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Contents lists available at ScienceDirect

Progress in Neurobiology journal homepage: www.elsevier.com/locate/pneurobio

Obesity – A neuropsychological disease? Systematic review and neuropsychological model Kamila Jauch-Chara *, Kerstin M. Oltmanns Department of Psychiatry and Psychotherapy, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany

A R T I C L E I N F O

A B S T R A C T

Article history: Received 10 December 2012 Received in revised form 26 November 2013 Accepted 8 December 2013 Available online xxx

Obesity is a global epidemic associated with a series of secondary complications and comorbid diseases such as diabetes mellitus, cardiovascular disease, sleep-breathing disorders, and certain forms of cancer. On the surface, it seems that obesity is simply the phenotypic manifestation of deliberately flawed food intake behavior with the consequence of dysbalanced energy uptake and expenditure and can easily be reversed by caloric restriction and exercise. Notwithstanding this assumption, the disappointing outcomes of long-term clinical studies based on this assumption show that the problem is much more complex. Obviously, recent studies render that specific neurocircuits involved in appetite regulation are etiologically integrated in the pathomechanism, suggesting obesity should be regarded as a neurobiological disease rather than the consequence of detrimental food intake habits. Moreover, apart from the physical manifestation of overeating, a growing body of evidence suggests a close relationship with psychological components comprising mood disturbances, altered reward perception and motivation, or addictive behavior. Given that current dietary and pharmacological strategies to overcome the burgeoning threat of the obesity problem are of limited efficacy, bear the risk of adverse side-effects, and in most cases are not curative, new concepts integratively focusing on the fundamental neurobiological and psychological mechanisms underlying overeating are urgently required. This new approach to develop preventive and therapeutic strategies would justify assigning obesity to the spectrum of neuropsychological diseases. Our objective is to give an overview on the current literature that argues for this view and, on the basis of this knowledge, to deduce an integrative model for the development of obesity originating from disturbed neuropsychological functioning. ß 2013 Elsevier Ltd. All rights reserved.

Keywords: Body weight regulation Psychosocial stress Depression Addiction Reward centers

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conventional models of obesity genesis . . . . . . . . . . . . . . . Excessive food intake and lack of physical activity . 2.1. 2.2. Genetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Current clinical therapy regimens. . . . . . . . . . . . . . . . . . . . Reduction of energy intake. . . . . . . . . . . . . . . . . . . . 3.1. Diet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Pharmacotherapy. . . . . . . . . . . . . . . . . . . . 3.1.2. Bariatric surgery . . . . . . . . . . . . . . . . . . . . 3.1.3. Boosting energy expenditure . . . . . . . . . . . . . . . . . . 3.2. Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Caffeine and ephedrine . . . . . . . . . . . . . . . 3.2.2.

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Abbreviations: ACC, anterior cingulate cortex; ACTH, adrenocorticotropin; ATP, adenosinetriphophate; BMI, body mass index; BT, behavioral therapy; cAMP, cycliccadenosine monophospate; CBT, cognitive behavioral therapy; CREB, cyclic AMP response element binding; CRF, corticotrophin-releasing factor; CRH, corticotropin-releasing hormone; DLPFC, dorsolateral prefrontal cortex; DSM, Diagnostic and Statistical Manual of Mental Disorders; FTO, obesity-associated gene; GLUT, glucose transporter; HPA axis, hypothalamus–pituitary–adrenal axis; LH, lateral hypothalamus; LTD, long-term depression; LTP, long-term potentiation; NA, nucleus accumbens; NHANES, National Health and Nutrition Examination Survey; NPY, neuropeptide Y; PCr, phosphocreatine; PFC, prefrontal cortex; tDCS, direct current stimulation; TMS, transcranial magnetic stimulation; VMH, ventromedial nucleus of hypothalamus; VTA, ventral tegmental area; WHO, World Health Organization. * Corresponding author. Tel.: +49 0451 500 6342; fax: +49 0451 500 3480. E-mail address: [email protected] (K. Jauch-Chara). 0301-0082/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pneurobio.2013.12.001

Please cite this article in press as: Jauch-Chara, K., Oltmanns, K.M., Obesity – A neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. (2014), http://dx.doi.org/10.1016/j.pneurobio.2013.12.001

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3.3.

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Behavioral therapeutic concepts . . . . . . . . . . . . . . . . Behavioral therapy. . . . . . . . . . . . . . . . . . . . 3.3.1. New cognitive behavioral therapy . . . . . . . 3.3.2. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Psychological and neurobiological aspects of obesity . . . . . Obesity and mood. . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Obesity and stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Addiction-like behavior . . . . . . . . . . . . . . . . . . . . . . . 4.3. 4.4. Motivation and reward . . . . . . . . . . . . . . . . . . . . . . . . Wanting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Liking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. 4.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurobiology of food intake regulation . . . . . . . . . . . . . . . . The glucostatic and lipostatic theories. . . . . . . . . . . . 5.1. Brain energy metabolism . . . . . . . . . . . . . . . . . . . . . . 5.2. A neuropsychological model of obesity genesis . . . . . . . . . . A proposed integration model for stress and reward 6.1. Summary of the main points . . . . . . . . . . . . . . . . . . . 6.2. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction In recent years, the prevalence of obesity has reached epidemic proportions. While in the 1980s the National Health and Nutrition Examination Survey (NHANES) estimated that 32.1% of people in the United States were overweight (body mass index [BMI] between 25 and 30 kg/m2) and 15.0% were obese (BMI  30.0 kg/ m2), data from 2007 to 2008 indicate that 68.0% of US adults had a BMI > 25, of whom 33.8% met the definition of obesity (Flegal et al., 2010). Currently, the World Health Organization (WHO) estimates that over 1 billion people around the globe are overweight and 300 million are obese (Waxman and Norum, 2004; Ford and Mokdad, 2008). It is predicted that by the year 2020 almost half of all American adults will meet the WHO criteria for obesity (Stewart et al., 2009) and that by 2030 almost 90% will display a BMI > 25.0 (Wang et al., 2008). In the United States, the proportion of the population meeting the clinical definition of obese has tripled in the last 20 years (Bessesen, 2008), while in Europe the prevalence of obesity has also increased over the past decades. In the 1980s, 15% of males and 22% of females had a BMI  30 (The WHO MONICA Project, 1988) whereas in the 2000s up to 28.3% of men and 36.5% women were considered obese (Berghofer et al., 2008). Obesity, however, does not limit itself to a metabolically regulated matter of visual appearance but, much more importantly, has a number of severe consequences on the individual’s overall health status. Data suggest an association between obesity and poorer health-related quality of life due to chronic disorders, smoking, and alcohol abuse (Sturm and Wells, 2001). A BMI  30 is considered a major risk factor for cardiovascular diseases (Ogden et al., 2007; Manson et al., 1995) and type 2 diabetes mellitus (Field et al., 2001; Oguma et al., 2005). Apart from this health hazard, excess weight gain also represents an enormous economic burden and results in one of the most extensive cash disbursements in national health care budgets (Wolf and Colditz, 1998). In the United States, for example, the overall direct costs of obesity treatment in 1995 were 2.7 times higher than those for arterial hypertension therapy (Finkelstein et al., 2003). By 1998, however, obesity related medical expenses were estimated to be as high as $78.5 billion, while they accounted for an estimated 10% of total annual US medical expenses, i.e. $147 billion, in 2008 (Finkelstein et al., 2009). To date, treatment of obesity has been fraught with disappointment for attending physicians as well as concerned subjects. Available therapeutic interventions for obesity such as diet,

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exercise, and pharmacological therapy are only promising for the duration of the actual treatment interval, while body weight reduction frequently regresses after a return to previous nutritional habits. Initially, diets (Sacks et al., 2009), exercise (Miller et al., 1997), and drug therapy (Rucker et al., 2007) indeed result in weight loss but, unfortunately, weight regain after discontinuation of the treatment as well as the lack of distinction between achievement and maintenance of weight loss (Mark, 2006; Wing et al., 2008) limit their efficacy in the long run. One must thus recognize that the factual causes of the obesity epidemic as well as the underlying mechanisms that control food intake behavior are still incompletely understood. In fact, there is a dichotomous conception of pathomechanisms, varying from a simple imbalance between energy intake and energy expenditure, to thrifty or ‘saver’ genes and the unhealthy modern lifestyle, up to metabolic or neuroendocrine alterations. This conceptual inhomogeneity reflects general disorientation in the attempt to solve the problem and illustrates the urgent need for a new and more efficient approach. In the following review we discuss traditional views, explain why current treatment strategies do not meet their expectations at this point, provide a synthesis of current findings indicating a close relationship between obesity and neurobiological as well as psychological aspects of overeating, and describe a model in which obesity development and the functional systems of stress and reward perception are integrated. 2. Conventional models of obesity genesis 2.1. Excessive food intake and lack of physical activity At first glance, obesity is a consequence of excessive food intake accompanied by a lack of physical activity in everyday life (Webber, 2003). It is currently considered that the type of food consumed, i.e. trans-fats and refined white flour carbohydrates in conjunction with low fiber content, may play an important role in the development of obesity. Indeed, data indicate that the high density, high palatability and widespread availability of food, high frequency of meals, boosted energy density of nutrients, and the preference for snacks over full meals all promote energy overconsumption, whereas concomitantly technical progress as well as sedentary occupational and leisure-time activities reduce the level of physical activity (French et al., 2001). Moreover, advertisements that declare high carbohydrate and energy dense foods as ‘low fat products’ falsely imply that these foodstuffs are of

