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Molecular bases of anorexia nervosa, bulimia nervosa and binge eating

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Molecular bases of anorexia nervosa, bulimianervosa and binge eating disorder: shedding lighton 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 onthe darkness, Journal of Neurogenetics

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REVIEW ARTICLE

Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder:shedding light on the darkness

Germ�an Cuestoa, Claude Everaertsb, Leticia G. Le�onc and Angel Acebesa

aCentre for Biomedical Research of the Canary Islands, Institute of Biomedical Technologies, University of La Laguna, Tenerife, Spain; bCentredes Sciences du Gout et de l'Alimentation, UMR 6265 CNRS, UMR 1324 INRA, Universit�e de Bourgogne Franche-Comt�e, Dijon, France;cCancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy

ABSTRACTEating-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 extremeanorexia nervosa. It also implies that people suffering an ED need to find psychiatric and psychologicalhelp 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 anoverview 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 facethis 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 HISTORYReceived 9 May 2017Revised 26 June 2017Accepted 5 July 2017

KEYWORDSEating disorders;pharmacology; neuromodu-lators; genetic approaches

Introduction

Eating-disorders (EDs) as anorexia nervosa (AN), bulimianervosa (BN) and binge-eating disorder (BED), have both adeep social impact and an enormous cost to public health-care systems (Keski-Rahkonen & Mustelin, 2016). Theexample of Europe is extremely illustrative: besides a veryhigh risk of premature mortality, more than 2/3 of thoseEDs patients had at least some role impairment in at leastone domain (Preti et al., 2009). In fact, the prevalence ofEDs has increased across time, particularly in the secondhalf of the twentieth century (Bulik et al., 2006). In the USA,20 million women and 10 million men had suffered from aclinically significant ED at some time in their life(Samnaliev, Noh, Sonneville, & Austin, 2015) with 7300worldwide deaths in 2010 (Lozano et al., 2012) resulting in2.2� 106 disability-adjusted life years (DALYs) (Murrayet al., 2012).

Anorexia nervosa is defined as an association of anabnormally low body weight, an intense fear of gainingweight and a distorted cognition regarding weight, shape,and drive for thinness. AN is a disorder but also a symptomof other disorders, as depression, bipolar disorder, anxietydisorders (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 uncontrolledovereating’ – 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 purgebehaviours (vomiting, laxatives, fasting, etc… ). That takesplace on average a minimum of twice weekly for three ormore months, or, in extreme cases, several times a day. BNis divided into two subtypes: the above-mentioned purging-type and the lesser-common non-purging type, characterisedby fasting or excessive exercise trying to compensate for thecalories obtained from the previous binge. Besides, thereexist 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) patientsshow 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 andBN, BED has been associated with medical and psychiatriccomorbidities, as mood (anxiety) and substance use disor-ders (Becker & Grilo, 2015). Interestingly, BED is the mostprevalent among all eating disorders, being higher in womenthan in men, and also the most underdiagnosed and under-treated, due to insufficient diagnostic criteria and lack ofavailable treatment options [see Section 2 below and alsoKornstein, Kunovac, Herman, & Culpepper (2016)].

Eating-disorders have been long considered as severe psy-chiatric disorders of unknown aetiology. As previously

CONTACT Angel Acebes aacebesv@ull.es Centre for Biomedical Research of the Canary Islands, Institute of Biomedical Technologies, Department of BasicMedical Sciences, Faculty of Medicine, University of La Laguna, 38071 La Laguna, Tenerife, Spain; Leticia G. Le�on gl.leticia@gmail.com CancerPharmacology Lab, University of Pisa, Ospedale di Cisanello, Edificio 6, via Paradisa, 2. 56124 Pisa, Italy� 2017 Informa UK Limited, trading as Taylor & Francis Group

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mentioned, BN and BED are closely related to affective,attention, emotional and mood disorders. Social cognitionencompass the psychological processes endowing individualsto observe, process, store and retrieve information obtainedfrom conspecifics in social interactions (Frith, 2008). Poorrecognition of emotions in others is documented in ANpatients and facial emotion recognition difficulties persist inthem even after recovery (Oldershaw et al., 2011). Besides,brain abnormalities have been described in AN patients,including abnormal neural activation (Uher et al., 2004) andaltered neurotransmitter function (Kaye, Fudge, & Paulus,2009). More research is crucial to establish links betweensocial cognition abnormalities and neurological defaults asso-ciated with AN (Cardi et al., 2015).

Under these grounds, deciphering unambiguously howthe brain controls food intake and satiation mechanisms iscrucial to know how eating-associated pathological disordersare 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, basalganglia, and the limbic system) with peripheral components(such as gustatory system, gastrointestinal nervous system,pancreas, liver, muscle, and adipose tissue), sustaining anexquisitely well-regulated homeostasis between food intakeand energy expenditure (Lenard & Berthoud, 2008;Mithieux, 2013). In addition to these circuits, the brainendocannabinoid system also acts as a key regulator for foodintake and energy balance (Cardinal et al., 2015; Di Marzoet al., 2001; DiPatrizio & Piomelli, 2012) through food-related olfactory-dependent mechanisms (Soria-Gomez,Bellocchio, & Marsicano, 2014) and is likely involved in thehedonic and emotional aspects of eating. In spite of thesefundamental advances, it is not completely understood howneuronal 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 brainstructures. More precisely, the hypothalamic arcuate nucleus(ARC) harbours two neuronal populations, one participatingto the synthesis of the appetite-stimulating neuropeptide Y(NPY) and Agouti-related peptide (AgRP) and the otherexpressing 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-mediatedpathways in the control of food intake and energy balance.Neuropeptides are a group of chemically diverse moleculesmodulating 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 neuralcircuits located in the hypothalamus (hunger signals, initiat-ing feeding behaviour) and the brainstem (satiation signals,limiting meal size) generating appropriate integratedresponses (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 circuitsunderlying these behaviours have been intensively studied.NPY/AgRP peptidergic neurons increase feeding intake byinhibiting POMC/CART system which stimulates anorexi-genic neurons in the lateral hypothalamus (LH) area, andstimulating 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 (Borglandet al., 2009).

Interestingly, several pieces of evidence indicate thatneurobiological mechanisms underlying ED might involve anoverreaction of the immune system, generating, in turn, adysfunction of neuropeptide signalling. Thus, reactiveImmunoglobulins (Igs) bind to food-intake neuropeptides(named peptide autoantibodies) and are identified in theserum of AN/BN patients, predominantly bound to a-MSHin hypothalamic neurons (Fetissov et al., 2005). In addition,the enterobacteria Caseinolytic protease B protein ClpB alsoact as an a-MSH-mimetic protein, triggering production ofIgs against a-MSH, reducing its anorexigenic effects(Tennoune et al., 2014). Interestingly, these circulating auto-antibodies might be purified in order to be employed aspharmacological tools in AN and BN (Smitka et al., 2013).

