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

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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 To link to this article: http://dx.doi.org/10.1080/01677063.2017.1353092

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Download by: [University of La Laguna Vicerrectorado] Date: 01 August 2017, At: 07:00 JOURNAL OF NEUROGENETICS, 2017 https://doi.org/10.1080/01677063.2017.1353092

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

German Cuestoa, Claude Everaertsb, Leticia G. Leon c 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 ARTICLE HISTORY Eating-disorders (EDs) consequences to human health are devastating, involving social, mental, emo- Received 9 May 2017 tional, physical and life-threatening aspects, concluding on impairment and death in cases of extreme Revised 26 June 2017 anorexia nervosa. It also implies that people suffering an ED need to find psychiatric and psychological Accepted 5 July 2017 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 KEYWORDS overview concerning the actual pharmacological and psychological treatments, the knowledge of cells, Eating disorders; circuits, neuropeptides, neuromodulators and hormones in the human brain- and other organs- under- pharmacology; neuromodu- lying these disorders, the studies in animal models and, finally, the genetic approaches devoted to face lators; genetic approaches 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.

Introduction carbohydrates and fat food are consumed in a very short- time period, followed by 1 or more compensatory purge Eating-disorders (EDs) as anorexia nervosa (AN), bulimia behaviours (vomiting, laxatives, fasting, etc … ). That takes nervosa (BN) and binge-eating disorder (BED), have both a place on average a minimum of twice weekly for three or deep social impact and an enormous cost to public health- more months, or, in extreme cases, several times a day. BN care systems (Keski-Rahkonen & Mustelin, 2016). The is divided into two subtypes: the above-mentioned purging- example of Europe is extremely illustrative: besides a very type and the lesser-common non-purging type, characterised high risk of premature mortality, more than 2/3 of those EDs patients had at least some role impairment in at least by fasting or excessive exercise trying to compensate for the one domain (Preti et al., 2009). In fact, the prevalence of calories obtained from the previous binge. Besides, there EDs has increased across time, particularly in the second exist comorbidities between BN and other disorders as sub- half of the twentieth century (Bulik et al., 2006). In the USA, stance abuse, affective disorders, and attention disorders 20 million women and 10 million men had suffered from a (Altman & Shankman, 2009; Hatsukami, Eckert, Mitchell, & clinically significant ED at some time in their life Pyle, 1984). Finally, Binge eating disorder (BED) patients (Samnaliev, Noh, Sonneville, & Austin, 2015) with 7300 show also repetitive and uncontrolled episodes of over con- worldwide deaths in 2010 (Lozano et al., 2012) resulting in sumption of larger amounts of food in a discrete period, but, 6 Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 2.2 10 disability-adjusted life years (DALYs) (Murray unlike BN and AN they do not show recurrent compensa- et al., 2012). tory purging, fasting and excessive exercise behaviours Anorexia nervosa is defined as an association of an (American Psychiatric Association, 2013). As for AN and abnormally low body weight, an intense fear of gaining BN, BED has been associated with medical and psychiatric weight and a distorted cognition regarding weight, shape, comorbidities, as mood (anxiety) and substance use disor- and drive for thinness. AN is a disorder but also a symptom ders (Becker & Grilo, 2015). Interestingly, BED is the most of other disorders, as depression, bipolar disorder, anxiety prevalent among all eating disorders, being higher in women disorders (obsessive–compulsive disorder, panic disorder, than in men, and also the most underdiagnosed and under- social phobias, and post-traumatic stress disorder) and sub- treated, due to insufficient diagnostic criteria and lack of stance abuse (O’Brien & Vincent, 2003; Woodside & Staab, available treatment options [see Section 2 below and also 2006). In turn, BN is characterized by episodes of binge eat- Kornstein, Kunovac, Herman, & Culpepper (2016)]. ing – defined itself as ‘recurrent periods of uncontrolled Eating-disorders have been long considered as severe psy- overeating’–in which big amounts of high-sugar, 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 ß 2017 Informa UK Limited, trading as Taylor & Francis Group 2 GERMAN CUESTO ET AL.

mentioned, BN and BED are closely related to affective, Seeley, Porte, & Schwartz, 1998). Single neuropeptides con- attention, emotional and mood disorders. Social cognition tribute to feeding behaviours in mammals (Dailey & encompass the psychological processes endowing individuals Bartness, 2009), and their roles in the neuronal circuits to observe, process, store and retrieve information obtained underlying these behaviours have been intensively studied. from conspecifics in social interactions (Frith, 2008). Poor NPY/AgRP peptidergic neurons increase feeding intake by recognition of emotions in others is documented in AN inhibiting POMC/CART system which stimulates anorexi- patients and facial emotion recognition difficulties persist in genic neurons in the (LH) area, and them even after recovery (Oldershaw et al., 2011). Besides, stimulating orexigenic neurons in the paraventricular nucleus brain abnormalities have been described in AN patients, (PVN) (Aponte, Atasoy, & Sternson, 2011; Atasoy, Betley, including abnormal neural activation (Uher et al., 2004) and Su, & Sternson, 2012; Wu, Boyle, & Palmiter, 2009). altered neurotransmitter function (Kaye, Fudge, & Paulus, Together, these neuropeptides translates the feeding behav- 2009). More research is crucial to establish links between iour in appetite as well as adaptive responses (Borgland social cognition abnormalities and neurological defaults asso- et al., 2009). ciated with AN (Cardi et al., 2015). Interestingly, several pieces of evidence indicate that Under these grounds, deciphering unambiguously how neurobiological mechanisms underlying ED might involve an the brain controls food intake and satiation mechanisms is overreaction of the immune system, generating, in turn, a crucial to know how eating-associated pathological disorders dysfunction of neuropeptide signalling. Thus, reactive are bypassing this control. To date, there is a good know- Immunoglobulins (Igs) bind to food-intake neuropeptides ledge about the bidirectional communication among exten- (named peptide autoantibodies) and are identified in the sive areas of the nervous system (including the cortex, basal serum of AN/BN patients, predominantly bound to a-MSH ganglia, and the limbic system) with peripheral components in hypothalamic neurons (Fetissov et al., 2005). In addition, (such as gustatory system, gastrointestinal nervous system, the enterobacteria Caseinolytic protease B protein ClpB also pancreas, liver, muscle, and ), sustaining an act as an a-MSH-mimetic protein, triggering production of exquisitely well-regulated between food intake Igs against a-MSH, reducing its anorexigenic effects and energy expenditure (Lenard & Berthoud, 2008; (Tennoune et al., 2014). Interestingly, these circulating auto- Mithieux, 2013). In addition to these circuits, the brain antibodies might be purified in order to be employed as endocannabinoid system also acts as a key regulator for food pharmacological tools in AN and BN (Smitka et al., 2013). intake and energy balance (Cardinal et al., 2015; Di Marzo In addition to the gastrointestinal-brain communication, et al., 2001; DiPatrizio & Piomelli, 2012) through food- gut microbiota plays an important role on nutriments related olfactory-dependent mechanisms (Soria-Gomez, absorption and energy expenditure. Likewise, the brain- Bellocchio, & Marsicano, 2014) and is likely involved in the gut-microbiota axis allows a bidirectional communication hedonic and emotional aspects of eating. In spite of these between gut microbes and the brain through endocrine, fundamental advances, it is not completely understood how neural, immune and metabolic pathways (Dinan & Cryan, neuronal feeding circuits regulate food intake and hence, 2017). Moreover, modifications of the gut microbiota have after energy repletion, yield to abolish new impulse to eat. also been described in AN patients (Armougom, Henry, The hypothalamus is crucial to integrate metabolic and sen- Vialettes, Raccah, & Raoult, 2009). It is also well character- sorial signals from the periphery, and from higher brain ized that the gut microbiome contributes to the pathogenesis structures. More precisely, the hypothalamic arcuate nucleus of malnutrition through nutrient metabolism and immune (ARC) harbours two neuronal populations, one participating function (Krajmalnik-Brown, Ilhan, Kang, & DiBaise, 2012). to the synthesis of the appetite-stimulating Besides, chronic constipation, a common feature in AN (NPY) and Agouti-related peptide (AgRP) and the other patients, is present prior to weight loss and causes changes expressing the two appetite-suppressing peptides proopiome- in gut microbiota, increasing Methanobrevibacter smithii le- vels (Kim et al., 2012). More interestingly, elevated plasma Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 lanocortin (POMC) and cocaine- and amphetamine- regulated transcript (CART) (see Lenard & Berthoud, 2008). concentrations of the ClpB have been detected in female This highlights the importance of neuropeptide-mediated patients with AN, BN, and BED when compared with pathways in the control of food intake and energy balance. healthy individuals (Breton et al., 2016). These findings open Neuropeptides are a group of chemically diverse molecules the possibility to manipulate gut microbiota (by using antibi- modulating physiological processes and behaviours in mam- otics) helping to improve nutritional therapy for ED patients. mals (van den Pol, 2012) and invertebrates (Taghert & Clearly, more research is needed at this point. Nitabach, 2012). Particularly relevant is the case of NPY, synthesized and released by many unrelated groups of neu- Pharmacology and pharmacotherapy tools in eating rons from different human brain regions and activating mul- disorders tiple different receptors in target neurons (van den Pol, 2012). Current treatments of the EDs are substantially multidimen- The brain homeostatic control of feeding involves neural sional and include psychotherapy, nutritional rehabilitation, circuits located in the hypothalamus (hunger signals, initiat- drug treatment and even light therapy, but unfortunately ing feeding behaviour) and the brainstem (satiation signals, often they have shown limited efficacy in ameliorating symp- limiting meal size) generating appropriate integrated toms not fully normalizing eating behaviours (Halmi, 2005). responses (Adan, Vanderschuren, & la Fleur, 2008; Woods, To date, psychotherapies such as cognitive behavioural JOURNAL OF NEUROGENETICS 3

