Starting and stopping eating Flashcards
What is the basis for the glucostatic theory? (5)
• 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 and we feel full
• It is logical therefore to presume that blood sugar level may relate to hunger (& satiety)
What was Mayer’s glucostatic theory and the evidence for it?
• 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
– 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)
Why is long term weight regulation is important? (4)
– To maintain fat stores in case of short term food shortages
– Need to change body weight in advance for seasonal variations
• Hibernation
• Migration
• Winter
What is the 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! 5
• 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
What is a 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
Why does the glucostatic model use a set point?
• 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
Why does the lipostatic use a set point?
• 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!
What is leptin?
• 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
What happens when levels of leptin change? (7)
• 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
• Leptin deficient mice become very obese lethargic
• Humans with defective leptin signaling also become obese and this may be reversed with leptin injections
• There is also mice which lacks leptin receptors and are obese but here leptin injections do not work
What rythm does leptin secretion follow?
• Leptin secretion follows a circadian rhythm 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)
How do the glucostatic and lipostatic theories fair? (7)
• 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
What is insulin? (5)
• 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
What do insulin deficiencies result in?
• 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
What are insulin’s effects on appetite? (5)
• 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)
What is cellular glucose metabolism? (5)
• 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 short-term 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 and biological process that lead to eating, satiation and satiety
What are 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)
What is CCK? (6)
Satiating agent
– 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
What 5 criteria does CCK have to meet to be a satiating agent?
• 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!
What is 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
What are CCK (3) and glucagons (1) mode of action?
• CCK appears to work via several routes
– Plasma CCK -> Brain receptors! traverses the BBB
– 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
How is food a satiating agent? (4)
• 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)
What is the effect of fatty food? (6)
• 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 –> weight gain
• 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)
What is the effect of low calorie food? (3)
• 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
What is the effect of nutrient type? What is this effect mediated by?
• 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 intestines vagus nerve connection is cut, then no nutrient type effect is observed, even when nutrients are directly injected into the gut
What is the effect of texture? (7)
• 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)
• 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
What are 5 issues of central mechanisms?
– 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
What was infered from RDs case?
• 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 asatiety center’
• Damage it and the result is hyperphagia (i.e. over eating)
What happens when we do hypothalamic lesions in rats?
• Although such rats appeared to behave normally many demonstrated hyperphagia and became obese/
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
How is VMH a satiety center (4)
• 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
Is there a hunger center?
• 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
What was Stellar’s theory? (4 + 3 problems)
– The VMH is a satiety center
– The LH is a hunger center
– Both centers utilised BSL and body temperature
– These centers worked in conjunction with other brain temp drops when get hungry and go up when eat areas and with other peripheral factors to regulate ingestion
• 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
What do lesions to the VMH and LH also do?
lesions in the VMH and LH as these also clearly alter
– Arousal
– Sensory processing
– Motor behaviour
What are the issues with 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)
– Fibres 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
What are other brain regions associated with feeding related activities?
• 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
How can we use neuropsychology to explore the neural correlates of feeding? (4)
• 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
What do the findings about memory and eating and memory in HM suggest?
– 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)
What is the link between eating and memory? (5)
• 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
• 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
What are the links between neurotransmitters and eating? (5)
• 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
How does 5HT affect eating? (6)
• 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
What does neuropeptide Y do? (7)
– 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
What does intracerebral corticotrophin releasing hormone (CRH) do? (7)
– 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 rats brain)
– Abnormally high CRH levels may result in anorexia
– Abnormally low CRH levels may result in obesity
What does intracerebral corticotrophin releasing hormone (CRH) do? (7)
– 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 rats brain)
– Abnormally high CRH levels may result in anorexia
– Abnormally low CRH levels may result in obesity
What does apolipoprotein A-IV (ap-A-IV) do? (4)
• 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
How do peripheral and central factors interact? (2)
– 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
Who is in control of what I eat? (3)
• 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
– I (i.e., self, conscious, voluntary) control my food intake
• Amnesia data
• Radical control of intake (hunger strikers)
– Here people voluntarily restrict intake to the point of death
• Some people can diet – and keep the weight of long term
What is the boundary model? (8)
• 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
• 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