In addition to the gastrointestinal-brain communication,gut microbiota plays an important role on nutrimentsabsorption and energy expenditure. Likewise, the brain-gut-microbiota axis allows a bidirectional communicationbetween gut microbes and the brain through endocrine,neural, immune and metabolic pathways (Dinan & Cryan,2017). Moreover, modifications of the gut microbiota havealso been described in AN patients (Armougom, Henry,Vialettes, Raccah, & Raoult, 2009). It is also well character-ized that the gut microbiome contributes to the pathogenesisof malnutrition through nutrient metabolism and immunefunction (Krajmalnik-Brown, Ilhan, Kang, & DiBaise, 2012).Besides, chronic constipation, a common feature in ANpatients, is present prior to weight loss and causes changesin gut microbiota, increasing Methanobrevibacter smithii le-vels (Kim et al., 2012). More interestingly, elevated plasmaconcentrations of the ClpB have been detected in femalepatients with AN, BN, and BED when compared withhealthy individuals (Breton et al., 2016). These findings openthe 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 eatingdisorders

Current treatments of the EDs are substantially multidimen-sional and include psychotherapy, nutritional rehabilitation,drug treatment and even light therapy, but unfortunatelyoften 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), dialecticalbehavioural therapy (DBT) or family-based therapy (FBT),remain the main treatments of EDs, even though some drugtherapies have been employed for some specific EDs. Themost demanded pharmacotherapy of EDs should induce aremission 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 noeffective drugs to overcome all these clinical features, exceptfluoxetine and lisdexamfetamine, the only drugs approved bythe international regulatory agencies for the treatment oftwo EDs (respectively BN and BED). Furthermore, numer-ous drugs used in psychiatric clinic (i.e. antipsychotics, anti-depressants, mood stabilizers, and selective norepinephrineand/or serotonin reuptake inhibitors) were also tested totreat clinical manifestations of EDs, showing variable results.In this review, we will highlight the main positive clinicalresults.

Anorexia nervosa

AntipsychoticsAntipsychotic drugs act by blocking dopamine receptors(Miller, 2009). While antipsychotics are known to increaseappetite and weight gain in patients with major psychiatricdisorders (schizophrenia or bipolar disorder; Hay &Claudino, 2012), most of them are paradoxically not usefulfor weight recovery in AN patients (McKnight & Park,2010). However, they are able to reduce AN psychologicalcomorbidities (body image alteration, pathological focus onweight 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 favourweight gain (Vandereycken, 1984), whereas second-gener-ation antipsychotics are proved more useful, in particularolanzapine, a D2/5HT2 antagonist. This second generationfavours an increase in weight, leads to a significant reductionin the ‘anorexic ruminations’ and depressive symptoms butalso 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 soextensively studied in the treatment of AN (Powers & Bruty,2009). While olanzapine is efficient in reducing psychiatricsymptoms associated with the AN promoting weight recov-ery, its side effects, such as extrapyramidal symptoms andcardiac troubles (QT prolongation), are dangerous for anor-exic patients. All the main international guidelines classifythe use of these second-generation antipsychotics just assecondary possibilities for AN treatment (Aigner, Treasure,Kaye, Kasper, & WFSBP Task Force On Eating Disorders,2011).

Finally, the azapirone derivative tandospirone, also knownas metanopirone, is a selective serotonin-1A (5-HT1A)receptor partial agonist (Tanaka et al., 1995) known toshown 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), butalso induces improvement in weight gain and psychopath-ology of the AN patients (Okita, Shiina, Nakazato, & Iyo,2013).

AntidepressantsWhile the use of antidepressant in the treatment of EDswould appear logical due to the high rates of comorbidity(greater than 50%) between EDs and mood depression(Mischoulon et al., 2011), the effectiveness of antidepressantsin the treatment of AN patients is weak. Thus, while tricyclicantidepressants (TCA) have not shown significant benefits(Halmi, Eckert, LaDu, & Cohen, 1986), the most recent sero-tonin reuptake inhibitors (SSRIs – fluoxetine) have shownvery little effectiveness in promoting weight regain in ANpatients (Walsh et al., 2006).

Bulimia nervosa

AntipsychoticsSecond-generation antipsychotics used in AN treatmentinduce or exacerbate the crisis of binge eating in patientswith EDs (McElroy, Guerdjikova, Mori, & O’Melia, 2012).

AntidepressantsContrarily to what is described for AN, antidepressants(including TCAs, SSRIs, Serotonin-norepinephrine reuptakeinhibitors (SNRIs), and monoamine oxidase inhibitors,MAOIs) are the mainstay of pharmacological treatment forBN, by reducing the dopamine crisis of binge eating andpurging 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 (aTCA also known as desmethylimipramine) inhibits thereuptake of norepinephrine and, to a minor extent, sero-tonin. Both imipramine and desipramine were demonstratedto reduce binge eating and to improve the comorbidities inshort-term treatments (Barlow, Blouin, Blouin, & Perez,1988; Walsh, Hadigan, Devlin, Gladis, & Roose, 1991).However, their side effects make them inadequate for BNlong-term treatments (Agras et al., 1992; Leitenberg et al.,1994). In turn, SSRIs (fluoxetine, citalopram, sertraline andfluvoxamine) 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 diseasewith frequent relapses, most trials lasted only several months(Martiadis, Castaldo, Monteleone, & Maj, 2007). However, a58-week study has demonstrated the efficacy of fluoxetine inreducing binge and purging episodes, obsessive–compulsive

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symptoms and the frequency of relapses (Romano, Halmi,Sarkar, Koke, & Lee, 2002). Finally, milnacipran is a dualacting antidepressant which inhibits the reuptake of bothserotonin and noradrenaline (SNRI) being efficient in theshort-term treatment of patients with BN (El-Giamal et al.,2003) and leading to a significant reduction in weekly bingeeating and vomiting frequency.

