~+__'''Obesity and the brain'''__+~ Hadar Zutta Annelise Svindland Verity Walsh <> = Introduction = Obesity is defined as an excess of body fat. A good indication of body fat content is body mass index (BMI) BMI= Kg/height m2. BMI over 30 kg is defined as obese. The problem with this method is that it doesn't take into account large muscle mass and doesn't measure direct adiposity so the best way to define obesity is the percentage of total body fat, 25% or greater in men and 35% or greater in women is classified as obese (The Textbook of Medical Physiology, Arthur C.Guyton). When appetite evokes a caloric intake above the metabolic use of the calories obesity results (page 530,Patho physilogy adaptations and Alterations in Function Barbra L. Bulloch). Food intake is regulated by neural centers, craving for food is a hunger sensation and the desire for food is appetite, normally a certain type. A satisfaction after the search and consumption of food is called satiety both the hunger and satiety center are contained in the hypothalamus of the brain. Control of food intake is participated in by several neuronal centers of hypothalamus (Figure 1). Feeding centers are the lateral nuclei of the hypothalamus and stimulating them cause's animal to eat greedily (hyperphagia). The lateral nuclei operates by exciting motor drive to look for food. The satiety centers are located on the ventromedial nuclei of the hypothalamus and gives nutritional satisfaction that inhibits feeding center. Complete satiety (aphagia) can be caused by electrical stimulation of the region. (Textbook of Medical Physiology, page 868, Arthur C. Guyton). {{attachment:hypothalamus.jpg|alt text|height="400"}} '''Figure 1: Hypothalamic nuclei''' (adapted from Textbook of Medical Physiology, page 733, Arthur C. Guyton) = Factors influencing food intake = == Stimulating or inhibiting neurons and neurotransmitters of hypothalamus == In the arcuate nuclei of the hypothalamus there are two important types of neurons that control appetite and energy expenditure (Figure 2) 1)Pro-opiomelanocortin (POMC) neurons producing alpha- melanocyte-stimulating hormone (α-MSH) and cocaine-, and amphetamine-related transcript (CART) 2)Orexigenic neurons producing neuropeptide Y (NPY) and agouti-related protein (AGRP) POMC neurons activation decreases food intake and increases energy expenditure, while the NYP-AGRP neurons increase food intake and decrease energy expenditure when activated. These neurons act as targets for the actions of hormones regulating appetite, for example, leptin, insulin, cholecystokinin (CCK) and ghrelin. α-MSH released from POMC neurons acts on melanocortin receptors (MCR, found in neurons of paraventricular nuclei). MCR has at least 5 subtypes, but the most important for regulating food intake and energy balance are the MCR-3 and MCR-4. Food intake is reduced when these receptors are activated and energy expenditure increased. Inhibition of these receptors increases food intake and decreases energy expenditure. The MCR activation to increase energy expenditure is regulated by activation of neuronal pathways. Energy stores of body are regulated by hypothalamic melanocortin systems, and extreme obesity is associated with defective signalling of the melanocortin pathways. MCR-4 mutations are most common single gene cause of human obesity. A natural antagonist of MCR-3 and MCR-4 is AGRP, released from the orexigenic neurons of the hypothalamus. It inhibits the effects of α-MSH to stimulate the MCR, therefore increases feeding. Due to gene mutation, excessive formation of AGRP in mice and humans is associated with excessive feeding and obesity. NPY is also released from orexigenic neurons of arcuate nuclei. Orexigenic neurons are activated to release NYP which stimulates appetite when energy stores of the body are low. Simultaneously activity of the POMC neurons decreases, therefore reducing their activity of the melanocortin pathway and further stimulating appetite. {{attachment:food intake.jpg|alt text|height="400"}} '''Figure 2: Feedback mechanisms for control of food intake''' (adapted from Textbook of Medical Physiology, page 868, Arthur C. Guyton) == Leptin == When we talk about obesity and the relationship with the brain, it is important to mention Leptin, which is one of the main factors when it comes to obesity. Leptin is secreted from the adipocytes in the adipose tissue. It is a peptide hormone, which plays a very important role in the regulation of energy intake and energy expenditure in the body. It also has an important role in food regulation. (Physiology Of Domestic Animals,pages 232-233, Øystein V.Sjaastad) Energy