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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/318840523 Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness Article in Journal of Neurogenetics · August 2017 DOI: 10.1080/01677063.2017.1353092 CITATIONS 3 READS 760 4 authors, including: Some of the authors of this publication are also working on these related projects: DIAMANTE View project Novel Antiproliferative Drugs View project Claude Everaerts French National Centre for Scientific Research 89 PUBLICATIONS 920 CITATIONS SEE PROFILE Leticia G León Erasmus MC 144 PUBLICATIONS 1,584 CITATIONS SEE PROFILE Angel Acebes Universidad de La Laguna 45 PUBLICATIONS 871 CITATIONS SEE PROFILE All content following this page was uploaded by Leticia G León on 30 October 2017. The user has requested enhancement of the downloaded file.

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Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darknessSee discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/318840523
Molecular bases of anorexia nervosa, bulimia nervosa and binge eating
disorder: shedding light on the darkness
Article  in  Journal of Neurogenetics · August 2017
DOI: 10.1080/01677063.2017.1353092
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Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness
Germán Cuesto, Claude Everaerts, Leticia G. León & Angel Acebes
To cite this article: Germán Cuesto, Claude Everaerts, Leticia G. León & Angel Acebes (2017): Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness, Journal of Neurogenetics
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Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness
German Cuestoa, Claude Everaertsb, Leticia G. Leonc and Angel Acebesa
aCentre for Biomedical Research of the Canary Islands, Institute of Biomedical Technologies, University of La Laguna, Tenerife, Spain; bCentre des Sciences du Gout et de l'Alimentation, UMR 6265 CNRS, UMR 1324 INRA, Universite de Bourgogne Franche-Comte, Dijon, France; cCancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy
ABSTRACT Eating-disorders (EDs) consequences to human health are devastating, involving social, mental, emo- tional, physical and life-threatening aspects, concluding on impairment and death in cases of extreme anorexia nervosa. It also implies that people suffering an ED need to find psychiatric and psychological help as soon as possible to achieve a fully physical and emotional recovery. Unfortunately, to date, there is a crucial lack of efficient clinical treatment to these disorders. In this review, we present an overview concerning the actual pharmacological and psychological treatments, the knowledge of cells, circuits, neuropeptides, neuromodulators and hormones in the human brain- and other organs- under- lying these disorders, the studies in animal models and, finally, the genetic approaches devoted to face this challenge. We will also discuss the need for new perspectives, avenues and strategies to be devel- oped in order to pave the way to novel and more efficient therapeutics.
ARTICLE HISTORY Received 9 May 2017 Revised 26 June 2017 Accepted 5 July 2017
KEYWORDS Eating disorders; pharmacology; neuromodu- lators; genetic approaches
Eating-disorders (EDs) as anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED), have both a deep social impact and an enormous cost to public health- care systems (Keski-Rahkonen & Mustelin, 2016). The example of Europe is extremely illustrative: besides a very high risk of premature mortality, more than 2/3 of those EDs patients had at least some role impairment in at least one domain (Preti et al., 2009). In fact, the prevalence of EDs has increased across time, particularly in the second half of the twentieth century (Bulik et al., 2006). In the USA, 20 million women and 10 million men had suffered from a clinically significant ED at some time in their life (Samnaliev, Noh, Sonneville, & Austin, 2015) with 7300 worldwide deaths in 2010 (Lozano et al., 2012) resulting in 2.2 106 disability-adjusted life years (DALYs) (Murray et al., 2012).
Anorexia nervosa is defined as an association of an abnormally low body weight, an intense fear of gaining weight and a distorted cognition regarding weight, shape, and drive for thinness. AN is a disorder but also a symptom of other disorders, as depression, bipolar disorder, anxiety disorders (obsessive–compulsive disorder, panic disorder, social phobias, and post-traumatic stress disorder) and sub- stance abuse (O’Brien & Vincent, 2003; Woodside & Staab, 2006). In turn, BN is characterized by episodes of binge eat- ing – defined itself as ‘recurrent periods of uncontrolled overeating’ – in which big amounts of high-sugar,
carbohydrates and fat food are consumed in a very short- time period, followed by 1 or more compensatory purge behaviours (vomiting, laxatives, fasting, etc… ). That takes place on average a minimum of twice weekly for three or more months, or, in extreme cases, several times a day. BN is divided into two subtypes: the above-mentioned purging- type and the lesser-common non-purging type, characterised by fasting or excessive exercise trying to compensate for the calories obtained from the previous binge. Besides, there exist comorbidities between BN and other disorders as sub- stance abuse, affective disorders, and attention disorders (Altman & Shankman, 2009; Hatsukami, Eckert, Mitchell, & Pyle, 1984). Finally, Binge eating disorder (BED) patients show also repetitive and uncontrolled episodes of over con- sumption of larger amounts of food in a discrete period, but, unlike BN and AN they do not show recurrent compensa- tory purging, fasting and excessive exercise behaviours (American Psychiatric Association, 2013). As for AN and BN, BED has been associated with medical and psychiatric comorbidities, as mood (anxiety) and substance use disor- ders (Becker & Grilo, 2015). Interestingly, BED is the most prevalent among all eating disorders, being higher in women than in men, and also the most underdiagnosed and under- treated, due to insufficient diagnostic criteria and lack of available treatment options [see Section 2 below and also Kornstein, Kunovac, Herman, & Culpepper (2016)].
Eating-disorders have been long considered as severe psy- chiatric disorders of unknown aetiology. As previously
CONTACT Angel Acebes [email protected] Centre for Biomedical Research of the Canary Islands, Institute of Biomedical Technologies, Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 La Laguna, Tenerife, Spain; Leticia G. Leon [email protected] Cancer Pharmacology Lab, University of Pisa, Ospedale di Cisanello, Edificio 6, via Paradisa, 2. 56124 Pisa, Italy 2017 Informa UK Limited, trading as Taylor & Francis Group
JOURNAL OF NEUROGENETICS, 2017 https://doi.org/10.1080/01677063.2017.1353092
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Under these grounds, deciphering unambiguously how the brain controls food intake and satiation mechanisms is crucial to know how eating-associated pathological disorders are bypassing this control. To date, there is a good know- ledge about the bidirectional communication among exten- sive areas of the nervous system (including the cortex, basal ganglia, and the limbic system) with peripheral components (such as gustatory system, gastrointestinal nervous system, pancreas, liver, muscle, and adipose tissue), sustaining an exquisitely well-regulated homeostasis between food intake and energy expenditure (Lenard & Berthoud, 2008; Mithieux, 2013). In addition to these circuits, the brain endocannabinoid system also acts as a key regulator for food intake and energy balance (Cardinal et al., 2015; Di Marzo et al., 2001; DiPatrizio & Piomelli, 2012) through food- related olfactory-dependent mechanisms (Soria-Gomez, Bellocchio, & Marsicano, 2014) and is likely involved in the hedonic and emotional aspects of eating. In spite of these fundamental advances, it is not completely understood how neuronal feeding circuits regulate food intake and hence, after energy repletion, yield to abolish new impulse to eat. The hypothalamus is crucial to integrate metabolic and sen- sorial signals from the periphery, and from higher brain structures. More precisely, the hypothalamic arcuate nucleus (ARC) harbours two neuronal populations, one participating to the synthesis of the appetite-stimulating neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and the other expressing the two appetite-suppressing peptides proopiome- lanocortin (POMC) and cocaine- and amphetamine- regulated transcript (CART) (see Lenard & Berthoud, 2008). This highlights the importance of neuropeptide-mediated pathways in the control of food intake and energy balance. Neuropeptides are a group of chemically diverse molecules modulating physiological processes and behaviours in mam- mals (van den Pol, 2012) and invertebrates (Taghert & Nitabach, 2012). Particularly relevant is the case of NPY, synthesized and released by many unrelated groups of neu- rons from different human brain regions and activating mul- tiple different receptors in target neurons (van den Pol, 2012).
The brain homeostatic control of feeding involves neural circuits located in the hypothalamus (hunger signals, initiat- ing feeding behaviour) and the brainstem (satiation signals, limiting meal size) generating appropriate integrated responses (Adan, Vanderschuren, & la Fleur, 2008; Woods,
Seeley, Porte, & Schwartz, 1998). Single neuropeptides con- tribute to feeding behaviours in mammals (Dailey & Bartness, 2009), and their roles in the neuronal circuits underlying these behaviours have been intensively studied. NPY/AgRP peptidergic neurons increase feeding intake by inhibiting POMC/CART system which stimulates anorexi- genic neurons in the lateral hypothalamus (LH) area, and stimulating orexigenic neurons in the paraventricular nucleus (PVN) (Aponte, Atasoy, & Sternson, 2011; Atasoy, Betley, Su, & Sternson, 2012; Wu, Boyle, & Palmiter, 2009). Together, these neuropeptides translates the feeding behav- iour in appetite as well as adaptive responses (Borgland et al., 2009).
Interestingly, several pieces of evidence indicate that neurobiological mechanisms underlying ED might involve an overreaction of the immune system, generating, in turn, a dysfunction of neuropeptide signalling. Thus, reactive Immunoglobulins (Igs) bind to food-intake neuropeptides (named peptide autoantibodies) and are identified in the serum of AN/BN patients, predominantly bound to a-MSH in hypothalamic neurons (Fetissov et al., 2005). In addition, the enterobacteria Caseinolytic protease B protein ClpB also act as an a-MSH-mimetic protein, triggering production of Igs against a-MSH, reducing its anorexigenic effects (Tennoune et al., 2014). Interestingly, these circulating auto- antibodies might be purified in order to be employed as pharmacological tools in AN and BN (Smitka et al., 2013).