Anticonvulsant mood stabilizersMany drugs described as ‘mood stabilizers’ are categorizedas anticonvulsants, and the term ‘anticonvulsant moodstabilizers’ is sometimes used to describe them as a class.Since the early 2000s, antiepileptic drugs (AEDs) have beenuseful in the treatment of psychiatric disorders related toEDs, such as headache, substance abuse, and bipolar, anxietyor personality disorders. Furthermore, many AEDs interactwith glutamatergic, GABAergic, serotonergic and dopamin-ergic systems in the regulation of appetite, food intake andweight (Gao & Horvath, 2008; Meister, 2007). For example,topiramate and zonisamide are associated with appetite andweight decrease (McElroy et al., 2009).

Numerous human clinical studies, and preclinical studiesin animals, have demonstrated the utility of topiramate(TPM) in neuroprotection against ischemia and brain inju-ries, body weight loss in obese subjects, mitigation of alcoholconsumption, 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 itseffect on kainite/AMPA glutamate receptors (Hettes et al.,2003). Thus, TPM improves multiple behavioural aspects ofBN: binge and purge symptoms are reduced, while self-esteem, eating attitudes, anxiety, body weight and bodyimage are also ameliorated (Nickel et al., 2005). Beside itsefficiency, 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 thecommon clinical practice.

Binge eating disorder

AmphetamineDue to their weak efficacy and severe side effects, the use ofdrugs to treat BED was limited until lisdexamfetamine dime-sylate (L-lysine-dextroamphetamine, LDX) was approved bythe 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 thetreatment 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 involvedin the modulation of appetite, hunger and eating behaviours(Guerdjikova, Mori, Casuto, & McElroy, 2016).

AntipsychoticsMemantine 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 generalizedanxiety disorder (Schwartz, Siddiqui, & Raza, 2012), atten-tion deficit hyperactivity disorder ADHD (Hosenbocus &Chahal, 2013) and obsessive compulsive disorder (Haghighiet al., 2013). Memantine has been proved effective in reduc-ing the frequency of binge days and episodes (Brennanet al., 2008; Hermanussen & Tresguerres, 2005).

AntidepressantsThe antidepressants are also useful in the treatment of BEDboth decreasing the binge seizure frequency and improvingsymptoms of depression and anxiety often present in BED.SSRIs seem to favour a significant reduction in binge crisishaving a modest effect in reducing the body weight of thepatients (Reas & Grilo, 2008; Stefano, Bacaltchuk, Blay, &Appolin�ario, 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 frequencyof 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, since2010, sibutramine has been withdrawn from European andUSA markets due to cardiovascular risks. Venlafaxine isanother SNRI that at low-dose (75mg/day) also acts as aweak inhibitor of norepinephrine re-uptake (Smith,Dempster, Glanville, Freemantle, & Anderson, 2002). Inaddition, Venlafaxine may be an effective treatment for BEDassociated with overweight or obesity in reducing of weeklybinge frequency, severity of binge-eating and mood symp-toms (McElroy et al., 2012). These effects can be related toits activity against impulse control disorders (ICD;Camardese, Picello, & Bria, 2008).

Finally, atomoxetine is a selective norepinephrinereuptake inhibitor (NRI) indicated for patients with atten-tion-deficit hyperactivity disorder and narcolepsy (Garnock-Jones & Keating, 2009). Although in 2007 McElroy’s teamhave shown preliminary evidence for the efficacy of atomo-xetine in BED (McElroy et al., 2007), no newer studies hasbeen devoted to this drug.

Anticonvulsant mood stabilizersIn studies in BED with obesity, Citalopram-treated patientsdisplayed a 94% reduction of binge eating and significantweight loss (McElroy et al., 2003). In turn, zonisamide is asulfonamide anticonvulsant approved for use as an adjunc-tive therapy in adults with partial-onset seizures and infantilespasm (Brodie, Ben-Menachem, Chouette, & Giorgi, 2012;Holder & Wilfong, 2011). Together with the CBT, zonisa-mide has proved useful in the treatment of obesity associatedBED, 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 substantiallythe same adverse effects as TPM.

Anti-obesity drugsThe 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 BEDobese patients, without weight loss (Stunkard, Berkowitz,Tanrikut, Reiss, & Young, 1996). However, fenfluramineworks only while it is taken and binge eating returns to pre-vious levels after medication. Fenfluramine was removedfrom its clinical use after reports of heart valve disease in1997 (Rothman & Baumann, 2002). In turn, orlistat is agastrointestinal lipase inhibitor that reduces the absorptionof 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 targetingweight 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(Fern�andez-Aranda et al., 2001; Hagler Robinson, 2009).

Anti-addiction drugsThe urge to consume food and the lack of control in BEDpatients resemble the strong impulse to consume alcoholand the absence of control found in Alcohol Use Disorder(AUD) patients (Pelchat, 2009). Indeed, BED and AUDshare 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 medicationshave 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 the1920s, and used since the 1950s to support the treatment ofchronic 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 innoradrenergic neurons (Barth & Malcolm, 2010). Used astreatment of BED, disulfiram effectively reduced the fre-quency of binge eating episodes in BED patients, and thiseffect is also considered to be due, at least in part, to DbHinhibition, as for cocaine use disorder (Farci et al., 2015).However, the use of disulfiram in the BED treatment may belimited by side effects or by the risk of exacerbation ofpsychotic disorders in BED patients.

In summary, the pharmacological treatment of EDs is inits early stages. Nowadays, no drug was especially designedto treat ED suffering patients, and current ED pharmaco-therapy is only the adaptation of some drugs previously used

in psychiatric clinic, showing generally undesirable sideeffects.

Neuropeptides, neurotransmitters and hormonesinvolved in EDs

Role of neuropeptides in EDs

Hunger signals results from internally generated metabolicdeficits yielding the animals to feed (Saper, Chou, &Elmquist, 2002). Feeding behaviour remains critical forrestoring metabolic homeostasis and, consequently, survival.Animals have evolved refined feedback mechanisms to regu-late energy expenditure and food consumption, rectifyingpossible 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 generatea response triggering feeding behaviours is insufficientlydocumented and, hence, understood. However, in this scen-ario, the crosstalk of neuropeptides within the nervous sys-tem and peripheral circulating hormones appears to beextremely relevant. Figure 1 shows a schematic summary ofthe information highlighted in this section. Indeed, neuro-peptides affect different complex behaviours at system, cellu-lar, and molecular levels in an age-dependent andhormonally 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/AgRPNeuropeptide 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 overhypothalamic–pituitary–adrenocortical axis, increasing theACTH, cortisol and prolactin release and have been involvedin appetite regulation. Cerebral injections of NPY induce thefood intake (Clark, Kalra, Crowley, & Kalra, 1984) and highlevels of NPY are associated with high food intake but lowphysical activity (Schwartz et al., 1996). Recent studies indi-cates AN patients are unable to up-regulate NPY system toadapt their energy demand when exposed to chronic under-nutrition, whereas the satisfaction for rapid food is due tothe triggered a-melanocyte-stimulating hormone (a-MSH)response occurred during lunchtime (Galusca et al., 2015).Besides, an abnormal increase of NPY have been found inAN and BN patients after consumption of high-carbohydrateand high-protein breakfast, suggesting alterations in regula-tion of gut–brain axis peptides and indicating that NPYplasma levels represent a good indicator for EDs (Sedlackovaet al., 2012). In an indirect manner, the anti-stress effects ofNPY are also relevant to ameliorate psychiatric conditions ofboth AN and BN patients. In turn, AgRP has been involvedin appetite regulation since passive stress prevents AgRP and

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orexin upregulation in response to activity in an anorexia ratmodel (Boersma et al., 2016).