therapy (CBT), cognitive analytic therapy (CAT), dialectical neurotransmission in hippocampus and cortex (Koyama, behavioural therapy (DBT) or family-based therapy (FBT), Nakajima, Fujii, & Kawashima, 1999; Rasmusson, Goldstein, remain the main treatments of EDs, even though some drug Deutch, Bunney, & Roth, 1994). Tandospirone is an anti- therapies have been employed for some specific EDs. The psychotic and anxiolytic drug clinically used to treat schizo- most demanded pharmacotherapy of EDs should induce a phrenia in China and Japan (Sumiyoshi et al., 2007), but remission of symptoms in the acute phase of the disease, also induces improvement in weight gain and psychopath- prevent relapse over time and be appropriate to treat fre- ology of the AN patients (Okita, Shiina, Nakazato, & Iyo, quent associated comorbidities. Nowadays, there are no 2013). effective drugs to overcome all these clinical features, except fluoxetine and lisdexamfetamine, the only drugs approved by Antidepressants the international regulatory agencies for the treatment of While the use of antidepressant in the treatment of EDs two EDs (respectively BN and BED). Furthermore, numer- would appear logical due to the high rates of comorbidity ous drugs used in psychiatric clinic (i.e. antipsychotics, anti- (greater than 50%) between EDs and mood depression depressants, mood stabilizers, and selective norepinephrine (Mischoulon et al., 2011), the effectiveness of antidepressants and/or serotonin reuptake inhibitors) were also tested to in the treatment of AN patients is weak. Thus, while tricyclic treat clinical manifestations of EDs, showing variable results. antidepressants (TCA) have not shown significant benefits In this review, we will highlight the main positive clinical (Halmi, Eckert, LaDu, & Cohen, 1986), the most recent sero- results. tonin reuptake inhibitors (SSRIs – fluoxetine) have shown very little effectiveness in promoting weight regain in AN Anorexia nervosa patients (Walsh et al., 2006). Antipsychotics Antipsychotic drugs act by blocking dopamine receptors Bulimia nervosa (Miller, 2009). While antipsychotics are known to increase Antipsychotics appetite and weight gain in patients with major psychiatric Second-generation antipsychotics used in AN treatment disorders (schizophrenia or bipolar disorder; Hay & induce or exacerbate the crisis of binge eating in patients Claudino, 2012), most of them are paradoxically not useful with EDs (McElroy, Guerdjikova, Mori, & O’Melia, 2012). for weight recovery in AN patients (McKnight & Park, 2010). However, they are able to reduce AN psychological comorbidities (body image alteration, pathological focus on Antidepressants weight and food, fear of gaining weight, obsessive–compul- Contrarily to what is described for AN, antidepressants sive symptoms, hyperarousal and agitation; see Powers & (including TCAs, SSRIs, Serotonin-norepinephrine reuptake Santana, 2004). inhibitors (SNRIs), and monoamine oxidase inhibitors, The first-generation of antipsychotics, pimozide and sul- MAOIs) are the mainstay of pharmacological treatment for piride, did not demonstrated sufficient capacity to favour BN, by reducing the dopamine crisis of binge eating and weight gain (Vandereycken, 1984), whereas second-gener- purging phenomena, improving anxiety moods (Capasso, ation antipsychotics are proved more useful, in particular Petrella, & Milano, 2009). However, although quite effective, olanzapine, a D2/5HT2 antagonist. This second generation both the clinical use of TCA and MAOIs are not recom- favours an increase in weight, leads to a significant reduction mended for their frequent adverse events. Desipramine (a in the ‘anorexic ruminations’ and depressive symptoms but TCA also known as desmethylimipramine) inhibits the also an improvement in obsessive–compulsive symptoms reuptake of norepinephrine and, to a minor extent, sero- (Brewerton, 2012; Flament, Bissada, & Spettigue, 2012). tonin. Both imipramine and desipramine were demonstrated Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 Other second-generation antipsychotics, such as risperidone, to reduce binge eating and to improve the comorbidities in quetiapine, aripiprazole, and ziprasidone, have not been so short-term treatments (Barlow, Blouin, Blouin, & Perez, extensively studied in the treatment of AN (Powers & Bruty, 1988; Walsh, Hadigan, Devlin, Gladis, & Roose, 1991). 2009). While olanzapine is efficient in reducing psychiatric However, their side effects make them inadequate for BN symptoms associated with the AN promoting weight recov- long-term treatments (Agras et al., 1992; Leitenberg et al., ery, its side effects, such as extrapyramidal symptoms and 1994). In turn, SSRIs (fluoxetine, citalopram, sertraline and cardiac troubles (QT prolongation), are dangerous for anor- fluvoxamine) were shown to reduce BN main symptoms exic patients. All the main international guidelines classify (Bacaltchuk & Hay, 2001; McElroy et al., 2003; Milano, the use of these second-generation antipsychotics just as Petrella, Sabatino, & Capasso, 2004). Among them, secondary possibilities for AN treatment (Aigner, Treasure, Fluoxetine has been the most studied being – since 1997 – Kaye, Kasper, & WFSBP Task Force On Eating Disorders, the only drug approved by the FDA for the treatment of BN, 2011). at a dose of 60 mg/day. Although BN is a chronic disease Finally, the azapirone derivative tandospirone, also known with frequent relapses, most trials lasted only several months as metanopirone, is a selective serotonin-1A (5-HT1A) (Martiadis, Castaldo, Monteleone, & Maj, 2007). However, a receptor partial agonist (Tanaka et al., 1995) known to 58-week study has demonstrated the efficacy of fluoxetine in shown enhanced cholinergic and dopaminergic reducing binge and purging episodes, obsessive–compulsive 4 GERMAN CUESTO ET AL.