In addition to the gastrointestinal-brain communication, gut microbiota plays an important role on nutriments absorption and energy expenditure. Likewise, the brain- gut-microbiota axis allows a bidirectional communication between gut microbes and the brain through endocrine, neural, immune and metabolic pathways (Dinan & Cryan, 2017). Moreover, modifications of the gut microbiota have also been described in AN patients (Armougom, Henry, Vialettes, Raccah, & Raoult, 2009). It is also well character- ized that the gut microbiome contributes to the pathogenesis of malnutrition through nutrient metabolism and immune function (Krajmalnik-Brown, Ilhan, Kang, & DiBaise, 2012). Besides, chronic constipation, a common feature in AN patients, is present prior to weight loss and causes changes in gut microbiota, increasing Methanobrevibacter smithii le- vels (Kim et al., 2012). More interestingly, elevated plasma concentrations of the ClpB have been detected in female patients with AN, BN, and BED when compared with healthy individuals (Breton et al., 2016). These findings open the possibility to manipulate gut microbiota (by using antibi- otics) helping to improve nutritional therapy for ED patients. Clearly, more research is needed at this point.
Pharmacology and pharmacotherapy tools in eating disorders
Current treatments of the EDs are substantially multidimen- sional and include psychotherapy, nutritional rehabilitation, drug treatment and even light therapy, but unfortunately often they have shown limited efficacy in ameliorating symp- toms not fully normalizing eating behaviours (Halmi, 2005). To date, psychotherapies such as cognitive behavioural
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therapy (CBT), cognitive analytic therapy (CAT), dialectical behavioural therapy (DBT) or family-based therapy (FBT), remain the main treatments of EDs, even though some drug therapies have been employed for some specific EDs. The most demanded pharmacotherapy of EDs should induce a remission of symptoms in the acute phase of the disease, prevent relapse over time and be appropriate to treat fre- quent associated comorbidities. Nowadays, there are no effective drugs to overcome all these clinical features, except fluoxetine and lisdexamfetamine, the only drugs approved by the international regulatory agencies for the treatment of two EDs (respectively BN and BED). Furthermore, numer- ous drugs used in psychiatric clinic (i.e. antipsychotics, anti- depressants, mood stabilizers, and selective norepinephrine and/or serotonin reuptake inhibitors) were also tested to treat clinical manifestations of EDs, showing variable results. In this review, we will highlight the main positive clinical results.
Anorexia nervosa
Antipsychotics Antipsychotic drugs act by blocking dopamine receptors (Miller, 2009). While antipsychotics are known to increase appetite and weight gain in patients with major psychiatric disorders (schizophrenia or bipolar disorder; Hay & Claudino, 2012), most of them are paradoxically not useful for weight recovery in AN patients (McKnight & Park, 2010). However, they are able to reduce AN psychological comorbidities (body image alteration, pathological focus on weight and food, fear of gaining weight, obsessive–compul- sive symptoms, hyperarousal and agitation; see Powers & Santana, 2004).
The first-generation of antipsychotics, pimozide and sul- piride, did not demonstrated sufficient capacity to favour weight gain (Vandereycken, 1984), whereas second-gener- ation antipsychotics are proved more useful, in particular olanzapine, a D2/5HT2 antagonist. This second generation favours an increase in weight, leads to a significant reduction in the ‘anorexic ruminations’ and depressive symptoms but also an improvement in obsessive–compulsive symptoms (Brewerton, 2012; Flament, Bissada, & Spettigue, 2012). Other second-generation antipsychotics, such as risperidone, quetiapine, aripiprazole, and ziprasidone, have not been so extensively studied in the treatment of AN (Powers & Bruty, 2009). While olanzapine is efficient in reducing psychiatric symptoms associated with the AN promoting weight recov- ery, its side effects, such as extrapyramidal symptoms and cardiac troubles (QT prolongation), are dangerous for anor- exic patients. All the main international guidelines classify the use of these second-generation antipsychotics just as secondary possibilities for AN treatment (Aigner, Treasure, Kaye, Kasper, & WFSBP Task Force On Eating Disorders, 2011).
Finally, the azapirone derivative tandospirone, also known as metanopirone, is a selective serotonin-1A (5-HT1A) receptor partial agonist (Tanaka et al., 1995) known to shown enhanced cholinergic and dopaminergic
neurotransmission in hippocampus and cortex (Koyama, Nakajima, Fujii, & Kawashima, 1999; Rasmusson, Goldstein, Deutch, Bunney, & Roth, 1994). Tandospirone is an anti- psychotic and anxiolytic drug clinically used to treat schizo- phrenia in China and Japan (Sumiyoshi et al., 2007), but also induces improvement in weight gain and psychopath- ology of the AN patients (Okita, Shiina, Nakazato, & Iyo, 2013).
Antidepressants While the use of antidepressant in the treatment of EDs would appear logical due to the high rates of comorbidity (greater than 50%) between EDs and mood depression (Mischoulon et al., 2011), the effectiveness of antidepressants in the treatment of AN patients is weak. Thus, while tricyclic antidepressants (TCA) have not shown significant benefits (Halmi, Eckert, LaDu, & Cohen, 1986), the most recent sero- tonin reuptake inhibitors (SSRIs – fluoxetine) have shown very little effectiveness in promoting weight regain in AN patients (Walsh et al., 2006).
Bulimia nervosa
Antipsychotics Second-generation antipsychotics used in AN treatment induce or exacerbate the crisis of binge eating in patients with EDs (McElroy, Guerdjikova, Mori, & O’Melia, 2012).
Antidepressants Contrarily to what is described for AN, antidepressants (including TCAs, SSRIs, Serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors, MAOIs) are the mainstay of pharmacological treatment for BN, by reducing the dopamine crisis of binge eating and purging phenomena, improving anxiety moods (Capasso, Petrella, & Milano, 2009). However, although quite effective, both the clinical use of TCA and MAOIs are not recom- mended for their frequent adverse events. Desipramine (a TCA also known as desmethylimipramine) inhibits the reuptake of norepinephrine and, to a minor extent, sero- tonin. Both imipramine and desipramine were demonstrated to reduce binge eating and to improve the comorbidities in short-term treatments (Barlow, Blouin, Blouin, & Perez, 1988; Walsh, Hadigan, Devlin, Gladis, & Roose, 1991). However, their side effects make them inadequate for BN long-term treatments (Agras et al., 1992; Leitenberg et al., 1994). In turn, SSRIs (fluoxetine, citalopram, sertraline and fluvoxamine) were shown to reduce BN main symptoms (Bacaltchuk & Hay, 2001; McElroy et al., 2003; Milano, Petrella, Sabatino, & Capasso, 2004). Among them, Fluoxetine has been the most studied being – since 1997 – the only drug approved by the FDA for the treatment of BN, at a dose of 60mg/day. Although BN is a chronic disease with frequent relapses, most trials lasted only several months (Martiadis, Castaldo, Monteleone, & Maj, 2007). However, a 58-week study has demonstrated the efficacy of fluoxetine in reducing binge and purging episodes, obsessive–compulsive
symptoms and the frequency of relapses (Romano, Halmi, Sarkar, Koke, & Lee, 2002). Finally, milnacipran is a dual acting antidepressant which inhibits the reuptake of both serotonin and noradrenaline (SNRI) being efficient in the short-term treatment of patients with BN (El-Giamal et al., 2003) and leading to a significant reduction in weekly binge eating and vomiting frequency.
Anticonvulsant mood stabilizers Many drugs described as ‘mood stabilizers’ are categorized as anticonvulsants, and the term ‘anticonvulsant mood stabilizers’ is sometimes used to describe them as a class. Since the early 2000s, antiepileptic drugs (AEDs) have been useful in the treatment of psychiatric disorders related to EDs, such as headache, substance abuse, and bipolar, anxiety or personality disorders. Furthermore, many AEDs interact with glutamatergic, GABAergic, serotonergic and dopamin- ergic systems in the regulation of appetite, food intake and weight (Gao & Horvath, 2008; Meister, 2007). For example, topiramate and zonisamide are associated with appetite and weight decrease (McElroy et al., 2009).
Numerous human clinical studies, and preclinical studies in animals, have demonstrated the utility of topiramate (TPM) in neuroprotection against ischemia and brain inju- ries, body weight loss in obese subjects, mitigation of alcohol consumption, drug addiction, post-traumatic stress disorder, BN and BED. Its efficiency in the treatment of EDs associ- ated with obesity – BN and BED – could be related to its effect on kainite/AMPA glutamate receptors (Hettes et al., 2003). Thus, TPM improves multiple behavioural aspects of BN: binge and purge symptoms are reduced, while self- esteem, eating attitudes, anxiety, body weight and body image are also ameliorated (Nickel et al., 2005). Beside its efficiency, TPM has some recognized several adverse events (paraesthesia, metabolic acidosis, nephrolithiasis, acute cog- nitive impairment, and acute myopia among others (Shank & Maryanoff, 2008) that must be taken into account in the common clinical practice.
Binge eating disorder
Amphetamine Due to their weak efficacy and severe side effects, the use of drugs to treat BED was limited until lisdexamfetamine dime- sylate (L-lysine-dextroamphetamine, LDX) was approved by the US food and drug administration (FDA) to treat moder- ate to severe BED in adults (50–70mg/day, US FDA, 2015). Nowadays, it is the only drug currently approved for the treatment of BED, and the second medication of any ED, after fluoxetine (approved for BN in 1997). LDX is an effica- cious treatment for BED by regulating dopamine (DA), nor- epinephrine (NE) and serotonin neurotransmitters involved in the modulation of appetite, hunger and eating behaviours (Guerdjikova, Mori, Casuto, & McElroy, 2016).
Antipsychotics Memantine is a non-competitive antagonist of N-methyl-D- aspartate receptors (NMDARs). Memantine therapy in
schizophrenic patients improves mainly negative symptoms (Velligan, Alphs, Lancaster, Morlock, & Mintz, 2009) show- ing also promising results in the treatment of generalized anxiety disorder (Schwartz, Siddiqui, & Raza, 2012), atten- tion deficit hyperactivity disorder ADHD (Hosenbocus & Chahal, 2013) and obsessive compulsive disorder (Haghighi et al., 2013). Memantine has been proved effective in reduc- ing the frequency of binge days and episodes (Brennan et al., 2008; Hermanussen & Tresguerres, 2005).