OrexinsOrexins, also known as hypocretins, are orexigenic neuralhormones expressed and secreted in the LH nucleus, but arealso expressed in peripheral tissues such as kidney, adrenalglands, pancreas, placenta, stomach, ileum, colon and colo-rectal epithelial cells (Nakabayashi et al., 2003). Orexinsinteract 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. Toexplain this finding, two different hypotheses have been for-mulated. In the first one, this up-regulation might resultfrom an adaptive mechanism to increase food intake againstunder nutrition. In the second, a chronic increase of orexi-genic neurons could reinforce dopamine-induced anxiety inthe reward system (see dopamine section below) of ANpatients, 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 relatedwith eating disorders at different levels: either by regulatingdirectly the appetite, but also regulating the reward systemand 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 asfrustration by predisposed people, triggering development ofanxiety and behavioural related disorders.

Proopiomelanocortin (POMC) and CARTProopiomelanocortin is a precursor polypeptide synthesizedmainly in the anterior pituitary, expressed as pre-proopiome-lanocortin and cleaved by the convertase prohormones 1 and2 generating a-MSH, ACTH, and the opioids beta-endorphinand Met-enkephalin. POMC is an anorexigenic peptide atthe hypothalamic ARC. Indeed, re-feeding after fasting indu-ces the activation of POMC neurons in ARC, promotingsatiety (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, melaninproduction in the skin, addictive behaviours and stress ma-nagement (Millington, 2007; Zhou & Kreek, 2015). POMCmRNA level increases after stress exposition and POMCneurons activate rapidly under emotional stressing condi-tions (J. Liu et al., 2007). These evidences define the role ofPOMC as a key communication link between brain feedingcontrol centre and stress systems (Ryan et al., 2014). In ad-dition, a-MSH, a POMC-derived peptide, is involved inmanifestation 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 arrowsindicate repression. Dopaminergic actions are shown in blue, whereas serotonergic actions are represented in orange. Abnormal levels reported on Eating disordersare indicated with yellow squares.

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Subhedar, 2010). Finally, intracerebroventricular injection ofMC4R 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 bothcentral and peripheral nervous system, playing an importantrole in the hypothalamus (Keller et al., 2006). As for POMC,CART hypothalamic secretion is regulated by leptin (Eliaset al., 1998) and it has been related with addictive beha-viours and stress responses (Bakhtazad, Vousooghi, Garmabi,& Zarrindast, 2016). The intracerebroventricular CARTadministration reduces appetite and increases energyexpenditure, but, under specific circumstances, hypothalamicCART has been considered also as orexigenic (Murphy,2005). An increase in CART expression has been alsoreported in the nucleus accumbens (NAc), mediating thehyperactivity in AN induced by activation of serotonin 5-HT4 receptor (Jean et al., 2007).

OxytocinOxytocin is a peptidic hormone involved in social, sexualand parental behaviours, among others (Ross & Young,2009). Several evidences connect oxytocin signalling andEDs. Indeed, recently, oxytocin treatment has been proposedagainst obesity (Altirriba, Poher, & Rohner-Jeanrenaud,2015), whereas oxytocin antagonist increases body weightgain (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 therelease, through the action of prolactin-releasing peptide, ofthe satiety signal cholecystokinin (CKK) (Yamashita et al.,2013). Actually, four-week chronic oxytocin treatmentreduces body weight in rhesus monkeys by decreasing foodintake and increasing energy expenditure and lipolysis(Blevins et al., 2015). This anorectic effect involves partiallythe 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 foundaltered in AN patients, but not in BN (Monteleone,Scognamiglio, Volpe, Di Maso, & Monteleone, 2016).Interestingly, oxytocin treatments decreased caloric intake inBN 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 specificoxytocin receptor genes polymorphisms have been recentlyfound (Acevedo, Valencia, Lutter, & McAdams, 2015; Kim,Kim, Kim, Shin, & Treasure, 2015). The oxitocinergic systemshows a higher regulation level, involving some other neuro-peptides like leptin, which has been reported to decreaseoxytocin release (Kutlu et al., 2010). In addition, AN andBN patients present lower serum activity of the prolyl-endo-peptidase, an enzyme involved in oxytocin cleavage (Maeset al., 2001).

Role of neurohormones in EDs: the ghrelin/leptin system

GhrelinGhrelin, the ‘hunger hormone’, is a peptidic hormoneexpressed 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 inKageyama, Takenoya, Shiba, & Shioda (2010)]. However, newstudies do not indicate ghrelin central nervous system synthe-sis (Cabral, L�opez Soto, Epelbaum, & Perell�o, 2017). In anycase, ghrelin main secretion starts when the stomach is empty(Williams, Cummings, Grill, & Kaplan, 2003). Ghrelinincreases 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 inthe same brain areas than the leptin receptor (Perello et al.,2012). Its activation triggers the synthesis of NPY, increasingappetite albeit ghrelin treatment was ineffective as a singleappetite stimulatory treatment in AN patients (Miljic et al.,2006). Furthermore, the effects of ghrelin also involve thereward 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 modulatesemotional arousal and feeding (Alvarez-Crespo et al., 2012).Surprisingly, several studies have reported elevated ghrelinlevels in AN patients (Blauwhoff-Buskermolen et al., 2017;Nakai et al., 2003; Tolle et al., 2003).

LeptinLeptin, the ‘satiety hormone’, is an adipocyte-derived hor-mone involved in the regulation of energy balance at bothlong- 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). Theexistence 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 werereported in AN and BN patients, but not in overweight BEDpatients. Interestingly, the inverse correlation was foundwhen measuring plasma-circulating levels of leptin receptorin the same groups. Conversely, an increased concentration ofNPY correlates to body mass deficiency coexisting with highconcentrations 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 werealso reported in acute ill AN girls (Dost�alov�a et al., 2005).