symptoms and the frequency of relapses (Romano, Halmi, schizophrenic patients improves mainly negative symptoms Sarkar, Koke, & Lee, 2002). Finally, milnacipran is a dual (Velligan, Alphs, Lancaster, Morlock, & Mintz, 2009) show- acting antidepressant which inhibits the reuptake of both ing also promising results in the treatment of generalized serotonin and noradrenaline (SNRI) being efficient in the anxiety disorder (Schwartz, Siddiqui, & Raza, 2012), atten- short-term treatment of patients with BN (El-Giamal et al., tion deficit hyperactivity disorder ADHD (Hosenbocus & 2003) and leading to a significant reduction in weekly binge Chahal, 2013) and obsessive compulsive disorder (Haghighi eating and vomiting frequency. et al., 2013). Memantine has been proved effective in reduc- ing the frequency of binge days and episodes (Brennan Anticonvulsant mood stabilizers et al., 2008; Hermanussen & Tresguerres, 2005). Many drugs described as ‘mood stabilizers’ are categorized ‘ as anticonvulsants, and the term anticonvulsant mood Antidepressants ’ stabilizers is sometimes used to describe them as a class. The antidepressants are also useful in the treatment of BED Since the early 2000s, antiepileptic drugs (AEDs) have been both decreasing the binge seizure frequency and improving useful in the treatment of psychiatric disorders related to symptoms of depression and anxiety often present in BED. EDs, such as headache, substance abuse, and bipolar, anxiety SSRIs seem to favour a significant reduction in binge crisis or personality disorders. Furthermore, many AEDs interact having a modest effect in reducing the body weight of the with glutamatergic, GABAergic, serotonergic and dopamin- patients (Reas & Grilo, 2008; Stefano, Bacaltchuk, Blay, & ergic systems in the regulation of appetite, food intake and Appolinario, 2008). Although the effect of fluoxetine is con- weight (Gao & Horvath, 2008; Meister, 2007). For example, troversial in humans (Arnold et al., 2002; Grilo, Crosby, topiramate and zonisamide are associated with appetite and Wilson, & Masheb, 2012), this drug (as TPM and sibutr- weight decrease (McElroy et al., 2009). amine) was reported to reduce binge eating in animal mod- Numerous human clinical studies, and preclinical studies els (Cifani, Polidori, Melotto, Ciccocioppo, & Massi, 2009). in animals, have demonstrated the utility of topiramate Two other drugs acting similar to antidepressants, duloxe- (TPM) in neuroprotection against ischemia and brain inju- tine and sibutramine, two serotonin re-uptake inhibitors ries, body weight loss in obese subjects, mitigation of alcohol (SNRIs), have shown the ability to reduce both the frequency consumption, drug addiction, post-traumatic stress disorder, of binge episodes crisis, body weight, and depressive symp- BN and BED. Its efficiency in the treatment of EDs associ- toms in patients with BED (Appolinario et al., 2003; ated with – BN and BED – could be related to its Guerdjikova et al., 2012; Milano et al., 2005). However, since effect on kainite/AMPA glutamate receptors (Hettes et al., 2010, sibutramine has been withdrawn from European and 2003). Thus, TPM improves multiple behavioural aspects of USA markets due to cardiovascular risks. Venlafaxine is BN: binge and purge symptoms are reduced, while self- another SNRI that at low-dose (75 mg/day) also acts as a esteem, eating attitudes, anxiety, body weight and body weak inhibitor of norepinephrine re-uptake (Smith, image are also ameliorated (Nickel et al., 2005). Beside its Dempster, Glanville, Freemantle, & Anderson, 2002). In efficiency, TPM has some recognized several adverse events addition, Venlafaxine may be an effective treatment for BED (paraesthesia, metabolic acidosis, nephrolithiasis, acute cog- associated with overweight or obesity in reducing of weekly nitive impairment, and acute myopia among others (Shank binge frequency, severity of binge-eating and mood symp- & Maryanoff, 2008) that must be taken into account in the toms (McElroy et al., 2012). These effects can be related to common clinical practice. its activity against impulse control disorders (ICD; Camardese, Picello, & Bria, 2008). Binge eating disorder Finally, atomoxetine is a selective norepinephrine Amphetamine reuptake inhibitor (NRI) indicated for patients with atten- Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 Due to their weak efficacy and severe side effects, the use of tion-deficit hyperactivity disorder and narcolepsy (Garnock- ’ drugs to treat BED was limited until lisdexamfetamine dime- Jones & Keating, 2009). Although in 2007 McElroy s team have shown preliminary evidence for the efficacy of atomo- sylate (L-lysine-dextroamphetamine, LDX) was approved by the US food and drug administration (FDA) to treat moder- xetine in BED (McElroy et al., 2007), no newer studies has ate to severe BED in adults (50–70 mg/day, US FDA, 2015). been devoted to this drug. Nowadays, it is the only drug currently approved for the treatment of BED, and the second medication of any ED, Anticonvulsant mood stabilizers after fluoxetine (approved for BN in 1997). LDX is an effica- In studies in BED with obesity, Citalopram-treated patients cious treatment for BED by regulating dopamine (DA), nor- displayed a 94% reduction of binge eating and significant epinephrine (NE) and serotonin neurotransmitters involved weight loss (McElroy et al., 2003). In turn, zonisamide is a in the modulation of appetite, hunger and eating behaviours sulfonamide anticonvulsant approved for use as an adjunc- (Guerdjikova, Mori, Casuto, & McElroy, 2016). tive therapy in adults with partial-onset seizures and infantile spasm (Brodie, Ben-Menachem, Chouette, & Giorgi, 2012; Antipsychotics Holder & Wilfong, 2011). Together with the CBT, zonisa- Memantine is a non-competitive antagonist of N-methyl-D- mide has proved useful in the treatment of obesity associated aspartate receptors (NMDARs). Memantine therapy in BED, in a one-year trial, with reduction of the binge JOURNAL OF NEUROGENETICS 5

manifestations and weight loss (Ricca, Castellini, Lo Sauro, in psychiatric clinic, showing generally undesirable side Rotella, & Faravelli, 2009). However, it presents substantially effects. the same adverse effects as TPM.