Antidepressants The antidepressants are also useful in the treatment of BED both decreasing the binge seizure frequency and improving symptoms of depression and anxiety often present in BED. SSRIs seem to favour a significant reduction in binge crisis having a modest effect in reducing the body weight of the patients (Reas & Grilo, 2008; Stefano, Bacaltchuk, Blay, & Appolinario, 2008). Although the effect of fluoxetine is con- troversial in humans (Arnold et al., 2002; Grilo, Crosby, Wilson, & Masheb, 2012), this drug (as TPM and sibutr- amine) was reported to reduce binge eating in animal mod- els (Cifani, Polidori, Melotto, Ciccocioppo, & Massi, 2009).
Two other drugs acting similar to antidepressants, duloxe- tine and sibutramine, two serotonin re-uptake inhibitors (SNRIs), have shown the ability to reduce both the frequency of binge episodes crisis, body weight, and depressive symp- toms in patients with BED (Appolinario et al., 2003; Guerdjikova et al., 2012; Milano et al., 2005). However, since 2010, sibutramine has been withdrawn from European and USA markets due to cardiovascular risks. Venlafaxine is another SNRI that at low-dose (75mg/day) also acts as a weak inhibitor of norepinephrine re-uptake (Smith, Dempster, Glanville, Freemantle, & Anderson, 2002). In addition, Venlafaxine may be an effective treatment for BED associated with overweight or obesity in reducing of weekly binge frequency, severity of binge-eating and mood symp- toms (McElroy et al., 2012). These effects can be related to its activity against impulse control disorders (ICD; Camardese, Picello, & Bria, 2008).
Finally, atomoxetine is a selective norepinephrine reuptake inhibitor (NRI) indicated for patients with atten- tion-deficit hyperactivity disorder and narcolepsy (Garnock- Jones & Keating, 2009). Although in 2007 McElroy’s team have shown preliminary evidence for the efficacy of atomo- xetine in BED (McElroy et al., 2007), no newer studies has been devoted to this drug.
Anticonvulsant mood stabilizers In studies in BED with obesity, Citalopram-treated patients displayed a 94% reduction of binge eating and significant weight loss (McElroy et al., 2003). In turn, zonisamide is a sulfonamide anticonvulsant approved for use as an adjunc- tive therapy in adults with partial-onset seizures and infantile spasm (Brodie, Ben-Menachem, Chouette, & Giorgi, 2012; Holder & Wilfong, 2011). Together with the CBT, zonisa- mide has proved useful in the treatment of obesity associated BED, in a one-year trial, with reduction of the binge
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manifestations and weight loss (Ricca, Castellini, Lo Sauro, Rotella, & Faravelli, 2009). However, it presents substantially the same adverse effects as TPM.
Anti-obesity drugs The serotonin releaser fenfluramine, also known as 3-tri- fluoromethyl-N-ethylamphetamine, is a highly effective ano- rectic agent in both laboratory animals and humans (Davis & Faulds, 1996; McGuirk, Goodall, Silverstone, & Willner, 1991). This drug reduced the frequency of seizures in BED obese patients, without weight loss (Stunkard, Berkowitz, Tanrikut, Reiss, & Young, 1996). However, fenfluramine works only while it is taken and binge eating returns to pre- vious levels after medication. Fenfluramine was removed from its clinical use after reports of heart valve disease in 1997 (Rothman & Baumann, 2002). In turn, orlistat is a gastrointestinal lipase inhibitor that reduces the absorption of dietary fat, indicated for weight loss and maintenance, being designed to treat obesity (Padwal & Majumdar, 2007). It has been used in individuals with BED primarily targeting weight loss rather than binge eating frequency (Grilo, Masheb, & Salant, 2005). It must be noted that orlistat mis- uses were reported in patients with BED and BN (Fernandez-Aranda et al., 2001; Hagler Robinson, 2009).
Anti-addiction drugs The urge to consume food and the lack of control in BED patients resemble the strong impulse to consume alcohol and the absence of control found in Alcohol Use Disorder (AUD) patients (Pelchat, 2009). Indeed, BED and AUD share similar neural substrates (Volkow, Wang, & Baler, 2011) activating the mesolimbic dopaminergic ‘reward’ sys- tem (Koob & Volkow, 2010; Umberg, Shader, Hsu, & Greenblatt, 2012). Therefore, almost all AUD medications have been tested in BED patients, with insignificant results, except disulfiram, the oldest medication approved for AUD (McElroy et al., 2012; Suh, Pettinati, Kampman, & O’Brien, 2006). Disulfiram is a carbamate derivative discovered in the 1920s, and used since the 1950s to support the treatment of chronic alcoholism by producing an acute sensitivity to etha- nol by inhibiting the aldehyde dehydrogenase (ALDH) involved in alcohol metabolism (Hald & Jacobsen, 1948). Disulfiram also inhibits the dopamine b-hydroxylase (DbH), responsible for converting dopamine to noradrenaline in noradrenergic neurons (Barth & Malcolm, 2010). Used as treatment of BED, disulfiram effectively reduced the fre- quency of binge eating episodes in BED patients, and this effect is also considered to be due, at least in part, to DbH inhibition, as for cocaine use disorder (Farci et al., 2015). However, the use of disulfiram in the BED treatment may be limited by side effects or by the risk of exacerbation of psychotic disorders in BED patients.
In summary, the pharmacological treatment of EDs is in its early stages. Nowadays, no drug was especially designed to treat ED suffering patients, and current ED pharmaco- therapy is only the adaptation of some drugs previously used
in psychiatric clinic, showing generally undesirable side effects.
Neuropeptides, neurotransmitters and hormones involved in EDs
Role of neuropeptides in EDs
Hunger signals results from internally generated metabolic deficits yielding the animals to feed (Saper, Chou, & Elmquist, 2002). Feeding behaviour remains critical for restoring metabolic homeostasis and, consequently, survival. Animals have evolved refined feedback mechanisms to regu- late energy expenditure and food consumption, rectifying possible imbalances and modifying feeding thresholds con- sidering both internal needs and food availability (Morton, Cummings, Baskin, Barsh, & Schwartz, 2006). How the ner- vous system integrates internal physiological state to generate a response triggering feeding behaviours is insufficiently documented and, hence, understood. However, in this scen- ario, the crosstalk of neuropeptides within the nervous sys- tem and peripheral circulating hormones appears to be extremely relevant. Figure 1 shows a schematic summary of the information highlighted in this section. Indeed, neuro- peptides affect different complex behaviours at system, cellu- lar, and molecular levels in an age-dependent and hormonally modulated manner (Figure 1).
Research evidences point directly to defaults in neuropep- tide levels and/or function in ED pathogeny. In this review, we have highlighted the most relevant:
NPY/AgRP Neuropeptide Y and Agouti-related peptide are both pro- duced mainly in the ventromedial part of the ARC hypotha- lamus by NPY/AgRP neurons (Broberger, Johansen, Johansson, Schalling, & H€okfelt, 1998; Chronwall et al., 1985). Both neuropeptides exert an orexigenic signal over hypothalamic–pituitary–adrenocortical axis, increasing the ACTH, cortisol and prolactin release and have been involved in appetite regulation. Cerebral injections of NPY induce the food intake (Clark, Kalra, Crowley, & Kalra, 1984) and high levels of NPY are associated with high food intake but low physical activity (Schwartz et al., 1996). Recent studies indi- cates AN patients are unable to up-regulate NPY system to adapt their energy demand when exposed to chronic under- nutrition, whereas the satisfaction for rapid food is due to the triggered a-melanocyte-stimulating hormone (a-MSH) response occurred during lunchtime (Galusca et al., 2015). Besides, an abnormal increase of NPY have been found in AN and BN patients after consumption of high-carbohydrate and high-protein breakfast, suggesting alterations in regula- tion of gut–brain axis peptides and indicating that NPY plasma levels represent a good indicator for EDs (Sedlackova et al., 2012). In an indirect manner, the anti-stress effects of NPY are also relevant to ameliorate psychiatric conditions of both AN and BN patients. In turn, AgRP has been involved in appetite regulation since passive stress prevents AgRP and
orexin upregulation in response to activity in an anorexia rat model (Boersma et al., 2016).
Orexins Orexins, also known as hypocretins, are orexigenic neural hormones expressed and secreted in the LH nucleus, but are also expressed in peripheral tissues such as kidney, adrenal glands, pancreas, placenta, stomach, ileum, colon and colo- rectal epithelial cells (Nakabayashi et al., 2003). Orexins interact with leptin either directly regulating neural orexi- genic pathways (Muroya et al., 2004) or indirectly, modulat- ing the activity of orexigenic neurons in the LH (Louis, Leinninger, Rhodes, & Myers, 2010). Interestingly, neuropep- tides as orexins, but also melanin-concentrating hormone (MCH) and 26RFa are up-regulated in AN patients. To explain this finding, two different hypotheses have been for- mulated. In the first one, this up-regulation might result from an adaptive mechanism to increase food intake against under nutrition. In the second, a chronic increase of orexi- genic neurons could reinforce dopamine-induced anxiety in the reward system (see dopamine section below) of AN patients, increasing their aversion to eat (Gorwood et al., 2016). Orexins are also involved in endocrine system regula- tion, playing an important role in insulin, glucagon and lep- tin secretion in response to glucose (Park et al., 2015). Interestingly, alterations in orexin signalling could be related with eating disorders at different levels: either by regulating directly the appetite, but also regulating the reward system and controlling anxiety levels. For this reason, orexin could
be the link between physiological and psychological compo- nents, since most of the eating disorders are caused by cul- tural pressure to thinness. This pressure often canalizes as frustration by predisposed people, triggering development of anxiety and behavioural related disorders.