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In summary, data obtained from ghrelin and leptin indi-cate that an alteration in hormonal milieu is relevant in theprogression of eating disorders, highlighting the role ofphysiological compensatory mechanisms trying to minimisethe pathology extent.

Other appetite regulatorsIn addition to the peptides and hormones described above,other regulators play a role on appetite regulation, and theiralterations 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 alsorelated with anxiety, panic and even hallucinations (Lenka,Arumugham, Christopher, & Pal, 2016; Zwanzger,Domschke, & Bradwejn, 2012). In a recent study, CCKexhibits similar plasma levels in AN patients compared tocontrol group both prior to and after a meal suggesting ahormonal adaptation (Cuntz et al., 2013). Inconsistently, inolder studies, plasma measurements performed in ANpatients 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 thisambiguity. In turn, Glucagon like peptide 1 (GLP-1) is abrain-gut peptide that exerts a hormone-neurotransmitteraction inhibiting food intake, energetic expenditure andinsulin levels (Richard et al., 2014; Shah & Vella, 2014). As asatiety inductor, GLP-1 interacts with the leptin and ghrelinsystem to induce satiation (Zhu et al., 2002), probably bydecreasing 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 significantlydecreased compared with normal individuals, insulin andglucagon levels were increased, indicating an alteration inglucose homeostasis (Tomasik, Sztefko, Starzyk, Rogatko, &Szafran, 2005). In addition, punctual GLP-1 secretorydecrease was also found in BN patients compared to healthycontrols, being this concurrence limited to bingeing andvomiting events (Brambilla, Monteleone, & Maj, 2009).Other gut peptide, Peptide tyrosine tyrosine (PYY) belongsto NPY family and is secreted in ileum and colon with ananorexigenic 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 inBN/BED compared with AN (Eddy et al., 2015). Finally,concerning opioid peptides, anandamide, also known asN-arachidonoylethanolamine (AEA), plays an important rolein feeding behaviour generating motivation and pleasure infood 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, whereasthe AEA mono-unsaturated analogue oleoylethanolamide(OEA) decreases food intake and body weight through acannabinoid receptor-independent mechanism (S Gaetani,Kaye, Cuomo, & Piomelli, 2008). In the same study, plasmalevels of anandamide were down-regulated in AN patients.As anandamide, other opioid peptides as hypothalamic

b-endorphin and dynorphin-A shown level changes in EDsanimal models (see Animal models section).

Dopamine and serotonin in EDs

Dopamine role in EDsDopamine is the most important regulator of reward behav-iours, including feeding and reproduction. These rewardbehaviours are conserved along phyla. In Drosophila, a smallgroup of dopaminergic neurons in the protocerebral anteriormedial (PAM) cluster send axons to the mushroom bodies(MBs), where appetitive olfactory associative memory isformed. After sugar ingestion, PAM dopaminergic neuronsare activated, generating a reward effect. These neuronsbecome overactivated under starving conditions (Liu et al.,2012). In mammals, abnormal function of mesocorticolimbicdopaminergic circuits impairs severely motivation andreward behaviours, contributing to pathological conditionssuch as depression, addictions, compulsive moods andapathy [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 mesocorticolimbicdopaminergic alterations correlate with an abnormally highphysical activity in AN and BN patients (Hebebrand et al.,2003) and can trigger a dopamine-dependent stress response(Kalyanasundar et al., 2015). This convergence betweendopamine levels, physical activity pattern alterations and eat-ing disorders points out towards a dysfunction in the dopa-minergic neuromodulatory system. In addition, it exists aclear association between dopaminergic pathways and eatingdisorders with psychiatric comorbidities including depres-sion, anxiety, compulsive disorders and even aggressivebehaviours (Jennings, Wildes, & Coccaro, 2017; Martinussenet al., 2016). In the last years, neuroimaging has reporteddopaminergic alterations in ED patients (Berner, Winter,Matheson, Benson, & Lowe, 2017). As examples, positronemission 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 intakeregulation, since the restoration of dopamine expression indopamine deficient mice causes hypophagia and bradykinesia(Hnasko et al., 2006).

Ghrelin, leptin and the dopamine-reward system: physio-logical roles and therapeutic potentialMany studies have been carried out to demonstrate thetherapeutic use of ghrelin in EDs with contradictory results:whereas some of them described that ghrelin administrationwas ineffective to increase the appetite in AN patients-prob-ably due to the high circulating ghrelin levels found in thesesubjects- (Miljic et al., 2006; Otto et al., 2001), others sug-gested that a ghrelin long-term treatment was efficient totreat AN patients (Hotta et al., 2009; Kawai et al., 2017). Inrodents, 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 basedanorexia in mice, confirming its role in the mesocorticolim-bic dopaminergic pathway (Legrand et al., 2016).

In turn, leptin is also involved in hedonic and rewardfeeding behaviour through mesocorticolimbic dopaminergicpathways, including NAc and ventral tegmental area (VTA).Whereas orexin coming from LH orexigenic neurons acti-vates VTA dopaminergic neurons, leptin reduces the LHorexin activation, lowers dopaminergic mesolimbic neuronsactivation, and decreases dopamine release in NAc, allthrough the activity of the neuropeptide galanin (Laqueet al., 2015). Thereby, leptin negatively modulates reward-related behaviour suppressing feeding (Leinninger et al.,2009). According to these findings, leptin antagonism mayrepresent a viable therapeutic strategy in ED.

Taken all these evidences together, the VTA to NAcdopaminergic projections can be considered as essential ele-ments of both ghrelin and leptin responsive circuits control-ling food reward behaviour, highlighting the complexity ofsignal integration within the VTA and locating this brainarea as a crucial target for therapeutically actions tacklingEDs (Skibicka et al., 2013).

