Feature Review

Molecular Psychiatry (2011) 16, 595–603; doi:10.1038/mp.2010.95; published online 14 September 2010

Role of the evolutionarily conserved starvation response in anorexia nervosa

D S Dwyer1,2, R Y Horton1 and E J Aamodt3

  1. 1Department of Psychiatry, LSU Health Sciences Center, Shreveport, LA, USA
  2. 2Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center, Shreveport, LA, USA
  3. 3Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA, USA

Correspondence: Dr DS Dwyer, Department of Psychiatry, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. E-mail: ddwyer@lsuhsc.edu

Received 22 March 2010; Revised 9 August 2010; Accepted 11 August 2010; Published online 14 September 2010.

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Abstract

This review will summarize recent findings concerning the biological regulation of starvation as it relates to anorexia nervosa (AN), a serious eating disorder that mainly affects female adolescents and young adults. AN is generally viewed as a psychosomatic disorder mediated by obsessive concerns about weight, perfectionism and an overwhelming desire to be thin. By contrast, the thesis that will be developed here is that, AN is primarily a metabolic disorder caused by defective regulation of the starvation response, which leads to ambivalence towards food, decreased food consumption and characteristic psychopathology. We will trace the starvation response from yeast to man and describe the central role of insulin (and insulin-like growth factor-1 (IGF-1))/Akt/ F-box transcription factor (FOXO) signaling in this response. Akt is a serine/threonine kinase downstream of the insulin and IGF-1 receptors, whereas FOXO refers to the subfamily of Forkhead box O transcription factors, which are regulated by Akt. We will also discuss how initial bouts of caloric restriction may alter the production of neurotransmitters that regulate appetite and food-seeking behavior and thus, set in motion a vicious cycle. Finally, an integrated approach to treatment will be outlined that addresses the biological aspects of AN.

Keywords:

Akt; anorexia nervosa; FOXO; Insulin/IGF-1

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Introduction

Previous reviews on anorexia nervosa (AN) have effectively covered behavioral aspects of eating disorders, genetic findings in anorexia and treatment approaches.1, 2, 3, 4 By contrast, this review will focus selectively on the possible etiology of AN with special emphasis on the biological factors that regulate appetite and food/nutrient-seeking behavior across species. On the basis of this analysis, we develop the thesis that AN may be caused by defects in the evolutionarily conserved response to food and nutrient shortage associated with reduced caloric intake. Implications for treatment will also be discussed.

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AN: description and clinical picture

According to DSM-IV criteria, AN is a mental disorder characterized by a refusal or failure to maintain or achieve minimally normal weight (85% of that expected on the basis of the age and height), intense fear of gaining weight despite excessive thinness and a disturbed perspective on body shape and weight that may include denial of the seriousness of the current condition. Delayed onset of reproductive maturation and amenorrhea are also commonly observed. There are two main subtypes of AN, restricting type and binge-eating/purging type, that are primarily distinguished by episodes of bingeing combined with compensatory strategies, including self-induced vomiting or excessive exercise. Bulimia nervosa (BN) is a closely related eating disorder that involves binge eating and subsequent inappropriate behavior (for example, vomiting and laxative abuse) to avoid weight gain.

The prevalence of AN in young women is reported to be in the range of 0.1–0.7%; it is rarer in males with a 10:1 ratio of females to males,1, 5 whereas BN has an estimated prevalence of 1–2% with a 25:1 female to male ratio.1 These disorders are often considered to predominantly afflict Western societies, although careful investigation of this issue may support a cultural basis for BN, but not AN.6 Together, these two eating disorders are more common than schizophrenia or bipolar disorder, and AN has the highest mortality rate of all (~10% or higher).7

Eating disorders typically first emerge in the mid-teenage years and may be short-lived and self-limiting in 10–20% of patients.1 On the other hand, AN is chronic and unremitting in about 20–30% of affected individuals. The latter group suffers the most weight loss, and is at greatest risk for suicide and serious medical complications, including hypothyroidism, loss of bone density, electrolyte disturbances, leukopenia and amenorrhea. Hospitalization is common for this population with an average cost per hospital stay of $10000–15000.8

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Biology of the starvation response

Individuals with AN restrict caloric intake to the point of self-starvation. The physiological reaction to starvation is complex involving both central and peripheral responses orchestrated by the nervous, endocrine and digestive systems.9, 10, 11 The goal of the starvation response is to conserve energy, delay growth processes, preserve cellular levels of ATP (in part, by increasing the efficiency of energy metabolism) and minimize oxidative damage. This response is essential for survival during times of food/nutrient shortage and is, consequently, highly conserved through evolution. In man, starvation elicits acute changes in the brain, especially the hypothalamus and brainstem related to nutrient sensing and satiety, a fall in blood levels of insulin, fatty acids and glucose (to a lesser degree) and suppression of the production of anorexigenic factors.12 With chronic starvation, glycogen stores are depleted as a source of energy, circulating levels of ketone bodies rise and counterregulatory mechanisms are initiated, including an increase in output from the sympathetic nervous system10, 11 with stimulation of food-seeking behavior (foraging). Further discussion of the biochemistry and physiology of starvation may be found elsewhere.10, 11