Please cite this article in press as: Jauch-Chara, K., Oltmanns, K.M., Obesity – A neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. (2014), http://dx.doi.org/10.1016/j.pneurobio.2013.12.001

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low energy content and incite people to increase their consumption of these obesity promoting products (Swinburn et al., 2004). However, the simple view that obesity is exclusively a result of random energy overconsumption disregards lifestyle influences and genetic determinants as well as sociological and psychological factors (Hill et al., 2003; Marti et al., 2004). Even more importantly, this view suggests that appetite and therefore body weight regulation are deliberately controllable and that weight gain is a result of lack of discipline, which is unanimously contradicted by the patients concerned as well as experienced therapists. 2.2. Genetics In the 1960s, James Neel proclaimed the ‘thrifty gene’ hypothesis to explain the evolutionary significance of obesity, stating that genetic predisposition for efficient fat storage represents a selective survival advantage in populations frequently experiencing starvation (Neel, 1962). Thus, in modern societies, subjects with this genotype might represent those that become extremely obese. This hypothesis is in line with the fact that Pima Indians and Pacific Islanders show a disproportionate percentage of obesity that cannot be explained by lifestyle, economic, or environmental factors alone (Bell et al., 2005; Friedman, 2003). Also, family, twin as well as adoption studies with heritability rates in the range of 25–40% and 50–80%, respectively, argued for the influence of genetic predisposition on body weight and feeding behavior in humans (Hebebrand and Hinney, 2009). Moreover, obesity-associated gene (FTO) studies further document the linkage between body weight and genetic factors, with (Bessesen, 2008) revealing that variant alleles in the first FTO intron are significantly associated with obesity-related traits (Loos and Bouchard, 2008). Data showed that homozygous individuals with a high-risk allele weighed 3 kg more than those with a low-risk allele (Freathy et al., 2008; Do et al., 2008). It has been suggested that the product of FTO is an enzyme involved in the demethylation of single stranded DNA in the hypothalamus and thus in energy balance regulation (Gerken et al., 2007). Analogously, a common gene variant close to the insulin-induced gene 2 (INSIG2) showed an association with a 2 kg weight gain in comparison to subjects with low-risk alleles (Herbert et al., 2006). Taken together, the data indicate an unquestionable relationship between genes and body weight gain. However, the degree of weight gain that can be explained by genetic predisposition is rather small. Moreover, it seems that environmental factors, such as low socioeconomic status, exert a greater impact on weight gain than genes do (Rennie and Jebb, 2005). A recent study among 12,000 interconnected subjects showed that the persons ‘risk of developing obesity over a 30 year follow up period increased by 57% if one of their friends became obese (Christakis and Fowler, 2007). 2.3. Lifestyle The majority of diseases plaguing industrial societies are seemingly initiated or triggered by the modern lifestyle, creating an environment of distress and stress-related conditions. A growing body of evidence indicates that chronic psychosocial stress leads to visceral obesity (Kyrou et al., 2006; Kyrou and Tsigos, 2007, 2008; Rosmond et al., 1996, 1998) and it has been suggested that psychosocial stress predicts the incidence of metabolic syndrome, i.e. a cluster of obesity, impaired glucose tolerance and lipid metabolism, and arterial hypertension (Raikkonen et al., 2007). In middle-aged individuals, chronic work stress (Chandola et al., 2006), depressive symptoms and feelings of anger (Raikkonen et al., 2002), as well as feelings of marital dissatisfaction, widowhood, and divorce (Troxel et al., 2005) considerably

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enhance the risk of illness due to metabolic syndrome. Several clinical features such as reduced heart rate variability (Carney et al., 2005), elevated heart rate (Carney et al., 2005), increased hypothalamic–pituitary–adrenocortical (HPA) axis activity (Bornstein et al., 2006), and elevated inflammatory markers, such as white blood cell count (Suarez et al., 2006) found in both psychosocial stress and metabolic syndrome argue for a tight linkage between them. However, although it has been suggested that these features may underlie the development of metabolic syndrome (Brunner et al., 2002) the cause-and-effect chain in this context is not yet clear. Moreover, intrinsic psychological status disconnected from environmental stress is a relevant interfering variable here. Negative emotions are related to blunted central nervous serotonin release (Ebmeier et al., 2006), which, in turn, is associated with metabolic syndrome (Muldoon et al., 2006). Persistently increased glucocorticoid release generated by the chronic stress that never ceases in modern lifestyle, however, progressively leads to visceral obesity, decreased muscle and bone mass, as well as insulin resistance (Kyrou and Tsigos, 2007). Lifestyle-induced stress therefore represents a most relevant candidate to add to those contributing to the obesity epidemic. Stress perception and coping, however, are mainly a psychological matter and hard to influence by dietary restrictions within the scope of prevalent therapeutic concepts. These are specified in the following chapter. 3. Current clinical therapy regimens 3.1. Reduction of energy intake 3.1.1. Diet At first glance, reducing energy uptake by dietary changes appears to be the appropriate solution to reduce body weight. Notwithstanding this perception, this simple concept does not compellingly lead to the desired results. During the past decade, the lack of strategies to contain the growing prevalence of obesity along with the limited success of pure dietary therapies triggered an intense debate about what types of diet are most effective to treat overweight. A meta-analysis including 447 participants indicated that low-carbohydrate diets are at least as efficient as low-fat diets to induce weight loss (Nordmann et al., 2006). These data are in line with randomized 1-year (Gardner et al., 2007) as well as 2-year (Shai et al., 2008) trials indicating that lowcarbohydrate diets represent an efficient treatment for body weight reduction. Moreover, a more recent 2-year study with 811 overweight adults showed that reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize (Sacks et al., 2009). However, small sample size, retention rates up to 50% within the first year, short duration, and frequent lack of data on adherence rates limit the explanatory power of these studies (Shai et al., 2008). The latter point is of particular importance since the resilience to adhere to the prescribed diet is highly associated with weight loss (Dansinger et al., 2005). Overall, body weight regain after weight reduction represents a major problem, as observed in trials of dietary therapy (Mark, 2006). Factors such as motivation and personality profile seem to be a key factor for successfully maintaining weight loss. Data indicate that psychosocial features such as depressive symptoms (Wing et al., 2008) and disinhibition of appetite in response to internal cues, such as feelings and thoughts, are strongly associated with weight regain (Wing et al., 2008; Niemeier et al., 2007; Byrne, 2002) in this context. 3.1.2. Pharmacotherapy Current pharmacological therapy of obesity comprises appetite suppressants (sibutramine), which have actually been withdrawn

Please cite this article in press as: Jauch-Chara, K., Oltmanns, K.M., Obesity – A neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. (2014), http://dx.doi.org/10.1016/j.pneurobio.2013.12.001

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from the market in some countries, and agents to reduce fat uptake in the gut (orlistat). Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30% (Davidson et al., 1999). Data showed that orlistat decreases body weight, body fat mass, waist circumference, blood glucose, and systolic as well as diastolic blood pressure (Rucker et al., 2007). However, adverse side effects, such as oily fecal discharge, reduce long-term compliance. Sibutramine, on the other hand, acts directly within the brain to enhance satiety, primarily by inhibiting reuptake of two neurotransmitters, norepinephrine and serotonin (Wirth and Krause, 2001). A recent meta-analysis indicated that sibutramine causes body weight loss and slows weight regain after the end of a diet (Rucker et al., 2007). But analogously, adverse side effects, i.e. increased heart rate and blood pressure, can limit its clinical use. Direct comparison of both orlistat and sibutramine showed that sibutramine has a modest but significantly greater weight loss effect (Rucker et al., 2007). Overall, both orlistat and sibutramine foster an average weight loss of 3–5 kg, i.e. a magnitude that is not only disappointing to treated subjects (Poston and Foreyt, 2000) but even negligible when talking about individual body weight beyond 150 kg. Moreover, the response to pharmacotherapy varies among individuals. Data indicate that only 40–60% of subjects with obesity show a response to an applied drug (Glazer, 2001). The major point of criticism, however, is the fact that treated subjects are not required to change their food intake habits and therefore cessation of the treatment is compellingly accompanied by rapid body weight regain (James et al., 2000). 3.1.3. Bariatric surgery To date, the greatest efficacy in rapid body weight loss is offered by bariatric surgery. A prospective controlled study involving 2010 subjects who underwent bariatric surgery and 2037 controls under customary non-surgical therapy revealed an almost 30% mortality reduction in surgically treated persons due to reduced rates of diabetes, cardiovascular disease, and cancer (Sjostrom et al., 2007, 2009). Moreover, a retrospective cohort study compared 9949 patients who underwent gastric bypass surgery with 9628 severely obese persons who applied for a driver’s license during a 7.1 year follow-up and showed total mortality was reduced by 40% after gastric bypass surgery (Adams et al., 2007). Overall, bariatric surgery in cases of severe obesity holds the advantage of long-term weight loss, little weight regain (Sjostrom et al., 2007), and a reduction in the severity of hallmarks of diabetes mellitus (Dixon et al., 2008; Rubino et al., 2010a). The underlying mechanisms for these alterations, however, are not fully understood. Nonetheless, some researchers have speculated that enhanced release of incretins and reduced secretion of gastric hormones play a role in this regard (Cummings, 2009; Rubino et al., 2010b). However, pre-existing psychological disorders in obese individuals, a major problem especially in patients with a BMI beyond 40 kg/m2, seem to persist or even rebound after bariatric surgery. Data indicated that a substantial number of obese subjects with presurgical mood disorders such as depression re-experience their symptoms after surgery (Elkins et al., 2005) and the overall risk of non-disease-related death, i.e. suicides and accidents, is 1.58 times higher in subjects after gastric bypass surgery than in obese controls (Adams et al., 2007). Recent data suggested that psychiatric screening is important when determining eligibility for bariatric surgery because patients with a body mass index  40 kg/m2 have a 5-fold greater risk of depression and half of bariatric surgery candidates are depressed (Chiles and van Wattum, 2010). Moreover, complications from body weight loss surgery are frequently observed. A study with 2522 adults who had undergone bariatric surgery showed a complication rate of 21.9% during the initial hospital stay and a total risk of 39.6% of