Serotonin function in EDSerotonin (5-hydroxitriptamin or 5-HT) is a monoamineneurotransmitter produced in the brain by neurons locatedin the dorsal and median raphe nuclei projecting to corticaland 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 moodregulation (Lambe, Fillman, Webster, & Shannon Weickert,2011; Mineur et al., 2015; Sumiyoshi, Kunugi, & Nakagome,2014). Serotonin modulates hunger, sleep, sex, emotions, andalso several endocrine processes (Haleem, 2012).Additionally, depressive, anxious, impulsive and obsessionalbehaviours, commonly related to ED, have been extensivelyrelated with serotonergic functions (Brewerton, 1992; Kaye,1997). AN and BN patients develop an egosyntonic personal-ity, implying that they do not perceive anything wrong withtheir acts. They consider their actions as reasonable andappropriate, perceiving their dysfunctional cognition regard-ing to their own weight and shape as perfectionism(Aardema, 2007). This particular trait shared between EDand other psychiatric diseases, taken together with the factthat medications acting over 5-HT pathways have somedegree of efficacy over AN and BN patients, suggests animportant role of serotonergic system dysfunction in EDonset and progression (Kaye, Bailer, Frank, Wagner, &Henry, 2005). Some authors directly assign to the serotoner-gic system the psychiatric symptomatic deteriorationobserved in AN and BN due to malnutrition, since trypto-phan (TRP), an essential amino acid only available in dietand precursor of 5-HT, is reduced in their diet (Haleem &Haider, 1996). The fact that re-feeding increases TRP plasmalevels 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/metabolismhomeostasis is found in other vertebrates as rodents but alsoin insects (Pool & Scott, 2014). Indeed, whereas NPY/AgRPneurons were proved to be involved in food intake stimulationin 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 wasdescribed in the insect model Drosophila melanogaster, theDrosophila NPF (Brown et al., 1999). Like NPY, DrosophilaNPF is expressed in only a small set of neurons in the fly brainmodulating neuronal circuits related to feeding behaviours,stress responses, metabolism, energy homeostasis, ethanolconsumption and also reproduction (Krashes et al., 2009;N€assel & Winther, 2010). In addition, the neuropeptide hugin,homologous to mammalian NeuromedinU, inhibits feedingbehaviour (Melcher & Pankratz, 2005). Subtypes of hugin neu-rons connect chemosensory to endocrine neurons producingthe Diuretic hormone 44 neuropeptide (Dh44), a homologueof 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 satietyin 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 thetranscript levels of the other suggesting a feedback regulationbetween two signalling pathways (S€oderberg et al., 2012).

With the help of the Drosophila sophisticated genetictoolkits and the deep knowledge of their sensory and centralnervous system circuitry, it is possible to further investigateand characterize neuropeptide function in food intake,energy balance and diet restriction, among other processes.Besides, the short life-cycle of Drosophila helps to assess therole of precocious aspects on food intake control.Furthermore, some recent methods developed in Drosophilahad 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 disordersconnected with food consumption, but also to identify evolu-tionarily conserved candidate genes and pathways relevant tohuman biology [see next section and Garlapow, Huang,Yarboro, Peterson, & Mackay (2015)].

Research using EDs animal models has also been highlyvaluable in the study of brain neurotransmitters and circuitryunderlying aberrant feeding behaviours. To date, somereward-related brain dysfunctions have been described onrodent animal models of AN, BN and BED, by affectingdopamine (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-

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based anorexia (ABA) model (Routtenberg & Kuznesof,1967), a restricted access to food increases the reinforcingeffects of DA when the rat finally eat, suggesting alterations inmesolimbic DA and also serotonin as a result of starvation.In addition, b-endorphin levels are high in plasma fromABA rats, due to rises in hypothalamic b-endorphin anddynorphin-A (Aravich, Rieg, Lauterio, & Doerries, 1993).Likewise, eating palatable food releases DA in a BN model,whereas purge behaviour attenuates a signal of satietydependent on ACh release. In this BN model, binge eating iscombined with gastric sham feeding in the rat to incorporateboth bingeing behaviour and purging component aspects(Avena, Rada, Moise, & Hoebel, 2006). With respect to BED,several animal models are available, by offering limitedaccess to a palatable high-fat or high-sugar food, providingad libitum access to standard rodent chow for several weeks,by alternating cyclic periods of food deprivation and feedingor even by using foot-shocks to generate binge eating beha-viour in rats. Data generated from BED animal models haveyielded important insights to concomitant physiological andneurochemical alterations associated to binge. Thus, bingeeating of a 10% sucrose solution causes a repeated release ofDA in the NAc similar to changes observed with drugdependency and obesity and have also unveiled a role forNAc ACh in binge eating behaviour (Avena, Rada, &Hoebel, 2008; Rada, Avena, & Hoebel, 2005). Concerningthe opioid system, the use of opioid antagonists as naltre-xone or naloxone (among others) was able to decrease intakeof 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 arat BED model, memantine treatment fully blocked the com-pulsivity associated with the intake of the highly palatablefood, confirming the potential therapeutic role of this drugin curing aspects of BED in humans (Popik, Kos, Zhang, &Bisaga, 2011; Smith et al., 2015).

In addition, rat animal models shared characteristics withhuman patient psychopathologies, including EDs co-morbi-dities, helping to find novel preventions or treatments (Lutzet al., 1998). As an example, many representative featuresfound in AN patients can be mimicked in a rat model of com-bined food restriction and increased physical activity (theabovementioned ABA model). Food restricted rats exhibitedthis hyperactivity and low leptin levels seem to contribute tothe phenotype of these AN rats because hyperactivity can bereduced by leptin supplementation (Dixon, Ackert, & Eckel,2003; Hebebrand et al., 2003). Additionally, a rat model ofBED combines the use of intermittent food restriction withfrustration stress (Micioni Di Bonaventura et al., 2014) assess-ing stress-induced food-reward behaviours that are crucial inthe development of eating disorders in humans. Moreover, ratstrains can be used to study reward-driven mechanisms byinvolving progressive tests where animals needs to gain theirfood (i.e. by pressing a lever), being more active to obtain pal-atable food sources. In this context, reward-deficit syndromescan 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 informationderived 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% forAN, 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 burdenwithin these disorders, followed by others (Clarke, Weiss, &Berrettini, 2012; Helder & Collier, 2011; Thornton, Mazzeo,& Bulik, 2011; Treasure et al., 2015). Several works describedspecifically the family aggregation (Hudson et al., 2006;Lilenfeld, Ringham, Kalarchian, & Marcus, 2008; Munn-Chernoff & Baker, 2016). All of them confirm that EDs havea family burden. However, family studies are unable toaddress whether family-related factors are genetic and/orenvironmental (Zerwas & Bulik, 2011).