Proopiomelanocortin (POMC) and CART Proopiomelanocortin is a precursor polypeptide synthesized mainly in the anterior pituitary, expressed as pre-proopiome- lanocortin and cleaved by the convertase prohormones 1 and 2 generating a-MSH, ACTH, and the opioids beta-endorphin and Met-enkephalin. POMC is an anorexigenic peptide at the hypothalamic ARC. Indeed, re-feeding after fasting indu- ces the activation of POMC neurons in ARC, promoting satiety (Fekete et al., 2012). Leptin is the key activating regu- lator of the CNS POMC system, which is involved in appe- tite but also regulation of sexual behaviour, lactation, reproductive cycle, central cardiovascular control, melanin production in the skin, addictive behaviours and stress ma- nagement (Millington, 2007; Zhou & Kreek, 2015). POMC mRNA level increases after stress exposition and POMC neurons activate rapidly under emotional stressing condi- tions (J. Liu et al., 2007). These evidences define the role of POMC as a key communication link between brain feeding control centre and stress systems (Ryan et al., 2014). In ad- dition, a-MSH, a POMC-derived peptide, is involved in manifestation of affective disorders like anxiety and depres- sion via MC4R response in the PVN and ARC nuclei, among others (Kokare, Dandekar, Singru, Gupta, &
Figure 1. The neuropeptide, neurotransmitter and hormonal control of food intake. This schematic picture shows the interrelationships among different modulators, brain areas and other body organs. Dotted lines indicate modulatory actions exerted outside the hypothalamus. Pointed arrows indicate activation and blunt arrows indicate repression. Dopaminergic actions are shown in blue, whereas serotonergic actions are represented in orange. Abnormal levels reported on Eating disorders are indicated with yellow squares.
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Subhedar, 2010). Finally, intracerebroventricular injection of MC4R agonists activates the hypothalamo–pituitary–adrenal (HPA) axis, increased anxiety and reduced food intake (Klenerova, Sery, & Hynie, 2008).
In turn, cocaine and amphetamine regulated transcript (CART) is an anorectic peptide widely expressed in both central and peripheral nervous system, playing an important role in the hypothalamus (Keller et al., 2006). As for POMC, CART hypothalamic secretion is regulated by leptin (Elias et al., 1998) and it has been related with addictive beha- viours and stress responses (Bakhtazad, Vousooghi, Garmabi, & Zarrindast, 2016). The intracerebroventricular CART administration reduces appetite and increases energy expenditure, but, under specific circumstances, hypothalamic CART has been considered also as orexigenic (Murphy, 2005). An increase in CART expression has been also reported in the nucleus accumbens (NAc), mediating the hyperactivity in AN induced by activation of serotonin 5- HT4 receptor (Jean et al., 2007).
Oxytocin Oxytocin is a peptidic hormone involved in social, sexual and parental behaviours, among others (Ross & Young, 2009). Several evidences connect oxytocin signalling and EDs. Indeed, recently, oxytocin treatment has been proposed against obesity (Altirriba, Poher, & Rohner-Jeanrenaud, 2015), whereas oxytocin antagonist increases body weight gain (Zhang & Cai, 2011). The release of oxytocin to blood- stream has been associated with the inhibition of appetite (Herisson, Brooks, Waas, Levine, & Olszewski, 2014) and the release, through the action of prolactin-releasing peptide, of the satiety signal cholecystokinin (CKK) (Yamashita et al., 2013). Actually, four-week chronic oxytocin treatment reduces body weight in rhesus monkeys by decreasing food intake and increasing energy expenditure and lipolysis (Blevins et al., 2015). This anorectic effect involves partially the inhibition of reward circuits (Peters, Bowen, Bohrer, McGregor, & Neumann, 2017), is accompanied by a reduc- tion of gastric empting and is blocked by an oxytocin recep- tor antagonist in rats (Wu, Doong, & Wang, 2008). According to this, circulating oxytocin levels has been found altered in AN patients, but not in BN (Monteleone, Scognamiglio, Volpe, Di Maso, & Monteleone, 2016). Interestingly, oxytocin treatments decreased caloric intake in BN patients but not in AN (Kim, Eom, Yang, Kang, & Treasure, 2015). Despite these contradictory findings, oxyto- cinergic system has been suggested to be involved in mecha- nisms underlying BN and eating disorders, since specific oxytocin receptor genes polymorphisms have been recently found (Acevedo, Valencia, Lutter, & McAdams, 2015; Kim, Kim, Kim, Shin, & Treasure, 2015). The oxitocinergic system shows a higher regulation level, involving some other neuro- peptides like leptin, which has been reported to decrease oxytocin release (Kutlu et al., 2010). In addition, AN and BN patients present lower serum activity of the prolyl-endo- peptidase, an enzyme involved in oxytocin cleavage (Maes et al., 2001).
Role of neurohormones in EDs: the ghrelin/leptin system
Ghrelin Ghrelin, the ‘hunger hormone’, is a peptidic hormone expressed in humans by P/D sub 1 gland cells of the sto- mach (Rindi et al., 2002), with lower expression in pancreas, gallbladder, colon, liver, colon and lungs (Kojima, Hosoda, & Kangawa, 2001). Ghrelin is also expressed in the brain (Cowley et al., 2003), where it exerts a paracrine effect by acti- vating orexigenic NPY/AgRP neurons and inhibiting anorexi- genic POMC neurons, increasing appetite [reviewed in Kageyama, Takenoya, Shiba, & Shioda (2010)]. However, new studies do not indicate ghrelin central nervous system synthe- sis (Cabral, Lopez Soto, Epelbaum, & Perello, 2017). In any case, ghrelin main secretion starts when the stomach is empty (Williams, Cummings, Grill, & Kaplan, 2003). Ghrelin increases gastric secretion and gastrointestinal motility to pre- pare the body for food intake [reviewed in Kirsz & Zieba (2011)]. The ghrelin/growth hormone secretagogue receptor (GHSR) is the only ghrelin receptor known, being located in the same brain areas than the leptin receptor (Perello et al., 2012). Its activation triggers the synthesis of NPY, increasing appetite albeit ghrelin treatment was ineffective as a single appetite stimulatory treatment in AN patients (Miljic et al., 2006). Furthermore, the effects of ghrelin also involve the reward system activation throughout dopaminergic pathways, (see Dopamine section below and also Perello & Dickson, 2015). It also exerts a neurogenic action in the hippocampus, facilitating learning and memory (Kim, Kim, & Park, 2017), and acts on the central nucleus of amygdala, where modulates emotional arousal and feeding (Alvarez-Crespo et al., 2012). Surprisingly, several studies have reported elevated ghrelin levels in AN patients (Blauwhoff-Buskermolen et al., 2017; Nakai et al., 2003; Tolle et al., 2003).
Leptin Leptin, the ‘satiety hormone’, is an adipocyte-derived hor- mone involved in the regulation of energy balance at both long- and short-term (Blundell, Goodson, & Halford, 2001). Leptin activity is exerted in the hypothalamic ARC, stimulat- ing anorexigenic neurons expressing POMC and cortico- tropin-release factor (CRF), and inhibiting orexigenic NPY/ AgRP neurons (Baver et al., 2014; Flak & Myers, 2016). The existence of low levels of plasma leptin in cerebrospinal fluid (hypoleptinemia) is a key endocrinological feature of AN (F€ocker et al., 2011; Hebebrand et al., 1997). Hence, altera- tions in leptin homeostasis could be crucial in eating disor- ders. Indeed, reduced plasma circulating leptin levels were reported in AN and BN patients, but not in overweight BED patients. Interestingly, the inverse correlation was found when measuring plasma-circulating levels of leptin receptor in the same groups. Conversely, an increased concentration of NPY correlates to body mass deficiency coexisting with high concentrations of leptin, suggesting disturbances in the regu- latory axis (Monteleone, Fabrazzo, Tortorella, Fuschino, & Maj, 2002). Reduced circulating leptin plasma levels but nor- mal leptin concentrations in subcutaneous adipose tissue were also reported in acute ill AN girls (Dostalova et al., 2005).
In summary, data obtained from ghrelin and leptin indi- cate that an alteration in hormonal milieu is relevant in the progression of eating disorders, highlighting the role of physiological compensatory mechanisms trying to minimise the pathology extent.
Other appetite regulators In addition to the peptides and hormones described above, other regulators play a role on appetite regulation, and their alterations have been linked to EDs onset and progression. Cholecystokinin (CCK) is a peptidic hormone of the gastro- intestinal system that promotes satiety, but has been also related with anxiety, panic and even hallucinations (Lenka, Arumugham, Christopher, & Pal, 2016; Zwanzger, Domschke, & Bradwejn, 2012). In a recent study, CCK exhibits similar plasma levels in AN patients compared to control group both prior to and after a meal suggesting a hormonal adaptation (Cuntz et al., 2013). Inconsistently, in older studies, plasma measurements performed in AN patients showed a postprandial increase in CKK levels, sug- gesting an implication in this ED (Tomasik, Sztefko, & Starzyk, 2004). More data are clearly necessary to solve this ambiguity. In turn, Glucagon like peptide 1 (GLP-1) is a brain-gut peptide that exerts a hormone-neurotransmitter action inhibiting food intake, energetic expenditure and insulin levels (Richard et al., 2014; Shah & Vella, 2014). As a satiety inductor, GLP-1 interacts with the leptin and ghrelin system to induce satiation (Zhu et al., 2002), probably by decreasing gastric emptying and acting on the brain to pro- duce a conditional taste aversion (Monteleone, Castaldo, & Maj, 2008). In AN patients, whereas GLP-1 was significantly decreased compared with normal individuals, insulin and glucagon levels were increased, indicating an alteration in glucose homeostasis (Tomasik, Sztefko, Starzyk, Rogatko, & Szafran, 2005). In addition, punctual GLP-1 secretory decrease was also found in BN patients compared to healthy controls, being this concurrence limited to bingeing and vomiting events (Brambilla, Monteleone, & Maj, 2009). Other gut peptide, Peptide tyrosine tyrosine (PYY) belongs to NPY family and is secreted in ileum and colon with an anorexigenic role (Karra, Chandarana, & Batterham, 2009). PYY plasma concentrations increases within 15min after eat- ing and lasts approximately 90min (Batterham & Bloom, 2003). Serum levels of PYY hormone are decreased in BN/BED compared with AN (Eddy et al., 2015). Finally, concerning opioid peptides, anandamide, also known as N-arachidonoylethanolamine (AEA), plays an important role in feeding behaviour generating motivation and pleasure in food consumption (Fuss et al., 2015; Mahler, Smith, & Berridge, 2007). Anandamide and hence, the endocannabi- noid system, shows a therapeutic relevance in EDs. The can- nabinoid agonists can alleviate anorexia and nausea, whereas the AEA mono-unsaturated analogue oleoylethanolamide (OEA) decreases food intake and body weight through a cannabinoid receptor-independent mechanism (S Gaetani, Kaye, Cuomo, & Piomelli, 2008). In the same study, plasma levels of anandamide were down-regulated in AN patients. As anandamide, other opioid peptides as hypothalamic
b-endorphin and dynorphin-A shown level changes in EDs animal models (see Animal models section).