Neuropeptides, neurotransmitters and hormones Anti-obesity drugs involved in EDs The serotonin releaser fenfluramine, also known as 3-tri- fluoromethyl-N-ethylamphetamine, is a highly effective ano- Role of neuropeptides in EDs rectic agent in both laboratory animals and humans (Davis Hunger signals results from internally generated metabolic & Faulds, 1996; McGuirk, Goodall, Silverstone, & Willner, deficits yielding the animals to feed (Saper, Chou, & 1991). This drug reduced the frequency of seizures in BED Elmquist, 2002). Feeding behaviour remains critical for obese patients, without weight loss (Stunkard, Berkowitz, restoring metabolic homeostasis and, consequently, survival. Tanrikut, Reiss, & Young, 1996). However, fenfluramine Animals have evolved refined feedback mechanisms to regu- works only while it is taken and binge eating returns to pre- late energy expenditure and food consumption, rectifying vious levels after medication. Fenfluramine was removed possible imbalances and modifying feeding thresholds con- from its clinical use after reports of heart valve disease in sidering both internal needs and food availability (Morton, 1997 (Rothman & Baumann, 2002). In turn, orlistat is a Cummings, Baskin, Barsh, & Schwartz, 2006). How the ner- gastrointestinal lipase inhibitor that reduces the absorption vous system integrates internal physiological state to generate of dietary fat, indicated for weight loss and maintenance, a response triggering feeding behaviours is insufficiently being designed to treat obesity (Padwal & Majumdar, 2007). documented and, hence, understood. However, in this scen- It has been used in individuals with BED primarily targeting ario, the crosstalk of neuropeptides within the nervous sys- weight loss rather than binge eating frequency (Grilo, tem and peripheral circulating hormones appears to be Masheb, & Salant, 2005). It must be noted that orlistat mis- extremely relevant. Figure 1 shows a schematic summary of uses were reported in patients with BED and BN the information highlighted in this section. Indeed, neuro- (Fernandez-Aranda et al., 2001; Hagler Robinson, 2009). peptides affect different complex behaviours at system, cellu- lar, and molecular levels in an age-dependent and hormonally modulated manner (Figure 1). Anti-addiction drugs Research evidences point directly to defaults in neuropep- The urge to consume food and the lack of control in BED tide levels and/or function in ED pathogeny. In this review, patients resemble the strong impulse to consume alcohol we have highlighted the most relevant: 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, NPY/AgRP ‘ ’ 2011) activating the mesolimbic dopaminergic reward sys- Neuropeptide Y and Agouti-related peptide are both pro- tem (Koob & Volkow, 2010; Umberg, Shader, Hsu, & duced mainly in the ventromedial part of the ARC hypotha- Greenblatt, 2012). Therefore, almost all AUD medications lamus by NPY/AgRP neurons (Broberger, Johansen, have been tested in BED patients, with insignificant results, Johansson, Schalling, & Hokfelt,€ 1998; Chronwall et al., except disulfiram, the oldest medication approved for AUD 1985). Both neuropeptides exert an orexigenic signal over ’ (McElroy et al., 2012; Suh, Pettinati, Kampman, & O Brien, hypothalamic–pituitary–adrenocortical axis, increasing the 2006). Disulfiram is a carbamate derivative discovered in the ACTH, cortisol and prolactin release and have been involved 1920s, and used since the 1950s to support the treatment of in appetite regulation. Cerebral injections of NPY induce the chronic alcoholism by producing an acute sensitivity to etha- food intake (Clark, Kalra, Crowley, & Kalra, 1984) and high Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 nol by inhibiting the aldehyde dehydrogenase (ALDH) levels of NPY are associated with high food intake but low involved in alcohol metabolism (Hald & Jacobsen, 1948). physical activity (Schwartz et al., 1996). Recent studies indi- Disulfiram also inhibits the dopamine b-hydroxylase (DbH), cates AN patients are unable to up-regulate NPY system to responsible for converting dopamine to noradrenaline in adapt their energy demand when exposed to chronic under- noradrenergic neurons (Barth & Malcolm, 2010). Used as nutrition, whereas the satisfaction for rapid food is due to treatment of BED, disulfiram effectively reduced the fre- the triggered a-melanocyte-stimulating hormone (a-MSH) quency of binge eating episodes in BED patients, and this response occurred during lunchtime (Galusca et al., 2015). effect is also considered to be due, at least in part, to DbH Besides, an abnormal increase of NPY have been found in inhibition, as for cocaine use disorder (Farci et al., 2015). AN and BN patients after consumption of high-carbohydrate However, the use of disulfiram in the BED treatment may be and high-protein breakfast, suggesting alterations in regula- limited by side effects or by the risk of exacerbation of tion of gut–brain axis peptides and indicating that NPY psychotic disorders in BED patients. plasma levels represent a good indicator for EDs (Sedlackova In summary, the pharmacological treatment of EDs is in et al., 2012). In an indirect manner, the anti-stress effects of its early stages. Nowadays, no drug was especially designed NPY are also relevant to ameliorate psychiatric conditions of to treat ED suffering patients, and current ED pharmaco- both AN and BN patients. In turn, AgRP has been involved therapy is only the adaptation of some drugs previously used in appetite regulation since passive stress prevents AgRP and 6 GERMAN CUESTO ET AL.

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.

upregulation in response to activity in an anorexia rat be the link between physiological and psychological compo- model (Boersma et al., 2016). 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. 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 Proopiomelanocortin (POMC) and CART glands, pancreas, placenta, stomach, ileum, colon and colo- Proopiomelanocortin is a precursor polypeptide synthesized rectal epithelial cells (Nakabayashi et al., 2003). Orexins mainly in the anterior pituitary, expressed as pre-proopiome- interact with either directly regulating neural orexi- lanocortin and cleaved by the convertase prohormones 1 and genic pathways (Muroya et al., 2004) or indirectly, modulat- 2 generating a-MSH, ACTH, and the opioids beta-endorphin ing the activity of orexigenic neurons in the LH (Louis, and Met-enkephalin. POMC is an anorexigenic peptide at Leinninger, Rhodes, & Myers, 2010). Interestingly, neuropep- the hypothalamic ARC. Indeed, re-feeding after fasting indu- Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 tides as orexins, but also melanin-concentrating hormone ces the activation of POMC neurons in ARC, promoting (MCH) and 26RFa are up-regulated in AN patients. To satiety (Fekete et al., 2012). Leptin is the key activating regu- explain this finding, two different hypotheses have been for- lator of the CNS POMC system, which is involved in appe- mulated. In the first one, this up-regulation might result tite but also regulation of sexual behaviour, lactation, from an adaptive mechanism to increase food intake against reproductive cycle, central cardiovascular control, melanin under nutrition. In the second, a chronic increase of orexi- production in the skin, addictive behaviours and stress ma- genic neurons could reinforce dopamine-induced anxiety in nagement (Millington, 2007; Zhou & Kreek, 2015). POMC the reward system (see dopamine section below) of AN mRNA level increases after stress exposition and POMC patients, increasing their aversion to eat (Gorwood et al., neurons activate rapidly under emotional stressing condi- 2016). Orexins are also involved in endocrine system regula- tions (J. Liu et al., 2007). These evidences define the role of tion, playing an important role in insulin, glucagon and lep- POMC as a key communication link between brain feeding tin secretion in response to glucose (Park et al., 2015). control centre and stress systems (Ryan et al., 2014). In ad- Interestingly, alterations in orexin signalling could be related dition, a-MSH, a POMC-derived peptide, is involved in with eating disorders at different levels: either by regulating manifestation of affective disorders like anxiety and depres- directly the appetite, but also regulating the reward system sion via MC4R response in the PVN and ARC nuclei, and controlling anxiety levels. For this reason, orexin could among others (Kokare, Dandekar, Singru, Gupta, & JOURNAL OF NEUROGENETICS 7