Genome-wide association studies

Genetic epidemiology transforms the way we look into theinfluence of genes and environmental factor in EDs.Genome-wide association studies (GWAS) show large scalegenetic studies of EDs that measure simultaneously hundredsof thousands of genetic variants scattered throughout thehuman 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 orBED than in healthy people. Each study can look at hun-dreds or thousands of SNPs in several tentative traits at thesame time. GWAS represent a promising way to study com-plex, common diseases in which many genetic variationscontribute to a person’s risk, allowing effect-size estimatesfor specific genetic variants, testing shared genetics by loo-king for correlations in effect-sizes across traits and notrequiring measurements of multiple traits per individual.The most common methods in this type of studies isMendelian randomisation, which uses significantly associatedSNPs as instrumental variables to attempt quantify causalrelationships between risk factors and disease (Bulik-Sullivanet 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 familyburden of those disorders and something crucially differentis to establish – by GWAS studies – the relationshipsbetween those disorders with genetic traits. To date, thereare not significant genes associated with EDs. In early stud-ies, it was thought that a question of sample size could bethe problem for the lack of significance, but nowadays eventhe most powerful set of data in AN, by far the ED withmore genetic available studies, could not get any significantrelation with any genetic trait (Boraska et al., 2014).

As an example, Root et al. (2011) defined seven differentphenotypes 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 in182 genes, but they were unable to significantly associate anySNPs with EDs psychological traits despite the huge samplesize: 1085 EDs participants and 677 controls (Root et al.,2011). However, in despite the fact that they fail to makeany significant association, they described two SNPS withpotential interest in future studies: (i) rs17719880 in KCNN3(potassium calcium activated channel), an important gene inneuronal excitability that could be related with schizophreniaand bipolar disorders and (ii) rs12744840 in HCRTR1,an orexin receptor gene (Sakurai et al., 1998).

Another genetic study was performed on 1533 twinAmerican women focusing in the analysis of 15 polymor-phisms in HTR2A, a gene implicated in appetite process andsatiety in BED (Koren et al., 2014). In this study, theauthors describe three main polymorphism for HTR2A:(i)� 1438G/A (rs6311) which have been associated withpoor treatment response in BN patients but the authorsfailed to find a significant genetic association with EDs char-acteristics and (ii) two other polymorphisms, rs6561333 andrs2296972, associated with less likelihood of BED. However,when those polymorphisms were corrected for multiple test-ing they were no longer significant; with only rs2296972remain significant as trend level (Koren et al., 2014).Likewise, the authors did not find any comorbidity betweenMDD (Mayor Depressive Disorder) and EDs.

Some cross-trait studies (Hinney et al., 2017) obtained asignificant genetic relationship with AN and body massindex (BMI) using a ‘cross-talking’ with two big GWAS, onefor AN (Boraska et al., 2014) and one for BMI (Locke et al.,2015), demonstrating the existence of gender correlationbetween the trait and those diseases. Indeed, in AN, 90% ofthe people affected are females (Yilmaz, Hardaway, & Bulik,2015) and BN is also gender specific, affecting mainly femalepopulation. Remarkably, there are almost no EDs studiesconducted with men (Munn-Chernoff & Baker, 2016).

As stated previously, Hinney et al. (2017) describedthree significantly altered loci correlating AN risk withincreased BMI. The genes associated to those loci areCTBP2, CCNE1, CARF and NBEAL1 but their relevance inAN risk mechanisms or BMI increases are still uncertain.Other comorbid interesting study with significant results isthe 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 ofcontrol (negative valence domain). This loss control is acore feature of BED as well as SUD and could be influ-enced by dopamine. In addition, a recent study describethat AN patients could present an unbalance in the rewardsystem involving dopamine circuits (see dopamine section),describing a marginally genetic association between AN andexcessive exercise, a rs17030795 located in PPP3CA(Gorwood et al., 2016). By their side, OPRD1 (opioid deltareceptor) and HTR1D (1D serotonin receptor) are beenassociated with AN by Bergen et al. (2003) and Wanggroups (Wang et al., 2011) confirming this association,although not backed by significant results. Other geneshave 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 receptorgene in serotonin path (Munn-Chernoff & Baker, 2016;Yilmaz et al., 2015) and (iii) SOX2 gene, in this case thestudy with a comorbidity of EDs and bipolar disorder(Bulik, Kleiman, & Yilmaz, 2016).

Finally, Munn-Chernoff et al. (2015) review deeply thepossible genetic overlap between alcohol use disorder (AUD)and bulimic behaviour, not obtaining statistical significancetowards EDs. Although specific genetic mechanism underly-ing comorbidity are unclear, at minimum, individuals withAUD should be screened for individual and family history ofEDs and vice versa, regardless of race. Even when the studyis unable to provide any statistically significant data, it isclear that AUD and bulimic behaviour share environmentalinfluences.

There could be several explanations for the lack of signifi-cance concerning GWAS studies in EDs. One is the potentialpopulation stratification, probably because we are not usingthe appropriate phenotypes to separate the patients. Theother one could be the sample size. As an example, inSchizophrenia studies, only a sample size of 5000 partici-pants allowed to obtain differences in genes with statisticalsignificance. Finally, it is necessary to consider the study ofEDs as comorbid with other disorders; alcohol abuse, sub-stance abuse, bipolar disorder, emotional instability, andobesity (Yilmaz et al., 2015).

Epigenetic studies

Epigenetic refers to heritable patterns of gene expression thatoccur without changes in the DNA sequence, that is, changesin phenotype not involving changes in genotype. Epigeneticshave a major role in genomic regulation, as a natural processwhich silence specific genes during development. At leastthree systems; DNA methylation, histone modification andnon-coding RNA (ncRNA)-associated gene silencing havebeen currently considered to initiate and sustain epigeneticchange (Brown et al., 2007; Campbell, Mill, Uher, &Schmidt, 2011; Egger, Liang, Aparicio, & Jones, 2004). Thefield of epigenetics is quickly growing and with it the under-standing that both the environment and individual lifestylecan also directly interact with the genome. For example,human epidemiological studies have provided evidence thatprenatal and early postnatal environmental factors influencethe adult risk of developing various chronic diseases andbehavioural disorders (Jirtle & Skinner, 2007; Pjetri,Schmidt, Kas, & Campbell, 2012).

Epigenetics changes play a role in causation of complexadult psychiatric and neurodegenerative disorders, with rear-rangements in DNMT (DNA-methyltransferase) genes.Recent evidence supports the idea that epigenetic mechanismmay 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

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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 maternaldepression have been linked to specific increases in methyla-tion of offspring glucocorticoid receptor (NR3C1) gene,yielding to altered cortisol responses and increased stressreactivity in the offspring (Steiger & Thaler, 2016).