complications within the subsequent six months (Encinosa et al., 2006). A meta-analysis indicated operative mortality rates up to 0.5% for gastric bypass, 0.1% for gastric banding, and 1.1% for malabsorptive procedures (Buchwald et al., 2004). Major complications of bariatric surgery include pulmonary embolism, respiratory failure, anastomotic leaks, stomal obstruction or stenosis, and bleeding (Steinbrook, 2004). Also, postoperative gastrointestinal complications are common after bariatric surgery (DeMaria, 2007). Dumping syndrome, a complex of neuroendocrine-mediated symptoms including facial flushing, palpitations, fatigue, and diarrhea, occurs in up to 70% of patients after gastric bypass (Stocker, 2003), whereas nausea and vomiting are found in more than 50% of cases undergoing restrictive surgery procedures (McMahon et al., 2006). Overall, despite the unquestioned benefit of the method in some cases, bariatric surgery bears a high risk of severe complications and cannot be considered an appropriate routine method to overcome the worldwide increasing problem of obesity (Table 1). 3.2. Boosting energy expenditure 3.2.1. Exercise Physical exercise represents one of the most frequently quoted methods for body weight reduction. A meta-analysis summarizing 25 years of weight loss research showed that a 15-week diet plus exercise program produced a body weight loss of about 11 kg, whereas exercise alone decreased body weight by 2.9 kg (Miller et al., 1997). More recent studies indicated, despite only modest or non-reductions in body weight, that exercise significantly decreased abdominal waist and hip circumference (Slentz et al., 2005; Church et al., 2009). Another study comprising more than 2600 adults, 60 years of age or older, demonstrated that the Table 1 Overview of current clinical therapy regiments. Intervention

Effectiveness

Impact assessment

Diet

Effective

Body weight regain after cessation High relapse rates

Exercise

Effective

Little weight loss of max. 3 kg

Orlistat

Effective

Adverse side effects such as oily fecal discharge Average weight loss only 3–5 kg Body weight regain after cessation

Sibutramine

Effective

Adverse cardiovascular side effects Average weight loss only 3–5 kg Body weight regain after cessation

Bariatric surgery

Effective

High costs Increased risk of depression Somatic complications such as dumping syndrome, vomiting, pulmonary embolism, anastomotic leaks, bleeding

Caffeine, ephedrine

Effective

Increased risk of adverse psychiatric, autonomic, or gastrointestinal side effects Heart palpitations Adverse cardiovascular events Little weight loss

Behavioral therapy (BT)

Effective

Stagnancy of weight loss Concomitant caloric restriction required High drop-out rates Weight regain after cessation

Cognitive behavioral therapy (CBT)

Effective

Concomitant caloric restriction required Not superior to BT Weight regain after cessation

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enhanced overall mortality in subjects with increased waist circumference was abolished if these subjects were in good physical shape (Sui et al., 2007). These data are in line with the observation that elevated BMI did not further increase mortality in subjects with a high fitness level (Church et al., 2005). Notwithstanding, physical activity alone results in a rather puny weight loss of only 3 kg (Miller et al., 1997). This degree of weight reduction thus does not offer a solution for obese subjects at the upper end of the BMI range and certainly does not foster motivation for regular exercise in the long run. 3.2.2. Caffeine and ephedrine Caffeine and ephedrine consumption are proposed as strategies for body weight loss and weight maintenance due to their energy expenditure-increasing effects. Both substances are thermogenic (Bray and Tartaglia, 2000). The stimulatory effect of caffeine on thermogenesis is based on mechanisms involving the inhibition of intracellular cyclic adenosine monophosphate (cAMP) (Dulloo, 1993), stimulation of the Cori- and FTA-triglyceride cycle (Yoshida et al., 1994), and catecholaminergic stimulation of adipocyte metabolism (Van Soeren et al., 1996). Moreover, data indicate that caffeine also has a direct food intake-reducing effect (Racotta et al., 1994). Ephedrine mediates the thermogenic effects by boosting epinephrine and norepinephrine release (Dulloo, 1993). The substance is able to enhance energy expenditure by about 10% in a dose-dependent manner over a period of several hours (Astrup et al., 1985; Shannon et al., 1999). Interestingly, the effects of ephedrine can be potentiated by caffeine (Shekelle et al., 2003). In a long-term study among 167 obese participants, the combination of both substances induced significantly greater weight loss than placebo administration (Boozer et al., 2002). However, the increased risks of adverse psychiatric, autonomic, or gastrointestinal side effects, as well as heart palpitations (Shekelle et al., 2003) limit the use of both substances. Whereas caffeine seems to be relatively safe due to rapid development of a tolerance to side effects (Diepvens et al., 2007), ephedrine may represent a serious health risk to some subjects since this substance is associated with adverse cardiovascular events (Haller and Benowitz, 2000). Moreover, data indicate that the combination with caffeine potentiates the adverse side-effects of ephedrine, inducing permanent increments in heart rate, blood pressure, and circulating glucose levels as well as a decrease in blood potassium levels (Haller et al., 2005). 3.3. Behavioral therapeutic concepts 3.3.1. Behavioral therapy Behavioral therapy (BT) for obesity is primarily based on the extinction of classically conditioned cues and creating new connections (Stuart, 1996), i.e. a process of connecting learned associations between food intake and a neutral stimulus such as listening to music. Behavioral techniques help patients to identify cue-signals that trigger inappropriate eating, learn to develop new behavioral patterns in the face of these cues, and seek positive reinforcement by replacing eating with alternative activities (Foster et al., 2005). BT is defined by three features (Wadden and Foster, 2000). First, goals must be clear and easy to appraise. Second, the treatment is process-oriented, i.e. patients are encouraged to identify potential factors that hinder or facilitate goal achievement. Third, BT prefers small and persistent over large and short-lived progress. Data have indicated that BT results in a mean short-term weight-loss of 9.6 kg, i.e. 10.6%, during a 21-week treatment phase and 6.0 kg after an 18 month follow-up (Wing, 2004). These data are in line with more recent studies offering similar results (Foster et al., 2005). However, stagnancy of weight loss and high dropout rates represent major problems for

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behavioral weight reduction programs. Data have shown that the majority of patients regain most or at least a portion of the body weight they had previously lost (Turk et al., 2009; Cussler et al., 2008). Moreover, studies published between 1974 and 2002 indicate that only 80% of patients are able to complete the therapy at all (Wing, 2004). Recent data suggested that stress (37%) and holidays (15%) represents the main cause of high dropout rates (Corbalan et al., 2009). 3.3.2. New cognitive behavioral therapy Cognitive behavioral therapy (CBT) is based on the theory that thoughts, beliefs, and cognition directly affect feelings and behavior (Duffy and Spence, 1993). CBT combines behavioral with cognitive techniques created to identify, evaluate, and restructure dysfunctional conditions as well as beliefs, and intends to transfer strategies of new skills and behaviors learned by therapy into everyday life (Butler et al., 2006; Cooper and Fairburn, 2001). Using this type of therapy regimen, patients learn to set realistic goals of weight change expectations, to evaluate body weight reduction processes by modifying eating and behavioral habits, and to revise negative thoughts in case of failure to reach therapy goals (Foster et al., 2005). New cognitive behavioral treatment has particularly been developed to minimize weight regain after body weight loss by overcoming psychological barriers of long-term adherence to successful weight control behavior (Cooper and Fairburn, 2001). This therapy addresses three key points: first, treatment must help the patient to accept any weight loss achieved; second: the patient must be encouraged to adopt weight stability but not weight loss as a goal; third: patients should acquire and use behavioral and cognitive skills to achieve successful weight control (Cooper and Fairburn, 2001). Data indicate that up to 90% of participants were able to complete CBT treatment, attaining an average loss of 10% of their initial body weight (Corbalan et al., 2009; Cooper et al., 2010). However, a recent randomized controlled trial shows that the majority of participants regained body weight within three years of follow-up, indicating that new CBT is not more successful than BT in preventing weight regains (Cooper et al., 2010). Nonetheless, BT and new CBT provide patients with strategies to increase the success rate of their treatment. Mode of food provision, i.e. structured meal plans or meals arranged in controlled portion sizes (Jeffery et al., 1993), modified expectations with realistic goals regarding weight loss (Chaput et al., 2005), and maintenance programs (Leibbrand and Fichter, 2002) facilitate the preservation of weight loss successes, resulting in up to 7.42% less weight one year after the end of the therapy compared with baseline (Cooper et al., 2010). Notwithstanding this, besides the application of behavioral techniques, concomitant caloric restriction as an inevitable part of the therapy is likely to be primarily responsible for the weight reducing effects of BT and CBT. 3.4. Conclusion Given that traditional strategies to overcome the exponentially growing problem of obesity are of limited efficacy, bear the risk of adverse side-effects, and in most cases are not curative, new therapeutic concepts must be considered. What all current therapies (except for behavioral treatments) have in common is an isolated focus on the goal of a negative systemic energy balance by environmental modification of conditions and, on the other hand, the neglect of intrinsic neurobiological and psychological aspects of overeating such as hypothalamic appetite regulation, mood, stress balancing, or reward perception. All currently applied therapeutic interventions to combat obesity are thus only promising for the duration of the actual treatment interval, while body weight reduction frequently regresses after return to previous nutritional habits. The central role and high significance