intake is food intake, and is negatively affected by leptin. The hormone works mainly on the hypothalamus through its receptor, OB-R (obese-receptor). Here it provides the central nervous system with information about the energy stored in the body, and in this way, helps the brain to establish energy homeostasis in the body. Energy homeostasis means that there is a balance between the energy coming in, the energy being used and the storage of energy. If there would be a leptin deficiency, the amount of energy stored would increase, and by this the body fat. In the body, the plasma concentration of leptin is different in the obese then in the lean individuals. Obese animals have a higher concentration of leptin. This is due to the relationship between plasma leptin concentration and body fat. If body fat decreases, so will the concentration of leptin. (Leptin access into the brain: A saturated transport mechanism in obesity,Bartolome Burguera) In these individuals, leptins effects are inhibited, leptin resistance occurs due to the high plasma leptin level. In other words, lack of leptin will lead to obesity. (Leptin Resistance and Obesity, Pablo J. Enriori). The way leptin accesses the brain, is by passing across the blood-brain barrier (BBB). And in this way it can reach the appetite center of the hypothalamus, and affect the food intake, by inhibiting it. The passing of leptin through the BBB is an important step in the regulation, and several pathways have been studied. (Leptin access into the brain: A saturated transport mechanism in obesity, Bartolome Burguera) From this information, we can see that leptin is a key hormone when it comes to the regulation of food intake, and that the deficiency of it can lead to obesity. == Reward Centre; “wanting” and “liking” == Food Reward; is a process which contains “liking” (hedonic impact), “wanting” (incentive motivation) and learning (associations and predictions). Hedonic hotspot; a neurochemically stimulated specific brain site that amplifies pleasurable “liking” reactions. “Liking”; mainly generated by subcortical brain systems, a hedonic reaction detected in neural signals and behaviour. “Wanting”; a motivation for reward evoked by reward cues. The brain mesolimbic systems are important to “wanting”, especially ones involving dopamine. The brain reward mechanisms influence the food we eat, how much we eat and how often by generating “liking” and “wanting” sensations for food. It is thought that this maybe one of the causes for rising obesity. The “liking” mechanism contains hedonic circuits that connect together hotspots in the forebrain limbic structures e.g. nucleus accumbens and ventral pallidum. “Wanting” mechanism has larger opioid networks in nucleus accumbens, striatum and amygdala. They also have mesolimbic dopamine systems and corticolimbic glutamate signals that interact. Foods we like have motivational power, the sight or smell of the food may entice us to eat, and even a small amount of the food can trigger us to eat more. It’s not the food or cue that influences us to eat, it’s the brains response of the perceiver’s to the stimuli. If temptations themselves arise in the brain they themselves can stimulate a sudden urge to eat without food being physically in front of us (temptation or pleasure of sweet, fatty or salty foods). The temptations evoke “liking” and “wanting” reactions which are generated by neural signals that associate desire or pleasure with the sensation. The Brain Reward Centre in Growing Obesity Rates; Modern temptations to eat and to not stop are stronger than they were in the past because of the excess of sugar, fat and salt in modern food. The traditions that used to limit snacking no longer exist so more food is consumed outside of meals. Portion sizes are more likely larger than recommended which means we eat more than we should in one meal. These trends may play into normal basis of brain reward system and let us succumb to desire and eat more. Both the brains “liking” and “wanting” mechanisms are stimulates by food cues. Satiety influences can diminish the ‘go systems’, however, no strong stop signal is ever generated to stop intake, only subdue the ‘go’ signal. Potential Roles of Brain Reward Systems in Obesity; Obesity has different underlying causes which vary from individual to individual. Classification and types of overeating; •Reward Dysfunction; Food reward functions if go wrong can lead to over eating. Reward dysfunction can cause foods to be hedonically “liked” too much. Individuals can “like” and “want” food more than average person as excessive activation “liking” substrates would increase