Dopamine and serotonin in EDs
Dopamine role in EDs Dopamine is the most important regulator of reward behav- iours, including feeding and reproduction. These reward behaviours are conserved along phyla. In Drosophila, a small group of dopaminergic neurons in the protocerebral anterior medial (PAM) cluster send axons to the mushroom bodies (MBs), where appetitive olfactory associative memory is formed. After sugar ingestion, PAM dopaminergic neurons are activated, generating a reward effect. These neurons become overactivated under starving conditions (Liu et al., 2012). In mammals, abnormal function of mesocorticolimbic dopaminergic circuits impairs severely motivation and reward behaviours, contributing to pathological conditions such as depression, addictions, compulsive moods and apathy [reviewed in Castrioto, Thobois, Carnicella, Maillet, & Krack (2016)]. As an example, reward system responsive- ness is heightened in adolescent suffering AN when under- weight and after weight restoration (DeGuzman, Shott, Yang, Riederer, & Frank, 2017). These mesocorticolimbic dopaminergic alterations correlate with an abnormally high physical activity in AN and BN patients (Hebebrand et al., 2003) and can trigger a dopamine-dependent stress response (Kalyanasundar et al., 2015). This convergence between dopamine levels, physical activity pattern alterations and eat- ing disorders points out towards a dysfunction in the dopa- minergic neuromodulatory system. In addition, it exists a clear association between dopaminergic pathways and eating disorders with psychiatric comorbidities including depres- sion, anxiety, compulsive disorders and even aggressive behaviours (Jennings, Wildes, & Coccaro, 2017; Martinussen et al., 2016). In the last years, neuroimaging has reported dopaminergic alterations in ED patients (Berner, Winter, Matheson, Benson, & Lowe, 2017). As examples, positron emission tomography (PET) shows a [11C]raclopride bind- ing increase in ventral striatum in recovered AN patients (Frank et al., 2005), whereas AN patients display a poor acti- vation in prefrontal cortex (PFC) (Nagamitsu et al., 2011). Finally, nigrostriatal pathway is also involved in food intake regulation, since the restoration of dopamine expression in dopamine deficient mice causes hypophagia and bradykinesia (Hnasko et al., 2006).
Ghrelin, leptin and the dopamine-reward system: physio- logical roles and therapeutic potential Many studies have been carried out to demonstrate the therapeutic use of ghrelin in EDs with contradictory results: whereas some of them described that ghrelin administration was ineffective to increase the appetite in AN patients-prob- ably due to the high circulating ghrelin levels found in these subjects- (Miljic et al., 2006; Otto et al., 2001), others sug- gested that a ghrelin long-term treatment was efficient to treat AN patients (Hotta et al., 2009; Kawai et al., 2017). In rodents, ghrelin injection increases food intake and triggers
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dopamine release (Abizaid et al., 2006; Kawahara et al., 2009). It also prevents the development of activity based anorexia in mice, confirming its role in the mesocorticolim- bic dopaminergic pathway (Legrand et al., 2016).
In turn, leptin is also involved in hedonic and reward feeding behaviour through mesocorticolimbic dopaminergic pathways, including NAc and ventral tegmental area (VTA). Whereas orexin coming from LH orexigenic neurons acti- vates VTA dopaminergic neurons, leptin reduces the LH orexin activation, lowers dopaminergic mesolimbic neurons activation, and decreases dopamine release in NAc, all through the activity of the neuropeptide galanin (Laque et al., 2015). Thereby, leptin negatively modulates reward- related behaviour suppressing feeding (Leinninger et al., 2009). According to these findings, leptin antagonism may represent a viable therapeutic strategy in ED.
Taken all these evidences together, the VTA to NAc dopaminergic projections can be considered as essential ele- ments of both ghrelin and leptin responsive circuits control- ling food reward behaviour, highlighting the complexity of signal integration within the VTA and locating this brain area as a crucial target for therapeutically actions tackling EDs (Skibicka et al., 2013).
Serotonin function in ED Serotonin (5-hydroxitriptamin or 5-HT) is a monoamine neurotransmitter produced in the brain by neurons located in the dorsal and median raphe nuclei projecting to cortical and striatal limbic regions. Serotonergic projections to hypo- thalamus are responsible of the satiety signal (Haleem & Haider, 1996) whereas projections to hippocampus, striatum, amygdala and frontal cortex are responsible of the mood regulation (Lambe, Fillman, Webster, & Shannon Weickert, 2011; Mineur et al., 2015; Sumiyoshi, Kunugi, & Nakagome, 2014). Serotonin modulates hunger, sleep, sex, emotions, and also several endocrine processes (Haleem, 2012). Additionally, depressive, anxious, impulsive and obsessional behaviours, commonly related to ED, have been extensively related with serotonergic functions (Brewerton, 1992; Kaye, 1997). AN and BN patients develop an egosyntonic personal- ity, implying that they do not perceive anything wrong with their acts. They consider their actions as reasonable and appropriate, perceiving their dysfunctional cognition regard- ing to their own weight and shape as perfectionism (Aardema, 2007). This particular trait shared between ED and other psychiatric diseases, taken together with the fact that medications acting over 5-HT pathways have some degree of efficacy over AN and BN patients, suggests an important role of serotonergic system dysfunction in ED onset and progression (Kaye, Bailer, Frank, Wagner, & Henry, 2005). Some authors directly assign to the serotoner- gic system the psychiatric symptomatic deterioration observed in AN and BN due to malnutrition, since trypto- phan (TRP), an essential amino acid only available in diet and precursor of 5-HT, is reduced in their diet (Haleem & Haider, 1996). The fact that re-feeding increases TRP plasma levels in AN patients correlating with a decrease in depres- sive symptoms supports their theory (Gauthier et al., 2014).
Animal models employed on EDs research
A striking parallelism to the existence of brain neuropeptider- gic circuits controlling mechanisms of food intake/metabolism homeostasis is found in other vertebrates as rodents but also in insects (Pool & Scott, 2014). Indeed, whereas NPY/AgRP neurons were proved to be involved in food intake stimulation in rats (Stanley, Kyrkouli, Lampert, & Leibowitz, 1986; Zarjevski, Cusin, Vettor, Rohner-Jeanrenaud, & Jeanrenaud, 1993), energy expenditure decrement (Billington, Briggs, Grace, & Levine, 1991) and hedonic feeding (Pandit, la Fleur, & Adan, 2013), a homologue of the mammalian NPY was described in the insect model Drosophila melanogaster, the Drosophila NPF (Brown et al., 1999). Like NPY, Drosophila NPF is expressed in only a small set of neurons in the fly brain modulating neuronal circuits related to feeding behaviours, stress responses, metabolism, energy homeostasis, ethanol consumption and also reproduction (Krashes et al., 2009; N€assel & Winther, 2010). In addition, the neuropeptide hugin, homologous to mammalian NeuromedinU, inhibits feeding behaviour (Melcher & Pankratz, 2005). Subtypes of hugin neu- rons connect chemosensory to endocrine neurons producing the Diuretic hormone 44 neuropeptide (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), responsible of the regulation of gut motility and excretion (Dus et al., 2015), and Drosophila insulin-like peptides (DILPs) (Kannan & Fridell, 2013). In turn, whereas dimin- ished signalling of DILPs affects food intake in flies, drosulfa- kinins (DSKs), cholecystokinin-like peptides, regulates satiety in Drosophila (S€oderberg, Carlsson, & N€assel, 2012). Interestingly, insulin-producing cells of the fly brain co- expresses both DILPs and DSKs, and each peptide affects the transcript levels of the other suggesting a feedback regulation between two signalling pathways (S€oderberg et al., 2012).
With the help of the Drosophila sophisticated genetic toolkits and the deep knowledge of their sensory and central nervous system circuitry, it is possible to further investigate and characterize neuropeptide function in food intake, energy balance and diet restriction, among other processes. Besides, the short life-cycle of Drosophila helps to assess the role of precocious aspects on food intake control. Furthermore, some recent methods developed in Drosophila had made possible to precisely quantify food intake, facilitat- ing advances on the genetic, neural, and environmental fac- tors modulating food consumption (Deshpande et al., 2014). This knowledge will be crucial not only to delineate the gen- etic and neural mechanisms of metabolism and disorders connected with food consumption, but also to identify evolu- tionarily conserved candidate genes and pathways relevant to human biology [see next section and Garlapow, Huang, Yarboro, Peterson, & Mackay (2015)].
Research using EDs animal models has also been highly valuable in the study of brain neurotransmitters and circuitry underlying aberrant feeding behaviours. To date, some reward-related brain dysfunctions have been described on rodent animal models of AN, BN and BED, by affecting dopamine (DA), serotonin and acetylcholine (ACh) neuro- transmitters but also opioid levels (Avena & Bocarsly, 2012). Thus, in an AN rodent model based on activity, the activity-
based anorexia (ABA) model (Routtenberg & Kuznesof, 1967), a restricted access to food increases the reinforcing effects of DA when the rat finally eat, suggesting alterations in mesolimbic DA and also serotonin as a result of starvation. In addition, b-endorphin levels are high in plasma from ABA rats, due to rises in hypothalamic b-endorphin and dynorphin-A (Aravich, Rieg, Lauterio, & Doerries, 1993). Likewise, eating palatable food releases DA in a BN model, whereas purge behaviour attenuates a signal of satiety dependent on ACh release. In this BN model, binge eating is combined with gastric sham feeding in the rat to incorporate both bingeing behaviour and purging component aspects (Avena, Rada, Moise, & Hoebel, 2006). With respect to BED, several animal models are available, by offering limited access to a palatable high-fat or high-sugar food, providing ad libitum access to standard rodent chow for several weeks, by alternating cyclic periods of food deprivation and feeding or even by using foot-shocks to generate binge eating beha- viour in rats. Data generated from BED animal models have yielded important insights to concomitant physiological and neurochemical alterations associated to binge. Thus, binge eating of a 10% sucrose solution causes a repeated release of DA in the NAc similar to changes observed with drug dependency and obesity and have also unveiled a role for NAc ACh in binge eating behaviour (Avena, Rada, & Hoebel, 2008; Rada, Avena, & Hoebel, 2005). Concerning the opioid system, the use of opioid antagonists as naltre- xone or naloxone (among others) was able to decrease intake of preferred fat and sucrose diets and also to suppress pala- table food intake (Boggiano et al., 2005; Naleid, Grace, Chimukangara, Billington, & Levine, 2007). Moreover, in a rat BED model, memantine treatment fully blocked the com- pulsivity associated with the intake of the highly palatable food, confirming the potential therapeutic role of this drug in curing aspects of BED in humans (Popik, Kos, Zhang, & Bisaga, 2011; Smith et al., 2015).