Subhedar, 2010). Finally, intracerebroventricular injection of Role of neurohormones in EDs: the /leptin system MC4R agonists activates the hypothalamo–pituitary–adrenal Ghrelin (HPA) axis, increased anxiety and reduced food intake ‘ ’ (Klenerova, Sery, & Hynie, 2008). Ghrelin, the hunger hormone , is a peptidic hormone In turn, cocaine and amphetamine regulated transcript expressed in humans by P/D sub 1 gland cells of the sto- (CART) is an anorectic peptide widely expressed in both mach (Rindi et al., 2002), with lower expression in pancreas, central and peripheral nervous system, playing an important gallbladder, colon, liver, colon and lungs (Kojima, Hosoda, role in the hypothalamus (Keller et al., 2006). As for POMC, & Kangawa, 2001). Ghrelin is also expressed in the brain CART hypothalamic secretion is regulated by leptin (Elias (Cowley et al., 2003), where it exerts a paracrine effect by acti- et al., 1998) and it has been related with addictive beha- vating orexigenic NPY/AgRP neurons and inhibiting anorexi- viours and stress responses (Bakhtazad, Vousooghi, Garmabi, genic POMC neurons, increasing appetite [reviewed in & Zarrindast, 2016). The intracerebroventricular CART Kageyama, Takenoya, Shiba, & Shioda (2010)]. However, new studies do not indicate ghrelin central nervous system synthe- administration reduces appetite and increases energy expenditure, but, under specific circumstances, hypothalamic sis (Cabral, Lopez Soto, Epelbaum, & Perello, 2017). In any CART has been considered also as orexigenic (Murphy, case, ghrelin main secretion starts when the stomach is empty 2005). An increase in CART expression has been also (Williams, Cummings, Grill, & Kaplan, 2003). Ghrelin reported in the nucleus accumbens (NAc), mediating the increases gastric secretion and gastrointestinal motility to pre- hyperactivity in AN induced by activation of serotonin 5- pare the body for food intake [reviewed in Kirsz & Zieba HT4 receptor (Jean et al., 2007). (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., Oxytocin 2012). Its activation triggers the synthesis of NPY, increasing Oxytocin is a peptidic hormone involved in social, sexual appetite albeit ghrelin treatment was ineffective as a single and parental behaviours, among others (Ross & Young, appetite stimulatory treatment in AN patients (Miljic et al., 2009). Several evidences connect oxytocin signalling and 2006). Furthermore, the effects of ghrelin also involve the EDs. Indeed, recently, oxytocin treatment has been proposed reward system activation throughout dopaminergic pathways, against obesity (Altirriba, Poher, & Rohner-Jeanrenaud, (see Dopamine section below and also Perello & Dickson, 2015), whereas oxytocin antagonist increases body weight 2015). It also exerts a neurogenic action in the hippocampus, gain (Zhang & Cai, 2011). The release of oxytocin to blood- facilitating learning and memory (Kim, Kim, & Park, 2017), stream has been associated with the inhibition of appetite and acts on the central nucleus of amygdala, where modulates (Herisson, Brooks, Waas, Levine, & Olszewski, 2014) and the emotional arousal and feeding (Alvarez-Crespo et al., 2012). release, through the action of prolactin-releasing peptide, of Surprisingly, several studies have reported elevated ghrelin the satiety signal (CKK) (Yamashita et al., levels in AN patients (Blauwhoff-Buskermolen et al., 2017; 2013). Actually, four-week chronic oxytocin treatment Nakai et al., 2003; Tolle et al., 2003). reduces body weight in rhesus monkeys by decreasing food intake and increasing energy expenditure and lipolysis Leptin (Blevins et al., 2015). This anorectic effect involves partially Leptin, the ‘satiety hormone’, is an adipocyte-derived hor- the inhibition of reward circuits (Peters, Bowen, Bohrer, mone involved in the regulation of energy balance at both McGregor, & Neumann, 2017), is accompanied by a reduc- long- and short-term (Blundell, Goodson, & Halford, 2001). tion of gastric empting and is blocked by an oxytocin recep- Leptin activity is exerted in the hypothalamic ARC, stimulat- tor antagonist in rats (Wu, Doong, & Wang, 2008). ing anorexigenic neurons expressing POMC and cortico- According to this, circulating oxytocin levels has been found tropin-release factor (CRF), and inhibiting orexigenic NPY/ altered in AN patients, but not in BN (Monteleone, AgRP neurons (Baver et al., 2014; Flak & Myers, 2016). The Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 Scognamiglio, Volpe, Di Maso, & Monteleone, 2016). existence of low levels of plasma leptin in cerebrospinal fluid Interestingly, oxytocin treatments decreased caloric intake in (hypoleptinemia) is a key endocrinological feature of AN BN patients but not in AN (Kim, Eom, Yang, Kang, & (Focker€ et al., 2011; Hebebrand et al., 1997). Hence, altera- Treasure, 2015). Despite these contradictory findings, oxyto- tions in leptin homeostasis could be crucial in eating disor- cinergic system has been suggested to be involved in mecha- ders. Indeed, reduced plasma circulating leptin levels were nisms underlying BN and eating disorders, since specific reported in AN and BN patients, but not in overweight BED oxytocin receptor genes polymorphisms have been recently patients. Interestingly, the inverse correlation was found found (Acevedo, Valencia, Lutter, & McAdams, 2015; Kim, when measuring plasma-circulating levels of leptin receptor Kim, Kim, Shin, & Treasure, 2015). The oxitocinergic system in the same groups. Conversely, an increased concentration of shows a higher regulation level, involving some other neuro- NPY correlates to body mass deficiency coexisting with high peptides like leptin, which has been reported to decrease concentrations of leptin, suggesting disturbances in the regu- oxytocin release (Kutlu et al., 2010). In addition, AN and latory axis (Monteleone, Fabrazzo, Tortorella, Fuschino, & BN patients present lower serum activity of the prolyl-endo- Maj, 2002). Reduced circulating leptin plasma levels but nor- peptidase, an enzyme involved in oxytocin cleavage (Maes mal leptin concentrations in subcutaneous adipose tissue were et al., 2001). also reported in acute ill AN girls (Dostalova et al., 2005). 8 GERMAN CUESTO ET AL.

In summary, data obtained from ghrelin and leptin indi- b-endorphin and dynorphin-A shown level changes in EDs cate that an alteration in hormonal milieu is relevant in the animal models (see Animal models section). progression of eating disorders, highlighting the role of physiological compensatory mechanisms trying to minimise Dopamine and serotonin in EDs the pathology extent. Dopamine role in EDs Other appetite regulators Dopamine is the most important regulator of reward behav- In addition to the peptides and hormones described above, iours, including feeding and reproduction. These reward other regulators play a role on appetite regulation, and their behaviours are conserved along phyla. In Drosophila, a small alterations have been linked to EDs onset and progression. group of dopaminergic neurons in the protocerebral anterior Cholecystokinin (CCK) is a peptidic hormone of the gastro- medial (PAM) cluster send axons to the mushroom bodies intestinal system that promotes satiety, but has been also (MBs), where appetitive olfactory associative memory is related with anxiety, panic and even hallucinations (Lenka, formed. After sugar ingestion, PAM dopaminergic neurons Arumugham, Christopher, & Pal, 2016; Zwanzger, are activated, generating a reward effect. These neurons Domschke, & Bradwejn, 2012). In a recent study, CCK become overactivated under starving conditions (Liu et al., exhibits similar plasma levels in AN patients compared to 2012). In mammals, abnormal function of mesocorticolimbic control group both prior to and after a meal suggesting a dopaminergic circuits impairs severely motivation and hormonal adaptation (Cuntz et al., 2013). Inconsistently, in reward behaviours, contributing to pathological conditions older studies, plasma measurements performed in AN such as depression, addictions, compulsive moods and patients showed a postprandial increase in CKK levels, sug- apathy [reviewed in Castrioto, Thobois, Carnicella, Maillet, gesting an implication in this ED (Tomasik, Sztefko, & & Krack (2016)]. As an example, reward system responsive- Starzyk, 2004). More data are clearly necessary to solve this ness is heightened in adolescent suffering AN when under- ambiguity. In turn, Glucagon like peptide 1 (GLP-1) is a weight and after weight restoration (DeGuzman, Shott, brain-gut peptide that exerts a hormone-neurotransmitter Yang, Riederer, & Frank, 2017). These mesocorticolimbic action inhibiting food intake, energetic expenditure and dopaminergic alterations correlate with an abnormally high insulin levels (Richard et al., 2014; Shah & Vella, 2014). As a physical activity in AN and BN patients (Hebebrand et al., satiety inductor, GLP-1 interacts with the leptin and ghrelin 2003) and can trigger a dopamine-dependent stress response system to induce satiation (Zhu et al., 2002), probably by (Kalyanasundar et al., 2015). This convergence between decreasing gastric emptying and acting on the brain to pro- dopamine levels, physical activity pattern alterations and eat- duce a conditional taste aversion (Monteleone, Castaldo, & ing disorders points out towards a dysfunction in the dopa- Maj, 2008). In AN patients, whereas GLP-1 was significantly minergic neuromodulatory system. In addition, it exists a decreased compared with normal individuals, insulin and clear association between dopaminergic pathways and eating glucagon levels were increased, indicating an alteration in disorders with psychiatric comorbidities including depres- glucose homeostasis (Tomasik, Sztefko, Starzyk, Rogatko, & sion, anxiety, compulsive disorders and even aggressive Szafran, 2005). In addition, punctual GLP-1 secretory behaviours (Jennings, Wildes, & Coccaro, 2017; Martinussen decrease was also found in BN patients compared to healthy et al., 2016). In the last years, neuroimaging has reported controls, being this concurrence limited to bingeing and dopaminergic alterations in ED patients (Berner, Winter, vomiting events (Brambilla, Monteleone, & Maj, 2009). Matheson, Benson, & Lowe, 2017). As examples, positron emission tomography (PET) shows a [11C]raclopride bind- Other gut peptide, Peptide tyrosine tyrosine (PYY) belongs ing increase in ventral striatum in recovered AN patients to NPY family and is secreted in ileum and colon with an (Frank et al., 2005), whereas AN patients display a poor acti- anorexigenic role (Karra, Chandarana, & Batterham, 2009). vation in prefrontal cortex (PFC) (Nagamitsu et al., 2011). PYY plasma concentrations increases within 15 min after eat- Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 Finally, nigrostriatal pathway is also involved in food intake ing and lasts approximately 90 min (Batterham & Bloom, regulation, since the restoration of dopamine expression in 2003). Serum levels of PYY hormone are decreased in dopamine deficient mice causes hypophagia and bradykinesia BN/BED compared with AN (Eddy et al., 2015). Finally, (Hnasko et al., 2006). concerning opioid peptides, anandamide, also known as N-arachidonoylethanolamine (AEA), plays an important role in feeding behaviour generating motivation and pleasure in Ghrelin, leptin and the dopamine-reward system: physio- food consumption (Fuss et al., 2015; Mahler, Smith, & logical roles and therapeutic potential Berridge, 2007). Anandamide and hence, the endocannabi- Many studies have been carried out to demonstrate the noid system, shows a therapeutic relevance in EDs. The can- therapeutic use of ghrelin in EDs with contradictory results: nabinoid agonists can alleviate anorexia and nausea, whereas whereas some of them described that ghrelin administration the AEA mono-unsaturated analogue oleoylethanolamide was ineffective to increase the appetite in AN patients-prob- (OEA) decreases food intake and body weight through a ably due to the high circulating ghrelin levels found in these cannabinoid receptor-independent mechanism (S Gaetani, subjects- (Miljic et al., 2006; Otto et al., 2001), others sug- Kaye, Cuomo, & Piomelli, 2008). In the same study, plasma gested that a ghrelin long-term treatment was efficient to levels of anandamide were down-regulated in AN patients. treat AN patients (Hotta et al., 2009; Kawai et al., 2017). In As anandamide, other opioid peptides as hypothalamic rodents, ghrelin injection increases food intake and triggers JOURNAL OF NEUROGENETICS 9