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of neurobiological and psychological aspects of food intake behavior will hence become clear in the next chapter. 4. Psychological and neurobiological aspects of obesity 4.1. Obesity and mood Appetite and body weight regulation are closely linked to mood, an interrelation that can be confirmed by most non-obese people. Among mood disorders, depression in particular seems to have a major influence on body weight dysregulation and vice versa. It is well known that typical or melancholic depression is accompanied by a decrease in appetite and body weight loss whereas atypical depression is characterized by increased appetite and weight gain (Schweiger et al., 2008). In any case, the diagnosis of a depressive disorder involves alterations in food intake behavior. According to the Diagnostic and Statistical Manual of Mental Disorders (DSMIV), which provides consistent terminology and standardized criteria for the classification of mental disorders, altered physical activity levels and eating disorders represent central features of major depression (American Psychiatric Association (APA), 1996). Moreover, the relationship between obesity and depression has been subject to a number of studies indicating a strong reciprocal connection (de Wit et al., 2009; Scott et al., 2008; Vogelzangs et al., 2010; Gadalla, 2009). A review of 20 cross-sectional and 4 longitudinal studies provided evidence that obesity increases the odds of developing depression (Atlantis and Baker, 2008). However, the exact cause-and-effect chain underlying this relationship is not clear. Data have indicated that depression may cause obesity by reducing physical activity, inducing changes in eating behavior (Hasler et al., 2005; Richardson et al., 2003), and enhancing the activity of stress systems (Bornstein et al., 2006; Holsboer, 2000). On the other hand, there is evidence that obesity may cause depression over time by its negative effects on selfimage (Roberts et al., 2003) and by enhancing the activity of inflammatory pathways (Emery et al., 2007; Shoelson et al., 2007). Moreover, obesity increases the risk of diabetes mellitus, a disease that enhances the risk of depression on its own (Ajilore et al., 2007). Diabetes and depression, however, seem to be interconnected by a dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis. In type 2 diabetes mellitus, the size of the relative abdominal mass correlates with salivary cortisol levels, a hormone which, it is known, exerts a depressiogenic action (Oltmanns et al., 2006; Fig. 1). Patients with major depressive disorder, in turn, display alterations in glucose metabolism as well as high cortisol values (Nathan et al., 1981; Amsterdam and Maislin, 1991). Therapeutic intervention against depression reverses both elevated cortisol concentrations and disturbed mood (Lustman and Clouse, 2005; Himmerich et al., 2006). A recent meta-analysis including more than 58,700 subjects revealed a bidirectional association between depression and obesity: obese persons had a 55% higher risk of developing depression over time in comparison to normal weight subjects, whereas subjects with depression had a 58% increased risk of becoming obese compared with healthy persons (Luppino et al., 2010). Overall, the relationship between depression and obesity is stronger than the relationship between depression and overweight, indicating obesity-degree dependence in this context. 4.2. Obesity and stress In addition, there is not only an association between depression and obesity but also between psychosocial stress and visceral obesity (Kyrou et al., 2006; Kyrou and Tsigos, 2007, 2008; Rosmond et al., 1996, 1998) due to activation of the HPA axis. This activation means that the hypothalamus releases corticotropin-releasing hormone (CRH) or, in the case of rodents, corticotrophin-releasing

Fig. 1. Relative abdominal mass in patients with type 2 diabetes after division into low- (n = 63), medium- (n = 64) and high- (n = 63) cortisol tertiles (means  s.e.m.). The small insert indicates relative abdominal mass when subjects with marked glucosuria (>10 g/l) were excluded. From Oltmanns et al. (2006). Copyright ß 2006 BioScientifica. All rights reserved.

factor (CRF), which stimulates the release and synthesis of adrenocorticotropin (ACTH). ACTH, in turn, increases the release of cortisol by the adrenal cortex (Nieuwenhuizen and Rutters, 2008). In particular, variations in HPA axis activity exert a strong influence on metabolic pathways. During acute stress, the brain focuses on the perceived threat, attention is enhanced, catabolism is initiated, and blood flow is redirected to provide the greatest perfusion of the brain and muscles (Kyrou and Tsigos, 2007). These changes are transient and occur to improve the individual’s chance of survival. Chronic stress exposure, by contrast, and a consecutively persistent HPA axis activation shift the metabolism toward a generalized catabolic state. Interestingly, two components of the HPA axis, i.e. CRH and glucocorticoids, exert opposite actions on food intake in this context. CRH is responsible for anorectic effects at the onset of a stress response resulting from the inhibition of orexigenic pathways that involve neuropeptide Y (NPY) (Heinrichs et al., 1993), whereas cortisol exerts orexigenic effects by potentiating NPY properties (Kuo et al., 2007) and, via a negative feedback mechanism, inhibiting CRH release (Benoit et al., 2000). Physiologically, the characteristics of cortisol are crucial for the provision of required energy to the brain and locomotor system during stressful periods. Apart from increased food intake, blood pressure and heart rate rise, insulin secretion is suppressed, and gluconeogenesis is initiated to increase the level of circulating glucose available for boosted brain and muscle activity. For our ancestors, this mechanism made sense in terms of success in hunting or surviving a fight. Chronic HPA axis activation in modern life, however, induces hypercortisolism which results in a pseudoCushing state, i.e. a phenotype resembling that of Cushing’s syndrome, characterized by facial as well as trunk and abdominal fat accumulation, insulin resistance, dyslipidemia, hyperglycemia, and hypertension (Newell-Price et al., 2006). Overall, there are strong differences between acute and chronic HPA-axis activation effects on metabolic pathways. As mentioned above, chronically elevated cortisol levels caused by stress exert orexigenic effects. Acutely, cortisol directly inhibits ACTH secretion within the first 18 h after stress (Dallman et al., 2003), while chronically persistent stress or a single stress stimulus of high intensity diminishes this feedback inhibition (Buwalda et al., 1999; Akana and Dallman, 1997) and acts in an excitatory way on the

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brain. As shown in rats, this feedback inhibition along with a corticosteroid-induced CRF rise induces activation of the ‘chronic stress-response network’ 24 h after stress onset (Dallman et al., 2003). From this time point, glucocorticoids systematically enlarge abdominal fat depots (Rebuffe-Scrive et al., 1992) and enhance the desire (Berridge and Robinson, 1998) for pleasurable and compulsive activities, i.e. wheel running (Moberg and Clark, 1976) as well as sucrose (Bhatnagar et al., 2000), fat (Levin et al., 2000), or drug (Goeders, 2002) ingestion, which, in turn, further motivates ingestion of ‘comfort food’, i.e. palatable foods with sensory qualities of high caloric content, in animals (Dallman et al., 2003) and humans (Epel et al., 2001). In addition, stress shifts ingestion behavior from habitual to preferably savory and sweet foods (Oliver et al., 2000), resulting in cheering up and better mood in humans (Canetti et al., 2002). Overall, elevated glucocorticoids stimulate craving for and ingestion of ‘comfort food’ that directly results in reductions in stress-induced negative effects on the nucleus accumbens caused by chronic stress (Berridge, 2004) and reduces the magnitude of HPA responses to stress (Bell et al., 2002; Pecoraro et al., 2004; Levin et al., 2000). Glucocorticoids hence increase the consumption of palatable, energy dense foods in animals (Bell et al., 2000; Dallman et al., 2006, 2003). In humans, rising stress in everyday life is linked to an enhanced desire for food (Epel et al., 2001; Zellner et al., 2006). Moreover, elevated sensitivity to stress was found to be related to obesity (Gluck et al., 2004) and increased food intake (Oliver and Wardle, 1999; Newman, O’Connor, and Conner, 2007). Laboratory studies indicate that women who display a high cortisol response to experimental stress induction by the Trier Social Stress Test (TSST) consume more calories, particularly in the form of high-fat food, after stress (Epel et al., 2001). More recent data showed that TSST intervention enhances post-stress carbohydrate intake in healthy men (Hitze et al., 2010). Additionally, high cortisol reactivity as assessed in a laboratory setting predicted higher amounts of calorie consumption under subsequent free-living conditions (Newman et al., 2007). Overall, there is strong evidence that stress-induced high HPA – axis activity predicts elevated intake of energy-dense foods and that humans showing high cortisol reactivity choose ‘comfort food’ to blunt their stress response (Adam and Epel, 2007). Chronic stress therefore represents a crucial candidate underlying the development of obesity. Hence, stress coping strategies appear useful in therapeutic approaches in this context. 4.3. Addiction-like behavior From a neuropsychological point of view, overeating displays a striking number of neurobiological similarities and behavioral analogies to substance dependence. Just as in addictive behavior, obese subjects have been found to ingest greater amounts of food (i.e. their ‘‘drug’’) than they initially intended and show a reduced ability to participate in a full range of social as well as occupational activities (Barry et al., 2009). Moreover, subjects with a BMI > 30 kg/m2 frequently make some unsuccessful efforts to control overeating and/or continue their overeating despite knowledge of the destructive consequences of obesity on their health status (Barry et al., 2009). These obvious analogies to addiction led to the proposal that obesity should be included in the upcoming DSM-V list (Volkow and O’Brien, 2007). However, based on the fact that research focusing on the role of neural mechanisms in the onset and maintenance of obesity is in its infancy, the Eating Disorders Work Group decided that obesity will not be included in DSM-V (Marcus and Wildes, 2012). Nonetheless, behavioral studies revealed that overeating/obesity and addiction both activate identical brain structures related to reward processing, motivation, decision-making, learning, and memory (Volkow and