In addition, rat animal models shared characteristics with human patient psychopathologies, including EDs co-morbi- dities, helping to find novel preventions or treatments (Lutz et al., 1998). As an example, many representative features found in AN patients can be mimicked in a rat model of com- bined food restriction and increased physical activity (the abovementioned ABA model). Food restricted rats exhibited this hyperactivity and low leptin levels seem to contribute to the phenotype of these AN rats because hyperactivity can be reduced by leptin supplementation (Dixon, Ackert, & Eckel, 2003; Hebebrand et al., 2003). Additionally, a rat model of BED combines the use of intermittent food restriction with frustration stress (Micioni Di Bonaventura et al., 2014) assess- ing stress-induced food-reward behaviours that are crucial in the development of eating disorders in humans. Moreover, rat strains can be used to study reward-driven mechanisms by involving progressive tests where animals needs to gain their food (i.e. by pressing a lever), being more active to obtain pal- atable food sources. In this context, reward-deficit syndromes can also be studied in rats whose dopamine synthesis or dopa- mine receptor signalling is disturbed (Gaetani et al., 2016). Remarkably, clinical findings and data obtained through neu- roimaging and pharmacotherapy studies of human
populations have supported and enhanced the information derived from rat models.
Genetic approaches
Genetically, EDs are aggregated in families (Zerwas & Bulik, 2011). Twins studies have provided an irrefutable proof, showing that the heritability of these disorders is 33–84% for AN, 28–83% for BN and 41–57% for BED (Munn-Chernoff & Baker, 2016). In 2003, Gorwood, Kipman, & Foulon (2003) published the first study indicating family burden within these disorders, followed by others (Clarke, Weiss, & Berrettini, 2012; Helder & Collier, 2011; Thornton, Mazzeo, & Bulik, 2011; Treasure et al., 2015). Several works described specifically the family aggregation (Hudson et al., 2006; Lilenfeld, Ringham, Kalarchian, & Marcus, 2008; Munn- Chernoff & Baker, 2016). All of them confirm that EDs have a family burden. However, family studies are unable to address whether family-related factors are genetic and/or environmental (Zerwas & Bulik, 2011).
Genome-wide association studies
Genetic epidemiology transforms the way we look into the influence of genes and environmental factor in EDs. Genome-wide association studies (GWAS) show large scale genetic studies of EDs that measure simultaneously hundreds of thousands of genetic variants scattered throughout the human genome. In the case of those specific for EDs, research focuses on single nucleotide polymorphisms (SNPs), traits, occurring more frequently in people with AN, BN or BED than in healthy people. Each study can look at hun- dreds or thousands of SNPs in several tentative traits at the same time. GWAS represent a promising way to study com- plex, common diseases in which many genetic variations contribute to a person’s risk, allowing effect-size estimates for specific genetic variants, testing shared genetics by loo- king for correlations in effect-sizes across traits and not requiring measurements of multiple traits per individual. The most common methods in this type of studies is Mendelian randomisation, which uses significantly associated SNPs as instrumental variables to attempt quantify causal relationships between risk factors and disease (Bulik-Sullivan et al., 2015). A complementary approach is to estimate gene- tic correlation, which includes the effects of all SNPs, includ- ing those that do not reach genome-wide significance.
Talking about EDs, one point is to demonstrate the family burden of those disorders and something crucially different is to establish – by GWAS studies – the relationships between those disorders with genetic traits. To date, there are not significant genes associated with EDs. In early stud- ies, it was thought that a question of sample size could be the problem for the lack of significance, but nowadays even the most powerful set of data in AN, by far the ED with more genetic available studies, could not get any significant relation with any genetic trait (Boraska et al., 2014).
As an example, Root et al. (2011) defined seven different phenotypes which are known to be associated with AN
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(drive for thinness, concern over mistakes, among others). They tried to correlate those phenotypes with 5151 SNPS in 182 genes, but they were unable to significantly associate any SNPs with EDs psychological traits despite the huge sample size: 1085 EDs participants and 677 controls (Root et al., 2011). However, in despite the fact that they fail to make any significant association, they described two SNPS with potential interest in future studies: (i) rs17719880 in KCNN3 (potassium calcium activated channel), an important gene in neuronal excitability that could be related with schizophrenia and bipolar disorders and (ii) rs12744840 in HCRTR1, an orexin receptor gene (Sakurai et al., 1998).
Another genetic study was performed on 1533 twin American women focusing in the analysis of 15 polymor- phisms in HTR2A, a gene implicated in appetite process and satiety in BED (Koren et al., 2014). In this study, the authors describe three main polymorphism for HTR2A: (i) 1438G/A (rs6311) which have been associated with poor treatment response in BN patients but the authors failed to find a significant genetic association with EDs char- acteristics and (ii) two other polymorphisms, rs6561333 and rs2296972, associated with less likelihood of BED. However, when those polymorphisms were corrected for multiple test- ing they were no longer significant; with only rs2296972 remain significant as trend level (Koren et al., 2014). Likewise, the authors did not find any comorbidity between MDD (Mayor Depressive Disorder) and EDs.
Some cross-trait studies (Hinney et al., 2017) obtained a significant genetic relationship with AN and body mass index (BMI) using a ‘cross-talking’ with two big GWAS, one for AN (Boraska et al., 2014) and one for BMI (Locke et al., 2015), demonstrating the existence of gender correlation between the trait and those diseases. Indeed, in AN, 90% of the people affected are females (Yilmaz, Hardaway, & Bulik, 2015) and BN is also gender specific, affecting mainly female population. Remarkably, there are almost no EDs studies conducted with men (Munn-Chernoff & Baker, 2016).
As stated previously, Hinney et al. (2017) described three significantly altered loci correlating AN risk with increased BMI. The genes associated to those loci are CTBP2, CCNE1, CARF and NBEAL1 but their relevance in AN risk mechanisms or BMI increases are still uncertain. Other comorbid interesting study with significant results is the one performed by Munn-Chernoff and Baker (2016). They associate EDs to substance use disorders (SUD), describing a possible unbalance in the system and loss of control (negative valence domain). This loss control is a core feature of BED as well as SUD and could be influ- enced by dopamine. In addition, a recent study describe that AN patients could present an unbalance in the reward system involving dopamine circuits (see dopamine section), describing a marginally genetic association between AN and excessive exercise, a rs17030795 located in PPP3CA (Gorwood et al., 2016). By their side, OPRD1 (opioid delta receptor) and HTR1D (1D serotonin receptor) are been associated with AN by Bergen et al. (2003) and Wang groups (Wang et al., 2011) confirming this association, although not backed by significant results. Other genes have been under the spot light and come out in GWAS
studies, but they fail to get significance. They are: (i) DRD2/ANKK1 gene and SNPs Val58Met in COMT gene, implicated in dopamine (Munn-Chernoff & Baker, 2016); (ii) 5-HTTLPR in 5HTT transporter and HTR2A receptor gene in serotonin path (Munn-Chernoff & Baker, 2016; Yilmaz et al., 2015) and (iii) SOX2 gene, in this case the study with a comorbidity of EDs and bipolar disorder (Bulik, Kleiman, & Yilmaz, 2016).
Finally, Munn-Chernoff et al. (2015) review deeply the possible genetic overlap between alcohol use disorder (AUD) and bulimic behaviour, not obtaining statistical significance towards EDs. Although specific genetic mechanism underly- ing comorbidity are unclear, at minimum, individuals with AUD should be screened for individual and family history of EDs and vice versa, regardless of race. Even when the study is unable to provide any statistically significant data, it is clear that AUD and bulimic behaviour share environmental influences.
There could be several explanations for the lack of signifi- cance concerning GWAS studies in EDs. One is the potential population stratification, probably because we are not using the appropriate phenotypes to separate the patients. The other one could be the sample size. As an example, in Schizophrenia studies, only a sample size of 5000 partici- pants allowed to obtain differences in genes with statistical significance. Finally, it is necessary to consider the study of EDs as comorbid with other disorders; alcohol abuse, sub- stance abuse, bipolar disorder, emotional instability, and obesity (Yilmaz et al., 2015).
Epigenetic studies
Epigenetic refers to heritable patterns of gene expression that occur without changes in the DNA sequence, that is, changes in phenotype not involving changes in genotype. Epigenetics have a major role in genomic regulation, as a natural process which silence specific genes during development. At least three systems; DNA methylation, histone modification and non-coding RNA (ncRNA)-associated gene silencing have been currently considered to initiate and sustain epigenetic change (Brown et al., 2007; Campbell, Mill, Uher, & Schmidt, 2011; Egger, Liang, Aparicio, & Jones, 2004). The field of epigenetics is quickly growing and with it the under- standing that both the environment and individual lifestyle can also directly interact with the genome. For example, human epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases and behavioural disorders (Jirtle & Skinner, 2007; Pjetri, Schmidt, Kas, & Campbell, 2012).
Epigenetics changes play a role in causation of complex adult psychiatric and neurodegenerative disorders, with rear- rangements in DNMT (DNA-methyltransferase) genes. Recent evidence supports the idea that epigenetic mechanism may help initiate and maintain EDs (Strober, Peris, & Steiger, 2014), for example AN has been genetically corre- lated with Schizophrenia (Bulik-Sullivan et al., 2015). Epigenetics modifications have a key role in the genetic
bases of the EDs owing to early life events, or familiar envir- onment (Munn-Chernoff & Baker, 2016). Epigenetic mech- anism also occurs during pregnancy, for example maternal depression have been linked to specific increases in methyla- tion of offspring glucocorticoid receptor (NR3C1) gene, yielding to altered cortisol responses and increased stress reactivity in the offspring (Steiger & Thaler, 2016).
