! • Presence of nutrients in the gut leads to the release of the protein PYY leading to a central suppression of NY (decreasing eating)! • Stomach cells secrete grehlin prior to a meal and reduce secretion after a meal. Grehlin enhances NY production in the hypothalamus (increasing eating)! • Gut bypass surgery affects release of grehlin and PYY, leading to reduced NY in the hypothalamus (decreasing eating)! • Knockout mice who lack the NY gene are normal. This indicates an evolutionary strategy to ensure multiple redundant systems for initiating feeding (i.e. the body relies upon multiple systems to initiate eating)! • It also suggests NY is short term regulatory agent! 53! Neuromodulators II! • Intracerebral corticotrophin releasing hormone (CRH)! – – – – – Appears to alter set point of body weight! Receptors in the hypothalamus for CRH! CRH levels are regulated by leptin! More leptin results in more CRH! More CRH translates into reduced food intake (when injected into a rat s brain)! – Abnormally high CRH levels may result in anorexia! – Abnormally low CRH levels may result in obesity! 54! Neuromodulators III! • Apolipoprotein A-IV (ap-A-IV)! • Increase associated with reduced appetite! • Ap-A-IV is a component of chylomicrons, bubble like structures which carry fat across the intestinal wall into the blood stream! • Thus the presence of ap-A-IV in the blood (and its level) may indicate the nutrient density of food! • The brain has ap-A-IV receptors and also appears to manufacture ap-A-IV centrally too! 55! Interaction of periphery & CNS! • We have now completed our review of central and peripheral mechanisms! • The next step is to consider how the peripheral and central mechanisms interact! • We have already examined several examples of this (viz the neuromodulators, NY, CRH and ap-A-IV) and there are many others…! – Fat & Paraventricular nucleus of the Hypothalamus! • High levels of leptin (an index of body fat) alter function of PVN cells reducing food intake! – CCK - Vagus - VMH! • CCK released in the intestine affects vagal function and hence activity in the VMH reducing food intake! 56! Who is in control of what I eat?! • There are three basic answers! – Environmental variables unconsciously influencing food intake! • E.g., Portion size, people, TV etc etc! – Biological variables unconsciously influencing food intake! • E.g., Lipostatic theory, CCK, neuromodulators etc etc! – I (i.e., self, conscious, voluntary) control my food intake! • Amnesia data – anything else?! • Radical control of intake (hunger strikers)! – Here people voluntarily restrict intake to the point of death! – Historically used as a form of social protest in Ireland & India ! » » » » Bobby Sands an IRA prisoner at the Maze! Ghandi (twice)! More recently at Guantanamo bay! Hunger strikers last on average around 40 days (70 tops)! • Some people can diet – and keep the weight of long term! • How do we reconcile these three?! 57! Boundary model! • The first possibility is the boundary model (Herman & Polivy)! • This presumes that most of the time eating behaviour is controlled by psychological and environmental variables! • But biological (physiology) provides the boundary conditions, that is:! • If we starve ourselves we start to get very uncomfortable! • If we really overeat we start to get very uncomfortable! • Boundary model extends to disordered eating (bingeing - changing satiety boundary; anorexia - changing hunger boundary! 58! Extending the boundary model! • We can extend the boundary model by thinking about short and long term control of energy intake! • Biology may set the boundaries for both short and longterm intake control ! – For both, our biology may make it easier to over-eat than to under-eat, and to gain weight rather than to lose it! • Within the ‘boundary’ of short-term energy regulation we might also think that involuntary/automatic influences may be more important than conscious control! • And that is about as close as we will get to any sort of grand model of food intake control! 59!