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Wise, 2005; Volkow et al., 2008). Reward processing in both overeating and addiction activate the mesencephalic dopaminergic system (Volkow and Wise, 2005). Repeated stimulation of this center consequently triggers activity in other transmitter systems, resulting in accumulated compulsive behavior and loss of control over food and substance intake, respectively (Volkow et al., 2008). Moreover, repeated supraphysiological dopamine stimulation from chronic drug abuse results in enhanced emotional reactivity to drugs, poor inhibitory control over drug consumption, and compulsive drug intake (Volkow and Li, 2004). Correspondingly, repeated exposure to foods with high fat and sugar content results in compulsive food consumption, poor control of food intake, and food stimuli conditioning (Avena et al., 2008). However, food intake is not only modulated by pathways of the reward system but also by multiple environmental, endocrine, and neurobiological factors (Stefater and Seeley, 2010; Fiiglewicz and Sipols, 2010). Nonetheless, data suggest that the mesencephalic dopaminergic system responds to food stimuli in the presence of postprandial satiety factors; hence, palatable high caloric foods can switch the regulation of food intake from homeostatic to rewarding pathways leading to overeating and obesity (Batterham et al., 2007), which argues for a close interactive relationship between the different systems. 4.4. Motivation and reward Independent of their function in addictive behavior, motivation and reward play a central role in overeating. Reward from palatable high-caloric foods is processed by a complex neuronal system comprising structures in the ventral striatum (nucleus accumbens, ventral pallidum) and midbrain (ventral tegmental area). The ventral tegmental area projects via the mesolimbic dopaminergic system to the nucleus accumbens, prefrontal cortex, hippocampus, and the amygdala (Zheng and Berthoud, 2007). The dopaminergic system, in turn, modulates appetitive motivational processes, i.e. reward processing (Volkow and Wise, 2005; Volkow et al., 2008; Wise, 2006). Abnormalities in dopamine metabolism result in a dysfunctional motivational response and an inability to cope with stress (Koob and Le Moal, 2008). Projections of the dopaminergic system from the amygdala and prefrontal cortex to the lateral hypothalamus, which are all directly involved in food intake regulation (Baldo and Kelley, 2007), are of particular importance. Data indicate that these projections are crucial for conditioned food intake (Petrovich et al., 2005). Moreover, it has been demonstrated that repeatedly presenting a combination of food with a tone or light (CS+, conditioned stimulus) can be conditioned over time in hungry rats. After several training sessions, even satiated rats consumed additional food upon exposure to the CS+ (Weingarten, 1983). Disruption of the ventro-medial prefrontal cortex or amygdala-hypothalamus projections, in turn, completely abolished conditioned food intake behavior (Petrovich and Gallagher, 2003; Petrovich et al., 2007). 4.4.1. Wanting Expanding this knowledge, Berridge and Robinson described three psychological components of reward, i.e. learning, wanting, and liking (Berridge and Robinson, 2003). They propose that activation of dopaminergic neurons along with an enhancement in dopamine signaling results in an increased ‘wanting’ of the reward and the willingness to work harder to obtain it (Berridge, 2007). Dopaminergic projections from the ventral tegmental area to the nucleus accumbens represent the key components of the implicit, unconscious ‘wanting’ system (Wyvell and Berridge, 2000). Importantly, these mesolimbic pathways are connected to neuroendocrine feedback loops that are able to modulate ‘wanting’ foods. For instance, leptin and insulin, two peripheral feedback

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hormones that exert anorexic effects on hypothalamic appetite regulation, act directly on dopamine neurons (Fiiglewicz, 2003; Hommel et al., 2006). Moreover, leptin also affects the mesolimbic dopaminergic system indirectly, i.e. via orexin neurons in the hypothalamus, which, in turn, project to the ventral tegmental area (Harris et al., 2005). In addition, peptide YY (PYY), a lower gut hormone that suppresses food intake (Batterham et al., 2002), also modulates the activity of the ventral tegmental area (Batterham et al., 2007). In contrast, ghrelin, a stomach-originating hormone with appetite-stimulating effects (Cummings, 2006), enhances reward processing and facilitates foraging behavior (Abizaid et al., 2006; Diano et al., 2006). Mesolimbic dopamine pathways constitute a circuit that mediates reward-associated food consumption (Berridge et al., 2009; Berthoud and Morrison, 2008). Comparisons between feeding and ‘wanting’ have been conducted in animals and in humans. In rodents, palatable energy dense foods, like addictive substances, are able to increase dopamine concentrations in the nucleus accumbens (NA) (Hernandez and Hoebel, 1988; Hajnal and Norgren, 2001). In humans, the link between dopamine 2 receptors and feeding has been studied by positron emission tomography (PET). Data indicate that consuming favorite foods induces dopamine release in the striatum, which, in turn, correlates with the rating on a food pleasantness scale (Small et al., 2003). Additionally, food deprivation is able to enhance the rewarding, in particular wanting, properties of food (Cameron et al., 2008). Moreover, pictures of energy dense foods increase the activity of the dorsal caudate nucleus in normalweight women and several regions of the limbic system including the PFC, amygdala, ventral striatum, insula, and hippocampus in obese women (Stoeckel et al., 2008). This difference clearly shows that frequent consumption of energy-dense foods activates some adaptive processes within the dopamine reward circuitry. Interestingly, imaging studies in obese participants showed a reduced striatal dopamine 2 and 3 receptor availability (Wang et al., 2001), an inverse association between dopamine receptor availability and BMI (Wang et al., 2001), as well as a negative correlation between BMI and striatal dopamine transporter availability (Chen et al., 2008). These studies indicate an understimulation of the reward system in obesity and suggest that overeating may represent a compensatory mechanism in this context. 4.4.2. Liking Neuronal circuits in the hindbrain, the nucleus accumbens, and the ventral pallidum represent key neurobiological components of the psychological term of ‘liking’ (Berthoud and Morrison, 2008), which is also regarded as the hedonic value of a food stimulus. Current knowledge indicates that the mu-opioid receptor of the endocannabinoid system plays an important role in ‘liking’. Endogenous opioids participate in the processing of reinforcing signals, and palatable high caloric foods are able to increase endogenous opioid gene expression (Will et al., 2003). Moreover, injection of the selective mu-opioid agonist DAMGO into the nucleus accumbens initiated consumption of palatable sweet or high-fat foods in satiated rats (Will et al., 2003; Kelley et al., 2002; Zhang et al., 2003). In addition, microinjections of a selective muopioid antagonist reduced sucrose consumption (Kelley et al., 1996). Also, chronic treatment with the non-selective opioid antagonist naloxone decreased intake of palatable energy dense foods (Levine and Billington, 2004). However, ‘liking’ by itself represents a triggered affective reaction, is closely connected to learned habits, and, importantly, largely does not underlie situation-dependent changes. Thus, food reward processing cannot occur without concomitant ‘wanting’, even if ‘liking’ is present (Berridge, 2009). Only the coincidence of both allows the ‘simple’ sensory pleasure to arouse the desire for more food (Berridge, 2009).