As mentioned previously, there is an imbalance in the dopamine reward circuit in EDs. Some epigenetics changes could be related with this mechanism. Indeed, Frieling et al. (2010) described higher levels of methylation in the promo- tors of DAT1 (dopamine active transporter 1) and DRD2 (dopamine receptor D2) in AN patients compared with healthy controls, indicating an increase in the expression of the DAT1 and a decrease in the expression of the DRD2. Other studies linked AN weight loss to hypermethylation and reduced expression of POMC (proopiomelanocortin) gene (Ehrlich et al., 2010; Steiger & Thaler, 2016). In add- ition, several studies carried out in BN women patients assessed the methylation status of specific genes showing: (i) hypermethylation in exon 1C region of the glucocorticoid receptor (GR) with comorbid BN and suicidal records; (ii) hypermethylation of the DRD2 promoter region with BN
and Borderline Personality Disorder and (iii) hypermethyla- tion of specific CpG sites in the BDNF gene promoter region with BN, with and without childhood abuse (Groleau et al., 2014; Steiger, Labonte, Groleau, Turecki, & Israel, 2013; Thaler et al., 2014).
Recently, several studies have investigated directly gen- ome-wide (GW) methylation in patients with EDs (Saffrey, Novakovic, & Wade, 2014; Tremolizzo et al., 2014). Thus, Booij and colleagues reported that a group of AN patients had higher mean and median global methylation level when compared to normal eaters. In this study, they also described significant group differences in 2 CpGs associated with NR1H3 gene and 3 CpGs associated with PXDNL gene, both genes involved in dopamine and glutamate signalling respectively and, hence, in reward dependence, mood and anxiety (Booij et al., 2015).
Transcriptome studies
Expression studies have been used mainly to confirm epigen- etic imbalances, or SNPs detected. Using transcriptomics, a recent study has shown how binge eating resulted in the downregulation of a set of genes involved in decreased
Table 1. Genetic studies on eating disorders.
Study Type Disorder Results
Bergen et al. (2003) GWAS AN OPRD1, HTR1D Brown et al. (2007) SNPs AN OPRD1, HTR1D Wang et al. (2011) GWAS AN OPRD1, HTR1D, CNV, the only one Boraska et al. (2014) GWAS AN No statistical significant data Tremolizzo et al. (2014) Epigenetics AN No significant data, but less methylated DNA in
fasting patient vs control. Correlating with plasma leptin and steroid hormone
Frieling et al. (2010) Epigenetics AN Hypermethylation in DAT1 (high express), DRD2 (low express)
Kern et al. (2012) Mouse models AN Mouse wt and ghrelin-/- treated with DRD2 inhibitors develop anorexia
Krajmalnik-Brown et al. (2012) Metagenomics Obesity & Anorexia Microbioma study (obesity vs undernutrition) Scott-Van Zeeland et al. (2014) Targeted sequencing AN EPHX2 variants related with susceptibility to AN Cui et al. (2013) Targeted sequencing,
(WGS and WES) AN and BN Mutations in ESRRA and HDAC4 increase the
risk of EDs Booij et al. (2015) Epigenetics AN AN have higher methylation level than controls:
(NR1H3 and PXDNL) Wade et al. (2013) GWAS EDs No significant but important genes: CLEC5A,
LOC136242, TSHZ1, SYTL5 for AN NT5C1B for BN and ATP8A2 for BED
Boraska et al. (2012) GWAS ED general Not significant but important: RUFY1, CCNL1, SEMA6D, SHC4, DLGAP1, SDPR, TRPS1 in EDs phenotypes
Munn-Chernoff and Baker (2016) GWAS EDs(BN) & SUD DRD2/ANKK1, and SNPs Val58Met in COMT Yilmaz et al. (2015) GWAS AN DRD2/ANKK1, and SNPs Val58Met in COMT Bulik et al. (2016) GWAS AN SOX2 Munn-Chernoff et al. (2015) GWAS AUD & BN No statistical significant genes Root et al. (2011) GWAS EDs psychological phenotypes No significant association, but important:
KCNN3, HCRTR1 Koren et al. (2014) GWAS BED No significant when FDR correction is applied,
HTR2A Hinney et al. (2017) Meta-analysis GWAS AN and BMI CTBP2, CCNE1, CARF and NBEAL1 Gorwood et al. (2016) GWAS AN & excessive exercise PPP3CA, DRD2 Steiger & Thaler (2016) Epigenetics EDs Hypermethylation NR3C1, POMC (low
expression) Ehrlich et al. (2010) Epigenetic AN Hypermethylation POMC (low expression) Groleau et al. (2014) Epigenetics BN and suicidality history Hypermethylation in exon 1C region of GR Steiger et al. (2013) Epigenetics BN and Border Line personality Hypermethylation of DRD2 promoter Thaler et al. (2014) Epigenetics BN and childhood abuse Hypermethylation in CpG sites in the BDNF
promoter Clarke et al. (2016) Targeted Sequencing AN No significant, but important mutation in BDNF
This table summarizes most of the genetics studies carried out in EDs. Columns show respectively authors, the type of genetic approach employed and the main results obtained.
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myelination as well as oligodendrocyte differentiation and expression (Kirkpatrick et al., 2017).
To conclude, even though there is an absence of signifi- cant correlation between EDs phenotypic characteristics and specific genetic trait, it is obvious that there exist a genetic imbalance which leads first to a pathway disparity, finally ending in an aberrant eating behaviour. Table 1 summarises most of the studies devoted to EDs, describing the type of genetic approach employed and the main result of the study. Undoubtedly, more epigenetic studies of those disorders which are crucially influenced by environmental circumstan- ces during early childhood development are mandatory for uncover the origins of these diseases.
Wrap-up and synthesis: towards a global approach
This review focused on three illnesses responsible of a high- increasing and extremely frequent phenomenon related to our daily way of living: pathologies associating to feeding dysfunctions. Besides, these EDs are complexes, affecting not only nutritional and physiological features but also social cognitive processes, psychological, mental and clinical aspects, reducing the life-quality of millions of worldwide inhabitants and generating a profound social impact. In spite of this fact, EDs tend to be exclusively considered as psychi- atric disorders, existing nowadays a profound imbalance between psychological and biological therapies. In addition, psychological help is not effective to achieve a fully physical and emotional recovery in most of the cases (Halmi, 2013). Concerning clinical treatment, unfortunately, to date, only two drugs (fluoxetine and lisdexamfetamine, respectively for BN and BED treatment) have been approved by the FDA and the international regulatory agencies for the treatment of EDs. Furthermore, there is a major lack of pharmacother- apy studies and treatments in children and teenagers suffer- ing from EDs. Under these grounds, a scientific multidisciplinary effort is mandatory to overcome this chal- lenge. The combination of genomics and epigenomics to identify new genes and biomarkers, the involvement of bio- informatics analysis to provide an integrative overview and generate a network interaction between SNPs and epigenetic modulation and the deep characterization of the neuropepti- des, neurotransmitters and hormones involved will allow a better understanding of EDs. In parallel, computational data and the creation of new databases will allow the develop- ment of molecules targeting specifically neuromodulators- and hormones-mediated signalling pathways involved in these illnesses. Finally, tailor medicine approaches based on genetic individual differences must be also applied in EDs patients. Indeed, an accurate diagnosis should include a gen- etic and epigenetic study accompanied by a family retro- spective revision, to understand the specific circumstances in each case and the possible genetic imbalance, identifying a list of genes as a first option to check for SNPs or epigenetic deregulation. This genetic imbalance would affect the regula- tion and function of neuromodulators and hormones in the brain and/or other organs, ultimately generating abnormal- ities in eating behaviours. For all these reasons, we strongly believe that it is urgent to develop a different way of
approach those disorders, which affects not only the patients but also the families and their environmental influences.
We appreciate the help of Dr. Cristina Martin-Higueras and laboratory members for their critical comments. This publication was supported by the Spanish National Programme for Research aimed at the Challenges of Society [DPI2015–66458-C2–2-R, MINECO] to AA and GC, an AIRC-iCARE Fellowship co-funded by European Community to LG and the CNRS, INRA, Burgundy Regional Council (PARI2012 and 2014) and University of Bourgogne Franche-Comte to CE.
Disclosure statement
No potential conflict of interest was reported by the authors.
This publication was supported by the Spanish National Programme for Research aimed at the Challenges of Society [DPI2015–66458-C2–2- R, MINECO] to AA and GC, an AIRC-iCARE Fellowship co-funded by European Community to LG and the CNRS, INRA, Burgundy Regional Council (PARI2012 and 2014) and University of Bourgogne Franche- Comte to CE.
Aardema, F. O. (2007). The menace within: obsessions and the self. International Journal of Cognitive Therapy, 21, 182–197. doi: 10.1891/088983907781494573
Abizaid, A., Liu, Z.-W., Andrews, Z.B., Shanabrough, M., Borok, E., Elsworth, J.D., … Horvath, T.L. (2006). Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neu- rons while promoting appetite. Journal of Clinical Investigation, 116, 3229–3239. doi: 10.1172/JCI29867
Acevedo, S.F., Valencia, C., Lutter, M., & McAdams, C.J. (2015). Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. Psychiatry Research, 228, 641–648. doi: 10.1016/j.psychres.2015.05.040
Adan, R.A.H., Vanderschuren, L.J.M.J., & la Fleur, S.E. (2008). Anti-obes- ity drugs and neural circuits of feeding. Trends in Pharmacological Sciences, 29, 208–217. doi: 10.1016/j.tips.2008.01.008
Agras, W.S., Rossiter, E.M., Arnow, B., Schneider, J.A., Telch, C.F., Raeburn, S.D., … Koran, L.M. (1992). Pharmacologic and cognitive- behavioral treatment for bulimia nervosa: A controlled comparison. American Journal of Psychiatry, 149, 82–87. doi: 10.1176/ajp.149.1.82
Aigner, M., Treasure, J., Kaye, W., & Kasper, S. & WFSBP Task Force On Eating Disorders. (2011). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. World Journal of Biological Psychiatry, 12, 400–443. doi: 10.3109/15622975.2011.602720
Altirriba, J., Poher, A.-L., & Rohner-Jeanrenaud, F. (2015). Chronic oxytocin Administration as a treatment against impaired leptin sig- naling or leptin resistance in obesity. Frontiers in Endocrinology, 6, 119. doi: 10.3389/fendo.2015.00119
Altman, S.E., & Shankman, S.A. (2009). What is the association between obsessive–compulsive disorder and eating disorders? Clinical Psychology Review, 29, 638–646. doi: 10.1016/j.cpr.2009.08.001
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders. (5th ed.). Arlington, VA: American Psychiatric Publishing.