the hedonic impact of the foods. This can be a cause of excessive (binge) eating and obesity. “Wanting” to eat alone can be another possibility for overeating. Smell sight or vivid imagination of food can be a trigger for compulsion to eat. •Passively Distorted Reward Function; The initial cause of distorted to eating maybe not be the brain reward system, but its function can be abnormally passive. The mechanism for “liking” and “wanting” may try to function as normal but in studies the neuroimaging appears abnormal. •Normal Resilience in Brain Reward; The cause can lie completely outside of the brain reward system , the brain reward system continues to work normally in cases of obesity and over eating.(Kent C.Berridge ''The tempted brain eats: Pleasure and desire circuits in obesity and eating disorders.'') == Stress as a promoter of eating intake == Stress promoters triggers eating palatable food in about 30% of the population. The assumption is that eating during stress acts as a hedonic self-medication for suppressing the stress. The suggested mechanism for this phenomenon is the CRF (corticotropic releasing factor) effect. In case of stress the brain releases CRF which causes an aversive state which triggers the need to eat comfort food as a self-medication. The effect of sugary food results in decreased HPA (hypothalamic-pituitary-adrenal)sensitivity and lower basal level of the CRF after stress. Blockade of CRF receptors may increase the uptake of less palatable food while decreases the intake for sucrose. On the other hand in the case of the central nucleus of amygldala where in the case of experimentally induced elevations of CRF level results in a decrease of ingestive behaviour and food intake. An explanation for this is certain regions of the brain where the effect of stress and CRF are expressed in "wanting" food without needing an aversive state to trigger the eating, seen in the nucleus accumbens where CRF microinjections triggers a "wanting" feeling for sugar by multiplying the motivational potency of sugar. It has been proven that not only distress triggers a "wanting" sensation but also incentive motivation does in the same CRF incentive mechanism. == Treatment of Obesity == The energy input must be decreased below the energy expenditure if a long term weight balance is to be obtained and sustained. For this to happen, a person seeking weight lose must either decrease the number of calories consumed and/or increase the amount of exercise being done. Drugs can be used to combat obesity, the most common of which is amphetamines which will inhibit the feeding centres of the brain. Another treatment for obesity is surgical procedures, most used are the gastric bypass and the gastric band surgeries. (Textbook medical physiology, Arthur C.Guyton. Page 868-870). = Conclusion = Many factors in the brain influence food regulation. It is evident that the brain, especially the hypothalamus, plays a huge role in the cause of obesity. The growing rate of obesity has many causes: genetic mutations (MCR-4 mutations), modern temptations that entice us to eat and the stresses of modern times which causes us to eat to self-comfort and reduce stress level. Obesity is one of the growing health concerns of the twenty first century, with many drugs and surgical producers to combat it. However, the best treatment is the oldest one, healthy eating and plenty of exercise leads to a happy body and mind. = References = Øystein V.Sjaastad, Knut Hove, Olav Sand. ''Physiology Of Domestic Animals'' (First edition, 2003). Page 232-233. Barbara L. Bullock, Pearl Philbrook Rosendahl. ''Patho physilogy adaptations and Alterations in Function'' (1984). Page 530. Arthur C.Guyton, John E.Hall. ''Textbook of Medical Physiology'' (11th edition, 2006). Page 860 and 868-872. Bartolome Burguera,Marta E. Couce. ''Leptin access into the brain: A saturated transport mechanism in obesity.'' (Volume 74, issues 4-5, 12. November 2001. Page 717-720). http://www.sciencedirect.com/science/article/pii/S0031938401006151 Kent C.Berridge, Chao-Yi Ho, Jocelyn M.Richard, Alexandra G. !DiFeliceantonio. ''The tempted brain eats: Pleasure and desire circuits in obesity and eating disorders.'' (Volume 1350, 2. September 2010. Neural Mechanisms of Ingestive Behaviour and Obesity. Page 46-64). http://www.sciencedirect.com/science/article/pii/S0006899310008115 Pablo J. Enriori, Anne E. Evans, Puspha Sinnayah, Michael A. Cowley. ''Leptin Resistance and Obesity''. Published online 6. September 2012. (Volume 14, Issue S8, Neurobiology of Obesity. Page 254S-258S. August 2006). http://onlinelibrary.wiley.com/doi/10.1038/oby.2006.319/full