Overall, mesolimbic dopamine pathways are essential to understanding food intake as a conditioned response to stress. Repeated activation of the reward system leads to neuroadaptive processes resulting in the development of addiction-like behavior and thereby, potentially, overeating. 4.5. Summary Taken together, there is neuroscientific and clinical evidence that obesity is closely linked to psychological factors such as depression and psychosocial stress. Moreover, obesity shows analogies to addictive characteristics including personality profile, compulsive behavior, and affected brain areas related to reward processing, motivation, decision-making, learning, and memory processing. For a deeper understanding of the interconnection between metabolic disturbances and psychological aspects, fundamental neurobiological mechanisms jointly orchestrating food intake regulation shall be addressed in the following section. 5. Neurobiology of food intake regulation Appetite and food intake are controlled by complex neuronal pathways with reciprocal connections between the hypothalamus, brainstem, and higher cortical centers (Suzuki et al., 2010). Overall energy homeostasis is closely regulated by central nervous mechanisms (Schwartz and Porte, 2005), including afferent inputs from the periphery as well as efferent signals controlling the function of peripheral organs (Schwartz, 2001; Schwartz et al., 2000). The cerebral ‘appetite center’, the hypothalamus, is influenced by endocrine and neuronal feedback signals from the periphery, and synchronizes appetite perception, food intake behavior, and organismic energy homeostasis. Different concepts on how and by which metabolic factor this complex system is mainly driven have been proclaimed in the past. 5.1. The glucostatic and lipostatic theories In the 1950s, two competing theories tried to explain which peripheral signals are able to dominate hypothalamic function in this context. The ‘glucostatic theory’ postulated that changes in blood glucose concentrations or arteriovenous glucose differences are detected by glucoreceptors located in the hypothalamus, and therefore regulate appetite feelings and energy intake dependent on the circulating blood glucose content (Mayer, 1952). This view was supported by human intervention studies showing that a transient decline in blood glucose initiated food ingestion (Campfield and Smith, 1990; Smith and Campfield, 1993). Moreover, further evidence suggested that postprandial blood glucose values were inversely related to subsequent food intake (Anderson et al., 2002). Notwithstanding these findings, some studies could not confirm the association between blood glucose content and appetite (Lavin et al., 1996; Flint et al., 2006). Moreover, blood glucose values interact with factors such as insulin and incretins, which render it difficult to differentiate whether blood glucose changes per se or other factors are responsible for the effects on food intake and feelings of hunger (Holt et al., 1996; Raben et al., 1996). Also, given the assumed relationship between blood glucose and appetite, patients with diabetes mellitus should be chronically satiated based on persistently elevated blood glucose levels, which is, as is known, not the case. The ‘lipostatic theory’, on the other hand, proposed that a ‘factor’ secreted by fat tissue reports the status of peripheral body energy, i.e. fat stores, to the hypothalamus and thus regulates feeding behavior and body fat mass (Kennedy, 1953). The molecular basis for this theory was built on the discovery of

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leptin, a hormone which is secreted by white adipocytes in direct proportion to the subcutaneous fat content, and its hypothalamic receptors (Ahima et al., 1996; Schwartz and Porte, 2005; Schwartz et al., 2000). Data showed that direct administration of leptin into the brain decreases food intake, boosts overall energy expenditure and, in cases of high cerebral leptin values persistence, reduces body weight (Ahima et al., 1999; Seeley and Woods, 2003; Flier, 2004; Elias et al., 1999; Schwartz et al., 2003). However, prior to the discovery of leptin, insulin produced in pancreatic b-cells was largely assumed to modulate food intake regulation by the brain (Woods et al., 1979, 1984). Both hormones, i.e. leptin and insulin, circulate in quantities proportional to body fat content (Niswender et al., 2004) and cross the central nervous system (CNS) barrier in proportion to their plasma levels (Schwartz et al., 1996; Baura et al., 1993). Their receptors are found in brain areas involved in food intake regulation as well as energy metabolism (Schwartz et al., 2001). Thus, both leptin and insulin meet the criteria for adiposity signals (Schwartz et al., 2001). The lipostatic theory, however, does not offer an explanation for why obese subjects with high levels of leptin and, in most cases, insulin as well, apparently still display chronically activated appetite centers and keep gaining weight. Taken together, a range of observations cannot be satisfactorily explained by these theories. Patients with type 2 diabetes, for example, experience feelings of hunger despite increased blood glucose values and, in cases of hypoglycemia, independent of their adipose tissue mass. The phenomenon of body weight regain after reducing, which frequently occurs beyond the initial measures taken, the so-called yo-yo effect, remains obscure on this basis. 5.2. Brain energy metabolism Appetite, food intake, and energy homeostasis are closely regulated by central nervous mechanisms, which involve assessing the cerebral energy need based on its the current ATP content. Generally, an energy-deficient state like hypoglycemia activates the hypothalamus via opening ATP sensitive potassium channels (KATPs) (Chan et al., 2007; Pocai et al., 2005) with a concomitant increase in feelings of hunger, enhancement in gluconeogenesis, and stress system activity as well as reduced insulin release from beta cells (Pocai et al., 2005). The decrease in insulin secretion suppressed by the activated sympathetic nervous system, in turn (Kurose et al., 1990), limits insulin-dependent glucose uptake via GLUT 4 (Cohen et al., 1995) and therefore increases blood glucose values as well as insulin-independent GLUT 1-mediated glucose transport across the blood–brain barrier (Seaquist et al., 2001). In the last few years, the interaction between brain energy homeostasis and systemic-metabolic regulation has been spotlighted (Chan et al., 2007; Pocai et al., 2005). Indeed, an observational study demonstrated an inverse relationship between the cerebral content of adenosinetriphosphate (ATP) and BMI (Schmoller et al., 2010; Fig. 2) and therefore suggested that brain energy metabolism may play a key role in the pathogenesis of obesity. Strikingly, within the organism, the brain is the only organ that is able to supply itself with energy, i.e. mainly glucose, dependent upon its own varying requirements (Peters et al., 2004, 2007). At a cellular level, this occurs via a mechanism termed ‘energy on demand’ (Magistretti et al., 1999). According to this mechanism, astrocytes receive a glutamate signal that is released by neurons upon excitation and are therefore stimulated to induce the translocation of glucose transporters (GLUT) 1 to the cell surface in the blood–brain barrier and thereby facilitate glucose transport into the brain. Through this mechanism, the brain can allocate glucose from the periphery to satisfy its own needs. Based on this principle, it has been suggested that a disturbance in glucose allocation to the brain leads to an energy undersupply that

Fig. 2. Mean values  SEM of cerebral high energy phosphates. Phosphocreatine (A) and total ATP (B) content in low weight (black triangles), normal weight (white circles), and obese (black circles) subjects are shown at baseline, during the glycemic decrease, and at the hypoglycemic plateau (n = 15 in each group). Because values are determined by calculating the area under the spectral peak, no units are indicated. Gray areas mark the hypoglycemic period; asterisks mark significant ANOVA group effects (*P < 0.05; **P < 0.01; ***P < 0.001). From Schmoller et al. (2010). Copyright ß 2010 Nature Publishing Group. All rights reserved.

is sensed by ATP-sensitive potassium channels, amongst others, in hypothalamic appetite centers that act as energy sensors signaling a famine to the brain under this condition. The consequence is chronically activated appetite centers persistently stimulating food intake and causing, in the long run, obesity (Peters et al., 2004, 2007). This view is supported by the insight that a decreased cerebral ATP content activates VMH neurons (Miki et al., 2001), resulting in glutamate release, sympathoadrenal system activation, and inhibition of insulin secretion from b-cells (Chan et al., 2007; Tong et al., 2007; Mulder et al., 2005; Ahren, 2000). Another study indicated the priority of brain energy supply over the periphery under conditions of energetic under- or oversupply, i.e. hypo- or hyperglycemia (Oltmanns et al., 2008). Interestingly, similar to the findings in obese subjects (Schmoller et al., 2010), a reduced high energy content in the brain has previously been found in patients with major depression (Renshaw et al., 2001), building a bridge to the psychological aspects again. In these patients, the energy content of the brain is inversely correlated with scores on the Hamilton depression scale, i.e. the severity of depressive symptoms. Treatment of the depression, in turn, reversed both brain energy status and mood (Iosifescu and Renshaw, 2003). Overall, there is a growing body of

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evidence that the brain energy content per se represents an important factor in the regulation of appetite, food intake, and energy turnover. In light of this view, the commonly prescribed reduced-calorie diet appears to be counterproductive as a treatment for obesity because caloric reduction only worsens the pre-existing cerebral energy undersupply, and causes a yo-yo effect after diet cessation because of compensatory ravenous appetite. Moreover, another finding supports the assumption that the brain energy content is crucial for the regulation of appetite and body weight. Since brain-specific insulin receptor knock-out in mice has been shown to cause a metabolic syndrome (Bruning et al., 2000), several studies have found that intracerebral insulin administration decreases food intake and body weight in rodents, baboons, and men (Brown et al., 2006; Chavez et al., 1995; Benedict et al., 2008; Hallschmid et al., 2004; Woods et al., 1979), enhances brown adipose tissue as well as postprandial thermogenesis (Sanchez-Alavez et al., 2010; Benedict et al., 2011), and inhibits endogenous glucose production (Obici et al., 2002; Pocai et al., 2005). The neurobiological mechanism underlying these effects, however, is not entirely identified so far, although an explanation suggests itself at this point. Insulin serves physiologically as a molecular energy provider facilitating cellular glucose uptake. It thus appears conceivable that CNS insulin may act accordingly in brain cells and therefore, through a rise in brain ATP, suppress appetite and food intake (Fig. 3). This view is supported by the observation that intact insulin receptor binding increases intracellular ATP and PCr levels in vitro (Huang et al., 2005; Henneberg and Hoyer, 1994). Consequently, one could assume that intracerebral insulin application facilitates not only the peripheral but also neuronal energy supply and that the increased levels of ATP and PCr, in turn, constitute a negative feedback signal to reduce subsequent food intake. This view, however, remains to be verified by future experiments. In summary, the CNS, in particular the hypothalamus, receives and integrates diverse information from the periphery in order to maintain its own energy homeostasis. Early theories postulated that blood glucose concentrations or fat tissue-secreted ‘factors’

