Lecture 12: Appetite and Eating PDF

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) e...

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