dopamine release (Abizaid et al., 2006; Kawahara et al., Animal models employed on EDs research 2009). It also prevents the development of activity based anorexia in mice, confirming its role in the mesocorticolim- A striking parallelism to the existence of brain neuropeptider- bic dopaminergic pathway (Legrand et al., 2016). gic circuits controlling mechanisms of food intake/metabolism In turn, leptin is also involved in hedonic and reward homeostasis is found in other vertebrates as rodents but also feeding behaviour through mesocorticolimbic dopaminergic in insects (Pool & Scott, 2014). Indeed, whereas NPY/AgRP pathways, including NAc and ventral tegmental area (VTA). neurons were proved to be involved in food intake stimulation Whereas orexin coming from LH orexigenic neurons acti- in rats (Stanley, Kyrkouli, Lampert, & Leibowitz, 1986; vates VTA dopaminergic neurons, leptin reduces the LH Zarjevski, Cusin, Vettor, Rohner-Jeanrenaud, & Jeanrenaud, orexin activation, lowers dopaminergic mesolimbic neurons 1993), energy expenditure decrement (Billington, Briggs, activation, and decreases dopamine release in NAc, all Grace, & Levine, 1991) and hedonic feeding (Pandit, la Fleur, through the activity of the neuropeptide galanin (Laque & Adan, 2013), a homologue of the mammalian NPY was et al., 2015). Thereby, leptin negatively modulates reward- described in the insect model Drosophila melanogaster, the related behaviour suppressing feeding (Leinninger et al., Drosophila NPF (Brown et al., 1999). Like NPY, Drosophila 2009). According to these findings, leptin antagonism may NPF is expressed in only a small set of neurons in the fly brain represent a viable therapeutic strategy in ED. modulating neuronal circuits related to feeding behaviours, Taken all these evidences together, the VTA to NAc stress responses, metabolism, energy homeostasis, ethanol dopaminergic projections can be considered as essential ele- consumption and also reproduction (Krashes et al., 2009; € ments of both ghrelin and leptin responsive circuits control- Nassel & Winther, 2010). In addition, the neuropeptide hugin, ling food reward behaviour, highlighting the complexity of homologous to mammalian NeuromedinU, inhibits feeding signal integration within the VTA and locating this brain behaviour (Melcher & Pankratz, 2005). Subtypes of hugin neu- area as a crucial target for therapeutically actions tackling rons connect chemosensory to endocrine neurons producing EDs (Skibicka et al., 2013). the Diuretic hormone 44 neuropeptide (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), responsible of the regulation of gut motility and excretion Serotonin function in ED (Dus et al., 2015), and Drosophila insulin-like peptides Serotonin (5-hydroxitriptamin or 5-HT) is a monoamine (DILPs) (Kannan & Fridell, 2013). In turn, whereas dimin- neurotransmitter produced in the brain by neurons located ished signalling of DILPs affects food intake in flies, drosulfa- in the dorsal and median raphe nuclei projecting to cortical kinins (DSKs), cholecystokinin-like peptides, regulates satiety € € and striatal limbic regions. Serotonergic projections to hypo- in Drosophila (Soderberg, Carlsson, & Nassel, 2012). thalamus are responsible of the satiety signal (Haleem & Interestingly, insulin-producing cells of the fly brain co- Haider, 1996) whereas projections to hippocampus, striatum, expresses both DILPs and DSKs, and each peptide affects the amygdala and frontal cortex are responsible of the mood transcript levels of the other suggesting a feedback regulation regulation (Lambe, Fillman, Webster, & Shannon Weickert, between two signalling pathways (Soderberg€ et al., 2012). 2011; Mineur et al., 2015; Sumiyoshi, Kunugi, & Nakagome, With the help of the Drosophila sophisticated genetic 2014). Serotonin modulates hunger, sleep, sex, emotions, and toolkits and the deep knowledge of their sensory and central also several endocrine processes (Haleem, 2012). nervous system circuitry, it is possible to further investigate Additionally, depressive, anxious, impulsive and obsessional and characterize neuropeptide function in food intake, behaviours, commonly related to ED, have been extensively energy balance and diet restriction, among other processes. related with serotonergic functions (Brewerton, 1992; Kaye, Besides, the short life-cycle of Drosophila helps to assess the 1997). AN and BN patients develop an egosyntonic personal- role of precocious aspects on food intake control. ity, implying that they do not perceive anything wrong with Furthermore, some recent methods developed in Drosophila had made possible to precisely quantify food intake, facilitat- Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 their acts. They consider their actions as reasonable and appropriate, perceiving their dysfunctional cognition regard- ing advances on the genetic, neural, and environmental fac- ing to their own weight and shape as perfectionism tors modulating food consumption (Deshpande et al., 2014). (Aardema, 2007). This particular trait shared between ED This knowledge will be crucial not only to delineate the gen- and other psychiatric diseases, taken together with the fact etic and neural mechanisms of metabolism and disorders that medications acting over 5-HT pathways have some connected with food consumption, but also to identify evolu- degree of efficacy over AN and BN patients, suggests an tionarily conserved candidate genes and pathways relevant to important role of serotonergic system dysfunction in ED human biology [see next section and Garlapow, Huang, onset and progression (Kaye, Bailer, Frank, Wagner, & Yarboro, Peterson, & Mackay (2015)]. Henry, 2005). Some authors directly assign to the serotoner- Research using EDs animal models has also been highly gic system the psychiatric symptomatic deterioration valuable in the study of brain neurotransmitters and circuitry observed in AN and BN due to malnutrition, since trypto- underlying aberrant feeding behaviours. To date, some phan (TRP), an essential amino acid only available in diet reward-related brain dysfunctions have been described on and precursor of 5-HT, is reduced in their diet (Haleem & rodent animal models of AN, BN and BED, by affecting Haider, 1996). The fact that re-feeding increases TRP plasma dopamine (DA), serotonin and acetylcholine (ACh) neuro- levels in AN patients correlating with a decrease in depres- transmitters but also opioid levels (Avena & Bocarsly, 2012). sive symptoms supports their theory (Gauthier et al., 2014). Thus, in an AN rodent model based on activity, the activity- 10 GERMAN CUESTO ET AL.