regulate feeding behavior. However, an inverse relationship between cerebral ATP content and body mass indicates that brain energy status per se may be centrally involved in the regulation of appetite, food intake, and organismic energy turnover. 6. A neuropsychological model of obesity genesis The previous chapters outline how obesity is linked to psychological disturbances such as depression and psychosocial stress and quotes a number of analogies between overeating and addiction in terms of reward processing, motivation, decisionmaking, learning, and memory consolidation. In this chapter, we provide an integrative model on the basis of an integrative synthesis of these findings, pointing to a new view on obesity pathogenesis that is therefore highly relevant for future prevention and therapy concepts. 6.1. A proposed integration model for stress and reward systems On the basis of the described insights we suggest that obesity is a consequence of cross-links between chronically enhanced stress axis activity and reward-related mechanisms within the mesolimbic system. Through a maladaptive formation of associative memory underlying reward-related learning and behavior, increased CRH values interfere both directly and via projection from hypothalamic orexin neurons with dopaminergic reward circuits and induce exceptionally long-lasting forms of synaptic plasticity that drive overeating. The consumption of palatable high caloric foods produces feelings of pleasure that initiate consolidation processes. This maladaptive learning occurs during early childhood and adolescence and unfolds its adverse potential on food consumption induced by chronically persistent stress or a trauma during adulthood. As outlined in the foregoing chapter, glucose, i.e. energy, supply in the brain is demanded via activation of stress systems. Thus, in case of pre-existing stress axes activation, e.g. because of psychological stress, this mechanism leads to a ceiling effect in

Fig. 3. Hypothesized mechanism of insulin action on hypothalamic appetite regulation. Insulin binds to its receptor (1), initiates translocation of the glucose transporter (GLUT) 4 to the cell surface (2) and hence amplifies cellular glucose uptake (3). Intracellular glucose is metabolized (4) and the synthesized ATP closes ATP sensitive potassium (KATP) channels (5). Closure of KATP channels, in turn, reduces appetite and food intake (6).

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stress hormonal concentrations which precludes such adjustable energy requests from the periphery to the CNS yielding, in the longterm, to decreased high energy phosphate levels. The accuracy of this view is supported by the fact that reduced cerebral energy content is frequently observed in individuals with obesity (Schmoller et al., 2010), diabetes (Bischof et al., 2004), or depression (Renshaw et al., 2001), i.e. in diseases associated with high stress axes activity (Chalew et al., 1995; Jauch-Chara et al., 2008). Such reduced brain energy content, generating a vicious circle, aggravates stress system activity because the brain perceives a life-threatening famine. In consequence, the energy-deprived brain activates its hypothalamic appetite centers to foster energy replenishment from foods and, because this state persists, obesity develops. Under physiological conditions, there is a negative feedback inhibition of the HPA axis. Chronic stress, however, enhances the duration and extent of hypothalamic CRH expression due to increased CRH mRNA values in brain areas associated with fear and emotion. This elevated expression of CRH not only prevents further elevation of HPA axis activity but also the development of the so called ‘stressed synapse’, i.e. persistent synaptic activation resulting in impaired signal transmission between neurons (Gallagher et al., 2008). Specifically, CRH induces long-term potentiation (LTP) within the ventral tegmental area (Saal et al., 2003) and amygdala (Rodriguez Manzanares et al., 2005), and reduces long-term amygdala depression (LTD) (Maroun, 2006). Moreover, chronically enhanced CRH levels are not only able to potentiate the stress-related enhancement in food intake behavior via persistent synaptic activation within these reward related brain areas but also via their direct physiological stimulatory influence on orexin neurons (Winsky-Sommerer et al., 2004), which are in a perfect neuroanatomical position to connect both stress response and reward processing for food. As described above, orexins are suited to interlink the stress and reward systems. These neuropeptide hormones are synthesized exclusively in hypothalamic neurons (Sakurai, 2007; de Lecea et al., 1998), although orexin axons and receptors are distributed over almost all brain areas including the cerebral cortex, hippocampus, thalamus, midbrain, and the spinal cord (Peyron et al., 1998; Kilduff and de Lecea, 2001). On the one hand, the orexinergic system represents an important component in the cascade of CRHmediated behavior under stressful conditions. Orexin injections induce physiological responses similar to those observed during stress (Ida et al., 2000). In rats, the activation of orexin neurons is necessary for developing a panic-prone state, while systemic orexin 1 receptor antagonists block panic responses (Johnson et al., 2010). In addition, humans with panic disorder show elevated orexin concentrations in the cerebrospinal fluid compared with healthy controls (Johnson et al., 2010). Therefore, we suggest that the activation of orexin cells by CRH represents an important part of stress signal integration and transmission to other brain regions. On the other hand, orexin neurons send dense projections back to CRH neurons, causing further activation of stress systems in the form of a forward feedback regulation (Johnson et al., 2010). Hence, we assume that the release of CRH induces a self-sustaining process that consists of stress and even more stress, which boosts the reward system activity and therefore increases food intake leading, in the long term, to the development of obesity. Due to the fact that the hypothalamus integrates signals from brainstem nuclei controlling homeostatic processes and from cortical and limbic centers that are related to motivational processes, the orexin system is linked to food reward. Orexinergic LH as well as dopaminergic VTA and NA shell neurons constitute a circuit that is important for reward processing (Harris and AstonJones, 2006). The dopamine-rich VTA, which participates in the control of behaviors associated with food reinforcement (Wise, 2004; Vittoz et al., 2008; Vittoz and Berridge, 2006), contains high

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Fig. 4. Main projections of orexin and dopamine neurons in the human brain. Green lines illustrate the orexigenic and red lines the dopaminergic pathways. Orexin neurons originating in the LHA and posterior hypothalamus send dense excitatory projections to the cerebral cortex, hippocampus, thalamus, midbrain, and the spinal cord. Orexin neurons are also connected to the dopaminergic reward system through the VTA and the hypothalamus. Dopamine neurons in the VTA, in turn, send axon projections to the nucleus accumbens, prefrontal cortex, hippocampus, and to the amygdala. Projections of the dopaminergic system from the amygdala and prefrontal cortex to the lateral hypothalamus are directly involved in food intake regulation. A, amygdala; H, hypothalamus; NA, nucleus accumbens, PVC, prefrontal cortex; VTA, ventral tegmental area.

levels of orexin receptors and receives considerable input from orexin neurons (Fadel and Deutch, 2002; Fig. 4). Overall, enhancement of LH orexin values increases dopamine concentrations within the VTA and PFC (Narita et al., 2006; Vittoz and Berridge, 2006; Vittoz et al., 2008) and activates the reward system. Moreover, orexin likewise plays an important role in the cue-induced reinstatement of food seeking. Both intra-VTA infusion of orexin as well as stimulation of LH neurons reinstate extinguished reward-seeking behavior in rodents (Harris et al., 2005) via reactivation of reward-learning pathways. Accordingly, intra-VTA infusion of orexin antagonists attenuates such behavior (Cason et al., 2010; Richards et al., 2008) and prevents the acquisition of conditioned responses to stimuli associated with reward (Narita et al., 2006). From our point of view, these data clearly show that orexin is crucial for stimulus-reward association building and that orexin modulates reward-related behavior. Interestingly, the excitatory activity of orexinergic and dopaminergic neurons can be influenced by extracellular ATP levels (Belcher et al., 2006; Trendelenburg and Bultmann, 2000; Krugel et al., 2001a). Overall, ATP-dependent pathways are associated with feeding behavior (Kittner et al., 2006), arousal (Wollmann et al., 2005), motivation (Krugel et al., 2004), and locomotor coordination (Belcher et al., 2006). In vivo studies show that endogenous ATP as well as its exogenously applied analogs facilitate dopaminergic functioning (Krugel et al., 1999). The administration of 2-methylthio-ATP (2-MeSATP) into dopaminergic neurons in the VTA and the NA increases extracellular dopamine concentrations in a dose-dependent manner (Krugel et al., 2001b), while the infusion of P2 receptor antagonists as well as long-term food restriction reduce extracellular dopamine levels (Kittner et al., 2000; Pothos, 2001). Overall, ATP has an influence on the decision to eat via modulating accumbal dopamine levels (Ishiwari et al., 2004). Therefore, we suggest that extracellular ATP content is able to reinforce the CRH- and orexin-induced activity of the reward system.