As mentioned previously, there is an imbalance in thedopamine reward circuit in EDs. Some epigenetics changescould 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 withhealthy controls, indicating an increase in the expression ofthe DAT1 and a decrease in the expression of the DRD2.Other studies linked AN weight loss to hypermethylationand reduced expression of POMC (proopiomelanocortin)gene (Ehrlich et al., 2010; Steiger & Thaler, 2016). In add-ition, several studies carried out in BN women patientsassessed the methylation status of specific genes showing: (i)hypermethylation in exon 1C region of the glucocorticoidreceptor (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 regionwith BN, with and without childhood abuse (Groleau et al.,2014; Steiger, Labont�e, 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 patientshad higher mean and median global methylation level whencompared to normal eaters. In this study, they also describedsignificant group differences in 2 CpGs associated withNR1H3 gene and 3 CpGs associated with PXDNL gene, bothgenes involved in dopamine and glutamate signallingrespectively and, hence, in reward dependence, mood andanxiety (Booij et al., 2015).

Transcriptome studies

Expression studies have been used mainly to confirm epigen-etic imbalances, or SNPs detected. Using transcriptomics, arecent study has shown how binge eating resulted in thedownregulation 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, HTR1DBrown et al. (2007) SNPs AN OPRD1, HTR1DWang et al. (2011) GWAS AN OPRD1, HTR1D, CNV, the only oneBoraska et al. (2014) GWAS AN No statistical significant dataTremolizzo et al. (2014) Epigenetics AN No significant data, but less methylated DNA in

fasting patient vs control. Correlating withplasma 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 DRD2inhibitors 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 ANCui et al. (2013) Targeted sequencing,

(WGS and WES)AN and BN Mutations in ESRRA and HDAC4 increase the

risk of EDsBooij 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 forBN and ATP8A2 for BED

Boraska et al. (2012) GWAS ED general Not significant but important: RUFY1, CCNL1,SEMA6D, SHC4, DLGAP1, SDPR, TRPS1 in EDsphenotypes

Munn-Chernoff and Baker (2016) GWAS EDs(BN) & SUD DRD2/ANKK1, and SNPs Val58Met in COMTYilmaz et al. (2015) GWAS AN DRD2/ANKK1, and SNPs Val58Met in COMTBulik et al. (2016) GWAS AN SOX2Munn-Chernoff et al. (2015) GWAS AUD & BN No statistical significant genesRoot et al. (2011) GWAS EDs psychological phenotypes No significant association, but important:

KCNN3, HCRTR1Koren et al. (2014) GWAS BED No significant when FDR correction is applied,

HTR2AHinney et al. (2017) Meta-analysis GWAS AN and BMI CTBP2, CCNE1, CARF and NBEAL1Gorwood et al. (2016) GWAS AN & excessive exercise PPP3CA, DRD2Steiger & 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 GRSteiger et al. (2013) Epigenetics BN and Border Line personality Hypermethylation of DRD2 promoterThaler et al. (2014) Epigenetics BN and childhood abuse Hypermethylation in CpG sites in the BDNF

promoterClarke 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 mainresults obtained.

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myelination as well as oligodendrocyte differentiation andexpression (Kirkpatrick et al., 2017).

To conclude, even though there is an absence of signifi-cant correlation between EDs phenotypic characteristics andspecific genetic trait, it is obvious that there exist a geneticimbalance which leads first to a pathway disparity, finallyending in an aberrant eating behaviour. Table 1 summarisesmost of the studies devoted to EDs, describing the type ofgenetic approach employed and the main result of the study.Undoubtedly, more epigenetic studies of those disorderswhich are crucially influenced by environmental circumstan-ces during early childhood development are mandatory foruncover 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 toour daily way of living: pathologies associating to feedingdysfunctions. Besides, these EDs are complexes, affecting notonly nutritional and physiological features but also socialcognitive processes, psychological, mental and clinicalaspects, reducing the life-quality of millions of worldwideinhabitants and generating a profound social impact. In spiteof this fact, EDs tend to be exclusively considered as psychi-atric disorders, existing nowadays a profound imbalancebetween psychological and biological therapies. In addition,psychological help is not effective to achieve a fully physicaland emotional recovery in most of the cases (Halmi, 2013).Concerning clinical treatment, unfortunately, to date, onlytwo drugs (fluoxetine and lisdexamfetamine, respectively forBN and BED treatment) have been approved by the FDAand the international regulatory agencies for the treatmentof 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 scientificmultidisciplinary effort is mandatory to overcome this chal-lenge. The combination of genomics and epigenomics toidentify new genes and biomarkers, the involvement of bio-informatics analysis to provide an integrative overview andgenerate a network interaction between SNPs and epigeneticmodulation and the deep characterization of the neuropepti-des, neurotransmitters and hormones involved will allow abetter understanding of EDs. In parallel, computational dataand the creation of new databases will allow the develop-ment of molecules targeting specifically neuromodulators-and hormones-mediated signalling pathways involved inthese illnesses. Finally, tailor medicine approaches based ongenetic individual differences must be also applied in EDspatients. Indeed, an accurate diagnosis should include a gen-etic and epigenetic study accompanied by a family retro-spective revision, to understand the specific circumstances ineach case and the possible genetic imbalance, identifying alist of genes as a first option to check for SNPs or epigeneticderegulation. This genetic imbalance would affect the regula-tion and function of neuromodulators and hormones in thebrain and/or other organs, ultimately generating abnormal-ities in eating behaviours. For all these reasons, we stronglybelieve that it is urgent to develop a different way of

approach those disorders, which affects not only the patientsbut also the families and their environmental influences.

Acknowledgements

We appreciate the help of Dr. Cristina Martin-Higueras and laboratorymembers for their critical comments. This publication was supportedby the Spanish National Programme for Research aimed at theChallenges of Society [DPI2015–66458-C2–2-R, MINECO] to AA andGC, an AIRC-iCARE Fellowship co-funded by European Communityto LG and the CNRS, INRA, Burgundy Regional Council (PARI2012and 2014) and University of Bourgogne Franche-Comt�e to CE.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

This publication was supported by the Spanish National Programmefor Research aimed at the Challenges of Society [DPI2015–66458-C2–2-R, MINECO] to AA and GC, an AIRC-iCARE Fellowship co-funded byEuropean Community to LG and the CNRS, INRA, Burgundy RegionalCouncil (PARI2012 and 2014) and University of Bourgogne Franche-Comt�e to CE.

ORCID

Leticia G. Le�on http://orcid.org/0000-0001-8781-7424Angel Acebes http://orcid.org/0000-0003-0020-1913

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