based anorexia (ABA) model (Routtenberg & Kuznesof, populations have supported and enhanced the information 1967), a restricted access to food increases the reinforcing derived from rat models. 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 Genetic approaches ABA rats, due to rises in hypothalamic b-endorphin and Genetically, EDs are aggregated in families (Zerwas & Bulik, dynorphin-A (Aravich, Rieg, Lauterio, & Doerries, 1993). 2011). Twins studies have provided an irrefutable proof, Likewise, eating palatable food releases DA in a BN model, showing that the heritability of these disorders is 33–84% for whereas purge behaviour attenuates a signal of satiety AN, 28–83% for BN and 41–57% for BED (Munn-Chernoff dependent on ACh release. In this BN model, binge eating is & Baker, 2016). In 2003, Gorwood, Kipman, & Foulon combined with gastric sham feeding in the rat to incorporate (2003) published the first study indicating family burden both bingeing behaviour and purging component aspects within these disorders, followed by others (Clarke, Weiss, & (Avena, Rada, Moise, & Hoebel, 2006). With respect to BED, Berrettini, 2012; Helder & Collier, 2011; Thornton, Mazzeo, several animal models are available, by offering limited & Bulik, 2011; Treasure et al., 2015). Several works described access to a palatable high-fat or high-sugar food, providing specifically the family aggregation (Hudson et al., 2006; ad libitum access to standard rodent chow for several weeks, Lilenfeld, Ringham, Kalarchian, & Marcus, 2008; Munn- by alternating cyclic periods of food deprivation and feeding Chernoff & Baker, 2016). All of them confirm that EDs have or even by using foot-shocks to generate binge eating beha- a family burden. However, family studies are unable to viour in rats. Data generated from BED animal models have address whether family-related factors are genetic and/or yielded important insights to concomitant physiological and environmental (Zerwas & Bulik, 2011). 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 Genome-wide association studies dependency and obesity and have also unveiled a role for Genetic epidemiology transforms the way we look into the NAc ACh in binge eating behaviour (Avena, Rada, & influence of genes and environmental factor in EDs. Hoebel, 2008; Rada, Avena, & Hoebel, 2005). Concerning Genome-wide association studies (GWAS) show large scale the opioid system, the use of opioid antagonists as naltre- xone or naloxone (among others) was able to decrease intake genetic studies of EDs that measure simultaneously hundreds of preferred fat and sucrose diets and also to suppress pala- of thousands of genetic variants scattered throughout the table food intake (Boggiano et al., 2005; Naleid, Grace, human genome. In the case of those specific for EDs, Chimukangara, Billington, & Levine, 2007). Moreover, in a research focuses on single nucleotide polymorphisms (SNPs), rat BED model, memantine treatment fully blocked the com- traits, occurring more frequently in people with AN, BN or pulsivity associated with the intake of the highly palatable BED than in healthy people. Each study can look at hun- food, confirming the potential therapeutic role of this drug dreds or thousands of SNPs in several tentative traits at the in curing aspects of BED in humans (Popik, Kos, Zhang, & same time. GWAS represent a promising way to study com- Bisaga, 2011; Smith et al., 2015). plex, common diseases in which many genetic variations ’ In addition, rat animal models shared characteristics with contribute to a person s risk, allowing effect-size estimates human patient psychopathologies, including EDs co-morbi- for specific genetic variants, testing shared genetics by loo- dities, helping to find novel preventions or treatments (Lutz king for correlations in effect-sizes across traits and not et al., 1998). As an example, many representative features requiring measurements of multiple traits per individual. found in AN patients can be mimicked in a rat model of com- The most common methods in this type of studies is bined food restriction and increased physical activity (the Mendelian randomisation, which uses significantly associated SNPs as instrumental variables to attempt quantify causal Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 abovementioned ABA model). Food restricted rats exhibited this hyperactivity and low leptin levels seem to contribute to relationships between risk factors and disease (Bulik-Sullivan the phenotype of these AN rats because hyperactivity can be et al., 2015). A complementary approach is to estimate gene- reduced by leptin supplementation (Dixon, Ackert, & Eckel, tic correlation, which includes the effects of all SNPs, includ- 2003; Hebebrand et al., 2003). Additionally, a rat model of ing those that do not reach genome-wide significance. BED combines the use of intermittent food restriction with Talking about EDs, one point is to demonstrate the family frustration stress (Micioni Di Bonaventura et al., 2014) assess- burden of those disorders and something crucially different ing stress-induced food-reward behaviours that are crucial in is to establish – by GWAS studies – the relationships the development of eating disorders in humans. Moreover, rat between those disorders with genetic traits. To date, there strains can be used to study reward-driven mechanisms by are not significant genes associated with EDs. In early stud- involving progressive tests where animals needs to gain their ies, it was thought that a question of sample size could be food (i.e. by pressing a lever), being more active to obtain pal- the problem for the lack of significance, but nowadays even atable food sources. In this context, reward-deficit syndromes the most powerful set of data in AN, by far the ED with can also be studied in rats whose dopamine synthesis or dopa- more genetic available studies, could not get any significant mine receptor signalling is disturbed (Gaetani et al., 2016). relation with any genetic trait (Boraska et al., 2014). Remarkably, clinical findings and data obtained through neu- As an example, Root et al. (2011) defined seven different roimaging and pharmacotherapy studies of human phenotypes which are known to be associated with AN JOURNAL OF NEUROGENETICS 11

(drive for thinness, concern over mistakes, among others). studies, but they fail to get significance. They are: (i) They tried to correlate those phenotypes with 5151 SNPS in DRD2/ANKK1 gene and SNPs Val58Met in COMT gene, 182 genes, but they were unable to significantly associate any implicated in dopamine (Munn-Chernoff & Baker, 2016); SNPs with EDs psychological traits despite the huge sample (ii) 5-HTTLPR in 5HTT transporter and HTR2A receptor size: 1085 EDs participants and 677 controls (Root et al., gene in serotonin path (Munn-Chernoff & Baker, 2016; 2011). However, in despite the fact that they fail to make Yilmaz et al., 2015) and (iii) SOX2 gene, in this case the any significant association, they described two SNPS with study with a comorbidity of EDs and bipolar disorder potential interest in future studies: (i) rs17719880 in KCNN3 (Bulik, Kleiman, & Yilmaz, 2016). (potassium calcium activated channel), an important gene in Finally, Munn-Chernoff et al. (2015) review deeply the neuronal excitability that could be related with schizophrenia possible genetic overlap between alcohol use disorder (AUD) and bipolar disorders and (ii) rs12744840 in HCRTR1, and bulimic behaviour, not obtaining statistical significance an orexin receptor gene (Sakurai et al., 1998). towards EDs. Although specific genetic mechanism underly- Another genetic study was performed on 1533 twin ing comorbidity are unclear, at minimum, individuals with American women focusing in the analysis of 15 polymor- AUD should be screened for individual and family history of phisms in HTR2A, a gene implicated in appetite process and EDs and vice versa, regardless of race. Even when the study satiety in BED (Koren et al., 2014). In this study, the is unable to provide any statistically significant data, it is authors describe three main polymorphism for HTR2A: clear that AUD and bulimic behaviour share environmental (i) 1438 G/A (rs6311) which have been associated with influences. poor treatment response in BN patients but the authors There could be several explanations for the lack of signifi- failed to find a significant genetic association with EDs char- cance concerning GWAS studies in EDs. One is the potential acteristics and (ii) two other polymorphisms, rs6561333 and population stratification, probably because we are not using rs2296972, associated with less likelihood of BED. However, the appropriate phenotypes to separate the patients. The when those polymorphisms were corrected for multiple test- other one could be the sample size. As an example, in ing they were no longer significant; with only rs2296972 Schizophrenia studies, only a sample size of 5000 partici- remain significant as trend level (Koren et al., 2014). pants allowed to obtain differences in genes with statistical Likewise, the authors did not find any comorbidity between significance. Finally, it is necessary to consider the study of MDD (Mayor Depressive Disorder) and EDs. EDs as comorbid with other disorders; alcohol abuse, sub- Some cross-trait studies (Hinney et al., 2017) obtained a stance abuse, bipolar disorder, emotional instability, and significant genetic relationship with AN and body mass obesity (Yilmaz et al., 2015). 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 Epigenetic studies between the trait and those diseases. Indeed, in AN, 90% of the people affected are females (Yilmaz, Hardaway, & Bulik, Epigenetic refers to heritable patterns of gene expression that 2015) and BN is also gender specific, affecting mainly female occur without changes in the DNA sequence, that is, changes population. Remarkably, there are almost no EDs studies in phenotype not involving changes in genotype. Epigenetics conducted with men (Munn-Chernoff & Baker, 2016). have a major role in genomic regulation, as a natural process As stated previously, Hinney et al. (2017) described which silence specific genes during development. At least three significantly altered loci correlating AN risk with three systems; DNA methylation, histone modification and increased BMI. The genes associated to those loci are non-coding RNA (ncRNA)-associated gene silencing have CTBP2, CCNE1, CARF and NBEAL1 but their relevance in been currently considered to initiate and sustain epigenetic AN risk mechanisms or BMI increases are still uncertain. change (Brown et al., 2007; Campbell, Mill, Uher, & Schmidt, 2011; Egger, Liang, Aparicio, & Jones, 2004). The

Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 Other comorbid interesting study with significant results is the one performed by Munn-Chernoff and Baker (2016). field of epigenetics is quickly growing and with it the under- They associate EDs to substance use disorders (SUD), standing that both the environment and individual lifestyle describing a possible unbalance in the system and loss of can also directly interact with the genome. For example, control (negative valence domain). This loss control is a human epidemiological studies have provided evidence that core feature of BED as well as SUD and could be influ- prenatal and early postnatal environmental factors influence enced by dopamine. In addition, a recent study describe the adult risk of developing various chronic diseases and that AN patients could present an unbalance in the reward behavioural disorders (Jirtle & Skinner, 2007; Pjetri, system involving dopamine circuits (see dopamine section), Schmidt, Kas, & Campbell, 2012). describing a marginally genetic association between AN and Epigenetics changes play a role in causation of complex excessive exercise, a rs17030795 located in PPP3CA adult psychiatric and neurodegenerative disorders, with rear- (Gorwood et al., 2016). By their side, OPRD1 (opioid delta rangements in DNMT (DNA-methyltransferase) genes. receptor) and HTR1D (1 D serotonin receptor) are been Recent evidence supports the idea that epigenetic mechanism associated with AN by Bergen et al.(2003) and Wang may help initiate and maintain EDs (Strober, Peris, & groups (Wang et al., 2011) confirming this association, Steiger, 2014), for example AN has been genetically corre- although not backed by significant results. Other genes lated with Schizophrenia (Bulik-Sullivan et al., 2015). have been under the spot light and come out in GWAS Epigenetics modifications have a key role in the genetic 12 GERMAN CUESTO ET AL.

bases of the EDs owing to early life events, or familiar envir- and Borderline Personality Disorder and (iii) hypermethyla- onment (Munn-Chernoff & Baker, 2016). Epigenetic mech- tion of specific CpG sites in the BDNF gene promoter region anism also occurs during pregnancy, for example maternal with BN, with and without childhood abuse (Groleau et al., depression have been linked to specific increases in methyla- 2014; Steiger, Labonte, Groleau, Turecki, & Israel, 2013; tion of offspring glucocorticoid receptor (NR3C1) gene, Thaler et al., 2014). yielding to altered cortisol responses and increased stress Recently, several studies have investigated directly gen- reactivity in the offspring (Steiger & Thaler, 2016). ome-wide (GW) methylation in patients with EDs (Saffrey, As mentioned previously, there is an imbalance in the Novakovic, & Wade, 2014; Tremolizzo et al., 2014). Thus, dopamine reward circuit in EDs. Some epigenetics changes Booij and colleagues reported that a group of AN patients could be related with this mechanism. Indeed, Frieling et al. had higher mean and median global methylation level when (2010) described higher levels of methylation in the promo- compared to normal eaters. In this study, they also described tors of DAT1 (dopamine active transporter 1) and DRD2 significant group differences in 2 CpGs associated with (dopamine receptor D2) in AN patients compared with NR1H3 gene and 3 CpGs associated with PXDNL gene, both healthy controls, indicating an increase in the expression of genes involved in dopamine and glutamate signalling the DAT1 and a decrease in the expression of the DRD2. respectively and, hence, in reward dependence, mood and Other studies linked AN weight loss to hypermethylation anxiety (Booij et al., 2015). and reduced expression of POMC (proopiomelanocortin) gene (Ehrlich et al., 2010; Steiger & Thaler, 2016). In add- Transcriptome studies ition, several studies carried out in BN women patients assessed the methylation status of specific genes showing: (i) Expression studies have been used mainly to confirm epigen- hypermethylation in exon 1C region of the glucocorticoid etic imbalances, or SNPs detected. Using transcriptomics, a receptor (GR) with comorbid BN and suicidal records; (ii) recent study has shown how binge eating resulted in the hypermethylation of the DRD2 promoter region with BN 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, AN and BN Mutations in ESRRA and HDAC4 increase the (WGS and WES) 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,

Downloaded by [University of La Laguna Vicerrectorado] at 07:00 01 August 2017 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. JOURNAL OF NEUROGENETICS 13

myelination as well as oligodendrocyte differentiation and approach those disorders, which affects not only the patients expression (Kirkpatrick et al., 2017). but also the families and their environmental influences. 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 Acknowledgements imbalance which leads first to a pathway disparity, finally We appreciate the help of Dr. Cristina Martin-Higueras and laboratory ending in an aberrant eating behaviour. Table 1 summarises members for their critical comments. This publication was supported most of the studies devoted to EDs, describing the type of by the Spanish National Programme for Research aimed at the – – genetic approach employed and the main result of the study. Challenges of Society [DPI2015 66458-C2 2-R, MINECO] to AA and GC, an AIRC-iCARE Fellowship co-funded by European Community Undoubtedly, more epigenetic studies of those disorders to LG and the CNRS, INRA, Burgundy Regional Council (PARI2012 which are crucially influenced by environmental circumstan- and 2014) and University of Bourgogne Franche-Comte to CE. ces during early childhood development are mandatory for uncover the origins of these diseases. Disclosure statement

Wrap-up and synthesis: towards a global approach No potential conflict of interest was reported by the authors. This review focused on three illnesses responsible of a high- increasing and extremely frequent phenomenon related to Funding our daily way of living: pathologies associating to feeding This publication was supported by the Spanish National Programme dysfunctions. Besides, these EDs are complexes, affecting not for Research aimed at the Challenges of Society [DPI2015–66458-C2–2- only nutritional and physiological features but also social R, MINECO] to AA and GC, an AIRC-iCARE Fellowship co-funded by cognitive processes, psychological, mental and clinical European Community to LG and the CNRS, INRA, Burgundy Regional aspects, reducing the life-quality of millions of worldwide Council (PARI2012 and 2014) and University of Bourgogne Franche- Comte to CE. 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 ORCID between psychological and biological therapies. In addition, Leticia G. Leon http://orcid.org/0000-0001-8781-7424 psychological help is not effective to achieve a fully physical Angel Acebes http://orcid.org/0000-0003-0020-1913 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 References and the international regulatory agencies for the treatment Aardema, F. O. (2007). The menace within: obsessions and the self. of EDs. Furthermore, there is a major lack of pharmacother- International Journal of Cognitive Therapy, 21, 182–197. doi: apy studies and treatments in children and teenagers suffer- 10.1891/088983907781494573 ing from EDs. 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