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As described above, stress reactions are accompanied by physiological reactions such as agitation, inner restlessness, and autonomic signs of anxiety such as tachycardia, sweating, and flushing. Humans and animals learn how to avoid/reduce unpleasant stress feelings via conditioning successful coping strategies. Because food intake is the most accessible and powerful tool to reduce HPA axis activity during childhood, eating is learned as a very efficient coping behavior. Consequently, chronic activation of the stress systems leads to a rise in food consumption. On the one hand, activation of the stress axes per se elicits the release of dopamine (Sauvage and Steckler, 2001), orexin (WinskySommerer et al., 2004), and endogenous opioids as part of a defense mechanism against detrimental stress effects at the neuronal and behavioral level (Drolet et al., 2001; O’Hare et al., 2004). On the other hand, food consumption, for its part, activates orexin neurons within the LH (Zheng et al., 2007; Harris et al., 2005) with concomitant stimulation of the dopamine-rich VTA and NA shell, i.e. brain areas that play a key role in reward processing (Harris and Aston-Jones, 2006). The repeated and/or prolonged stimulation of the mesolimbic dopamine system, in turn, leads to adaptation mechanisms at the cellular and molecular levels (Nestler, 2005) that serve to increase the drive for food intake (Volkow and Wise, 2005). The resulting addiction-like behavior is associated with an understimulated dopaminergic system and increased cyclic AMP response element binding (CREB) protein (Nestler, 2005). Additionally, abrupt replacement of a highly palatable energy dense diet by a less palatable low-energy one decreases CREB levels in the striatum (Teegarden and Bale, 2007) and even amplifies the preference for palatable energy dense foods (Barrot et al., 2002), while long-lasting exposure to a palatable high calorie diet increases the concentrations of deltaFosB in the nucleus accumbens (Nestler et al., 2001; Teegarden and Bale, 2007) and enhances the sensitivity to food reward (Olausson et al., 2006). In our opinion, such adaptation mechanisms within the mesolimbic dopamine circuitry constitute a vicious circle: The consumption of comfort food leads to an activation of reward pathways while withdrawal of rewarding food, i.e. dietary restriction, and/or a decrease in CNS dopamine concentrations drives stress system activity, which, in turn, leads to enhanced consumption of palatable energy dense foods (Pecoraro et al., 2004). Apart from food intake per se, contextual stimuli associated with food consumption are also able to increase Fos activity (Schroeder et al., 2001, 2003). Moreover, contextual stimuli also enhance homer 1A and arc gene expression within the CNS (Kelley et al., 2005). Against the background that homer 1A as well as the arc genes play important roles in learning, memory, and neuronal plasticity (Bramham et al., 2010; Neves et al., 2008), their respective activity increases provide further evidence for foodinduced neuromolecular adaptation processes. Furthermore, the activation of homer 1A and arc gene expression interfaces with the dopaminergic reward circuitry, causing initiation of reward seeking behavior (Kelley et al., 2005) in the presence of such conditioned contextual cues later in life. Hence, once conditioned, contextual stimuli drive food intake. Taken together, frequently repeated or persistent periods of mild stress keep the stress system in a chronically activated state. This activation is attended by a reduction in cerebral ATP content as well as an increase in CRH secretion and glucocorticoid levels. On the one hand, the elevation in CRH levels leads to a hyperactive HPA axis with concomitant consumption of palatable high calorie foods. On the other hand, CRH influences the signal transmission between neurons and activates mesolimbic reward pathways. The ensuing repeated activation of the dopaminergic mesolimbic reward system leads to cerebral adaptation mechanisms at the cellular and molecular levels, resulting in the development of

addiction-like behavior and initiation of a vicious circle. Thenceforward, each decrease in dopamine concentration in the NA shell and the VTA initiates reward seeking behavior and enhances HPA axis activity resulting in further activation of the reward system and intake of palatable energy dense foods. In this context, both dieting and caloric restriction act as physiological stressors which lead to understimulation of the reward system accompanied by further activation of stress axis activity. The subsequent increase in the drive for energy dense foods induces, in the long term, body weight gain which is not only attended by weight regain but also by weight overshoot, i.e. development of a higher BMI than before dieting. 6.2. Summary of the main points In order to facilitate the understanding of our neuropsychological view of obesity pathogenesis, we summarize the main points in the following: (1) Chronic stress enhances food intake. Increasing stress in daily life and chronic HPA axis hyperactivity is linked to enhanced appetite for food intake, consumption of palatable high calorie foods, and obesity in humans and animals. Laboratory studies show that social stress induction enhances post-stress carbohydrate intake and high-fat food consumption. These data indicate that animals and humans choose energy dense foods to blunt their stress responses. (2) Food intake activates the reward circuitry. The consumption of palatable energy dense foods increases cerebral dopamine concentrations and activates reward-related pathways. Additionally, the enhancement in dopamine signaling correlates positively with the rating of food pleasantness in humans. Thus, stimulation of mesolimbic dopamine pathways is able to foster food intake in response to stress. (3) Stress per se stimulates the reward system. CRH release potentiates the stress-related enhancement in food intake behavior in two ways: On the one hand, CRH induces persistent synaptic activation within reward-related brain areas like the VTA and the amygdala. On the other hand, this hormone has a direct physiological stimulatory influence on orexin as well as dopamine neurons and elicits the release of endogenous opioids as a part of a defense mechanism against detrimental stress effects at the neuronal and behavioral levels. Overall, the ensuing activation of the reward system potentiates stressinduced food intake behavior. (4) We suggest that obesity is a consequence of a vicious circle built on cross-links between chronically enhanced stress axis activity and reward-related mechanisms within the mesolimbic system. Activation of stress systems leads to CRH release, HPA axis hyperactivity, alterations in signal transmission within the brain, and adverse stress feelings such as agitation, inner restlessness, and tachycardia, sweating, and flushing. During childhood, food intake is a readily accessible and powerful tool to down-regulate HPA axis activity. Therefore, in case of repeated activation of stress systems, eating is conditioned as a successful stress coping strategy. Thereafter, each perception of agitation or autonomic reaction to stress initiates food intake behavior. The resulting consumption of palatable high calorie foods, however, activates mesolimbic reward pathways as a side effect. This effect is further potentiated by the direct stimulatory influence of CRH on dopamine and orexin neurons. The ensuing recurrent activation of the dopaminergic reward system leads to neuroadaptative processes within the brain resulting in understimulated reward pathways and the development of addiction-like behavior. Thenceforward, each decrease in cerebral dopamine

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levels initiates reward-seeking behavior and further activates the HPA axis resulting in intake of palatable energy dense foods and, in the long term, body weight gain. 7. Conclusions and perspectives Although obesity seems to result from a non-compensated increase in energy intake, data show that body weight regulation is more complex than assumed by this traditional view. As demonstrated by the disappointing results of numerous followup studies, maintaining reduced body weight by diet or physical activity represents the greatest challenge for the long-term management of obesity. Initially, reduced-calorie diets indeed result in clinically meaningful weight loss but their meager longterm effects are sobering. The lack of distinction between weight loss achievement and maintenance as well as frequent weight regain after weight loss is a crucial problem for dietary therapy. In contrast to the conventional mode of thinking, a growing body of evidence including neurotransmitter regulation, neuronal projection pathways, clinical comorbidities, and behavioral studies imply that overeating and obesity are tightly linked to neurobiological and psychological aspects such as mood status, addictive behavior, motivation and reward processing as well as coping with psychosocial stress. In particular the involvement of neuronal pathways that include brain areas assigned to reward, motivation, learning, memory, and cortical inhibitory control render obvious that therapeutic approaches which are solely based on metabolic intervention are grossly insufficient to contain the problem. The growing epidemic of obesity thus requires a change in thinking to overcome this challenge. A step in the right direction would be to realize that overeating has a neuropsychological background and respective clinical concepts necessarily need to be integrated into its prevention and therapy. On the basis of the insight that the development of obesity involves multiple brain circuits and causes neuronal adaptation processes within the CNS, prevention as well as treatment of obesity should be comprehensive and multimodal. In particular, efficient stress control should be considered in early childhood. In addition, psychotherapeutic concepts such as conventionally applied treatments for addiction, methods of conditioning to disconnect feelings of stress and reward from food intake behavior, or learning stress coping strategies are conceivable in this context. But neurobiomedical approaches to influence neurotransmitter and neurohumoral circuits involved in mood regulation, reward perception, or addictive behavior such as serotonin, dopamine, or glutamate systems may also be appropriate targets of psychopharmacological strategies to overcome the neuropsychological problem of obesity in the future. In fact, several medications with properties of inhibiting dopamine reuptake like Bupropion, drugs modulating dopamine activity such as Topiramide, and the opioid antagonist Naltrexone have been reported to promote weight loss, indicating that strategies targeting the improvement of dopamine functions within the mesolimbic reward system are useful in the treatment of obesity. However, to date, the long-term efficacy of these medications on weight loss and weight maintenance is unclear and needs further evaluation. At minimum, obesity is a brain disease that is mediated by the interaction between energy homeostasis, detrimental hyperactivity of the stress systems, and activation of dopaminergic reward pathways. Chronic consumption of comfort foods alters brain functions within the mesolimbic circuitry. Moreover, behavioral studies in individuals with obesity show that overeating is triggered by reinforced reactivity of this circuitry to stimuli associated with palatable high calorie foods. This fact underlies the inability of obese subjects to control food intake during exposure to

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Please cite this article in press as: Jauch-Chara, K., Oltmanns, K.M., Obesity – A neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. (2014), http://dx.doi.org/10.1016/j.pneurobio.2013.12.001

Obesity--a neuropsychological disease? Systematic review and neuropsychological model.

Obesity is a global epidemic associated with a series of secondary complications and comorbid diseases such as diabetes mellitus, cardiovascular disea...
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