Aponte, Y., Atasoy, D., & Sternson, S.M. (2011). AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without train- ing. Nature Neuroscience, 14, 351–355. doi: 10.1038/nn.2739
Appolinario, J.C., Bacaltchuk, J., Sichieri, R., Claudino, A.M., Godoy- Matos, A., Morgan, C., … Coutinho, W. (2003). A randomized, double-blind, placebo-controlled study of sibutramine in the treat- ment of binge-eating disorder. Archives of General Psychiatry, 60, 1109–1116. doi: 10.1001/archpsyc.60.11.1109
Aravich, P.F., Rieg, T.S., Lauterio, T.J., & Doerries, L.E. (1993). Beta- endorphin and dynorphin abnormalities in rats subjected to exercise and restricted feeding: Relationship to anorexia nervosa? Brain Research, 622, 1–8. Retrieved from http://www.ncbi.nlm.nih.gov/ pubmed/790218710.1016/0006-8993(93)90794-N
Armougom, F., Henry, M., Vialettes, B., Raccah, D., & Raoult, D. (2009). Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and methanogens in anor- exic patients. PloS One, 4, e7125. doi: 10.1371/journal.pone.0007125
Arnold, L.M., McElroy, S.L., Hudson, J.I., Welge, J.A., Bennett, A.J., & Keck, P.E. (2002). A placebo-controlled, randomized trial of fluoxet- ine in the treatment of binge-eating disorder. Journal of Clinical Psychiatry, 63, 1028–1033. Retrieved from http://www.ncbi.nlm.nih. gov/pubmed/1244481710.4088/JCP.v63n1113
Atasoy, D., Betley, J.N., Su, H.H., & Sternson, S.M. (2012). Deconstruction of a neural circuit for hunger. Nature, 488, 172–177. doi: 10.1038/nature11270
Avena, N.M., & Bocarsly, M.E. (2012). Dysregulation of brain reward sys- tems in eating disorders: Neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa. Neuropharmacology, 63, 87–96. doi: 10.1016/j.neuropharm.2011.11.010
Avena, N.M., Rada, P., & Hoebel, B.G. (2008). Underweight rats have enhanced dopamine release and blunted acetylcholine response in the nucleus accumbens while bingeing on sucrose. Neuroscience, 156, 865–871. doi: 10.1016/j.neuroscience.2008.08.017
Avena, N.M., Rada, P., Moise, N., & Hoebel, B.G. (2006). Sucrose sham feeding on a binge schedule releases accumbens dopamine repeatedly and eliminates the acetylcholine satiety response. Neuroscience, 139, 813–820. doi: 10.1016/j.neuroscience.2005.12.037
Bacaltchuk, J., & Hay, P. (2001). Antidepressants versus placebo for people with bulimia nervosa. The Cochrane Database of Systematic Reviews, CD003391. doi: 10.1002/14651858.CD003391
Bakhtazad, A., Vousooghi, N., Garmabi, B., & Zarrindast, M.R. (2016). CART peptide and opioid addiction: Expression changes in male rat brain. Neuroscience, 325, 63–73. doi: 10.1016/j.neuroscience.2016.02.071
Barlow, J., Blouin, J., Blouin, A., & Perez, E. (1988). Treatment of buli- mia with desipramine: A double-blind crossover study. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie, 33, 129–133. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/328463010. 1177/070674378803300211
Barth, K.S., & Malcolm, R.J. (2010). Disulfiram: An old therapeutic with new applications. CNS & Neurological Disorders Drug Targets, 9, 5–12. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 2020181010.2174/187152710790966678
Batterham, R.L., & Bloom, S.R. (2003). The gut hormone peptide YY regulates appetite. Annals of the New York Academy of Sciences, 994, 162–168. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/ 1285131210.1111/j.1749-6632.2003.tb03176.x
Baver, S.B., Hope, K., Guyot, S., Bjørbaek, C., Kaczorowski, C., & O’connell, K.M.S. (2014). Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. Journal of Neuroscience, 34, 5486–5496. doi: 10.1523/ JNEUROSCI.4861-12.2014
Becker, D.F., & Grilo, C.M. (2015). Comorbidity of mood and sub- stance use disorders in patients with binge-eating disorder: Associations with personality disorder and eating disorder pathology. Journal of Psychosomatic Research, 79, 159–164. doi: 10.1016/ j.jpsychores.2015.01.016
Bergen, A.W., van den Bree, M.B.M., Yeager, M., Welch, R., Ganjei, J.K., Haque, K., … Kaye, W.H. (2003). Candidate genes for anorexia nervosa in the 1p33-36 linkage region: Serotonin 1D and delta opi- oid receptor loci exhibit significant association to anorexia nervosa. Molecular Psychiatry, 8, 397–406. doi: 10.1038/sj.mp.4001318
Berner, L.A., Winter, S.R., Matheson, B.E., Benson, L., & Lowe, M.R. (2017). Behind binge eating: A review of food-specific adaptations of neurocognitive and neuroimaging tasks. Physiology & Behavior, 176, 59–70. doi: 10.1016/j.physbeh.2017.03.037
Billington, C.J., Briggs, J.E., Grace, M., & Levine, A.S. (1991). Effects of intracerebroventricular injection of neuropeptide Y on energy metab- olism. American Journal of Physiology, 260(2 Pt 2), R321–R327. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1996719
Blauwhoff-Buskermolen, S., Langius, J.A.E., Heijboer, A.C., Becker, A., de van der Schueren, M.A.E., & Verheul, H.M.W. (2017). Plasma ghrelin levels are associated with anorexia but not cachexia in patients with NSCLC. Frontiers in Physiology, 8, 119. doi: 10.3389/ fphys.2017.00119
Blevins, J.E., Graham, J.L., Morton, G.J., Bales, K.L., Schwartz, M.W., Baskin, D.G., & Havel, P.J. (2015). Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology, 308, R431–R438. doi: 10.1152/ajpregu.00441.2014
Blundell, J.E., Goodson, S., & Halford, J.C. (2001). Regulation of appe- tite: Role of leptin in signalling systems for drive and satiety. International Journal of Obesity and Related Metabolic Disorders, 25 Suppl 1, S29–S34. doi: 10.1038/sj.ijo.0801693
Boersma, G.J., Liang, N.-C., Lee, R.S., Albertz, J.D., Kastelein, A., Moody, L.A., … Tamashiro, K.L. (2016). Failure to upregulate Agrp and Orexin in response to activity based anorexia in weight loss vul- nerable rats characterized by passive stress coping and prenatal stress experience. Psychoneuroendocrinology, 67, 171–181. doi: 10.1016/ j.psyneuen.2016.02.002
Boggiano, M.M., Chandler, P.C., Viana, J.B., Oswald, K.D., Maldonado, C.R., & Wauford, P.K. (2005). Combined dieting and stress evoke exaggerated responses to opioids in binge-eating rats. Behavioral Neuroscience, 119, 1207–1214. doi: 10.1037/0735-7044.119.5.1207
Booij, L., Casey, K.F., Antunes, J.M., Szyf, M., Joober, R., Isra€el, M., & Steiger, H. (2015). DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study. International Journal of Eating Disorders, 48, 874–882. doi: 10.1002/eat.22374
Boraska, V., Davis, O.S.P., Cherkas, L.F., Helder, S.G., Harris, J., Krug, I., … Zeggini, E. (2012). Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics?: The Official Publication of the International Society of Psychiatric Genetics, 159B, 803–811. doi: 10.1002/ajmg.b.32087
Boraska, V., Franklin, C.S., Floyd, J.A.B., Thornton, L.M., Huckins, L.M., Southam, L., … Bulik, C.M. (2014). A genome-wide associ- ation study of anorexia nervosa. Molecular Psychiatry, 19, 1085–1094. doi: 10.1038/mp.2013.187
Borgland, S.L., Chang, S.-J., Bowers, M.S., Thompson, J.L., Vittoz, N., Floresco, S.B., … Bonci, A. (2009). Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. Journal of Neuroscience, 29, 11215–11225. doi: 10.1523/JNEUROSCI.6096-08.2009
Brambilla, F., Monteleone, P., & Maj, M. (2009). Glucagon-like peptide- 1 secretion in bulimia nervosa. Psychiatry Research, 169, 82–85. doi: 10.1016/j.psychres.2008.06.040
Brennan, B.P., Roberts, J.L., Fogarty, K.V., Reynolds, K.A., Jonas, J.M., & Hudson, J.I. (2008). Memantine in the treatment of binge eating disorder: An open-label, prospective trial. International Journal of Eating Disorders, 41, 520–526. doi: 10.1002/eat.20541
D ow
nl oa
de d
Brewerton, T. (1992). Serotonin function in depression: Effects of sea- sonality? American Journal of Psychiatry, 149, 1277. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1482444
Brewerton, T.D. (2012). Antipsychotic agents in the treatment of ano- rexia nervosa: neuropsychopharmacologic rationale and evidence from controlled trials. Current Psychiatry Reports, 14, 398–405. doi: 10.1007/s11920-012-0287-6
Broberger, C., Johansen, J., Johansson, C., Schalling, M., & H€okfelt, T. (1998). The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate- treated mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 15043–15048. Retrieved from http:// www.ncbi.nlm.nih.gov/pubmed/9844012
Brodie, M.J., Ben-Menachem, E., Chouette, I., & Giorgi, L. (2012). Zonisamide: Its pharmacology, efficac