Evolutionarily conserved aspects of the starvation response will be the focus of this review. The insulin- insulin-like growth factor-1 (IGF-1) /Akt/ F-box transcription factor (FOXO) pathway (depicted in Figure 1) has a central role in the regulation of this conserved response.13 The Forkhead proteins are transcriptional regulators that are divided into subfamilies (FOXA–FOXQ) with diverse members, including hepatic nuclear factor (HNF)-3α (FOXA1), FOXC2 and FOXO3.14 They regulate embryogenesis, cell cycling/differentiation, cell energetics and resistance to oxidative stress.15, 16, 17 The FOXO subfamily controls the expression of various genes, such as Mn-superoxide dismutase, cyclin D, tyrosine hydroxylase, tryptophan hydroxylase and IGF-1 binding protein.16, 17 In general, Forkhead proteins integrate extracellular signals with internal conditions to determine metabolic state and cell fate. They are tightly regulated by Akt, which is downstream of insulin/IGF-1 receptors.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Major components of the evolutionarily conserved starvation response. The insulin-IGF-1/Akt/FOXO signaling pathway is depicted here with human/C. elegans counterparts (e.g., the C. elegans version of the insulin-IGF-1 receptor is DAF-2). In some cases (e.g., PDK-1), the same terminology is used across species. Functional outcomes of signaling are shown at the bottom, and the semi-circle arrow indicates that this response can become a vicious cycle. This scheme is not intended to represent the entire control of feeding and appetite nor the full extent of complex interactions among components of the pathway. Additional neuropeptides, hormones (ghrelin and leptin), receptors and signaling molecules (e.g., Rheb and protein kinase A) are involved in this regulation, but are beyond the scope of the present review. Moreover, certain functional connections (e.g., S6K1 regulation of AMPK and IRS proteins and rictor-Akt/ serum- and glucocorticoid-inducible kinase -1 interactions) have been omitted for the sake of simplicity.

Full figure and legend (104K)Download PowerPoint slide (896 KB)

We suggest that defective regulation of the pathway in Figure 1 may ultimately give rise to AN similar to insulin deficiency (or resistance) causing diabetes. If this idea is correct, then there should be evidence for similar phenotypes (for example, decreased appetite, reduced food intake and delayed reproductive maturation) in model organisms with mutations in crucial genes that regulate foraging and feeding. In the next sections, we will briefly summarize key observations of ‘anorexic phenotypes’ from yeast, Caenorhabditis elegans, Drosophila and mice, and discuss the implications for disease causation and treatment in AN.

Yeast

Saccharomyces cerevisiae undergo characteristic morphological changes when starved of nutrients, especially nitrogen.18 In response to starvation, individual cells elongate and colonies form thin filaments or pseudohyphae that extend away from the area of nutrient deficiency. This pseudohyphal growth is a primitive form of foraging aimed at locating nutrients over a distance.18, 19 Zhu et al.19 reported that Forkhead genes have a critical role in the regulation of foraging in S. cerevisiae. Knockout of two isoforms of FOXO-related genes (FKH1 and FKH2) promoted cell elongation and pseudohyphal growth even under fed conditions. By contrast, overexpression of FKH2 inhibited the normal foraging response of yeast to nitrogen starvation, that is, it suppressed activity aimed at locating nutrients. It is interesting that the Forkhead homologs in yeast also control the cell cycle and sexual differentiation.20 The closest homolog of FOXO in yeast, HCM1, regulates the expression of both FKH1 and FKH2.21

Caenorhabditis elegans (nematode)

The soil nematode, C. elegans, has emerged as a valuable model organism because it has a simple, well-defined nervous system, yet exhibits a full range of behavior and learning. Ease of genetic approaches and availability of the complete genome sequence are also major advantages of this organism. Studies in C. elegans, have yielded a number of clues about the possible origins of AN. Recent findings by our group reveal that reduction-of-function mutations in the C. elegans insulin/IGF-1 receptor gene (daf-2) decrease foraging and feeding (pharyngeal pumping) after removal of animals from a bacterial food source.22

Important insights have also been provided by Mori and colleagues who studied temperature preferences (thermotaxis) related to starvation in mutant animals with so-called abnormal hunger orientation (or Aho phenotype).23 Wild-type animals move away from their original cultivation temperature when that temperature is paired with starvation, whereas Aho mutants remain at the original temperature despite having been paired with starvation. It is interesting that the aho-2 mutation was mapped to a C. elegans insulin gene, ins-1.24

A second genetic defect related to thermotaxis, tax-4, results in an ‘anorexic phenotype.’ tax-4 mutants spontaneously wander off food, consume less and develop more slowly than wild-type counterparts.25 The tax-4 gene encodes a cyclic nucleotide-gated channel, and interacts genetically with daf-16 (FOXO). It is involved in neuronal development, and is expressed in sensory and gustatory neurons, including the ones that synthesize and release insulin molecules, such as DAF-28 and INS-1. An association between defective sensory function and anorexic phenotype in C. elegans is consistent with observations of impaired sensory and gustatory function in AN patients.26, 27 Although impaired olfactory function in AN is not a universal finding,28 it is interesting that a reduction in the hedonic perception of food following a stroke was associated with a chronic decrease in appetite and weight loss.29

Simple genetic mutations can also produce the opposite phenotype, such as an increase in food-seeking behavior and feeding. For example, tph-1 mutants, which lack serotonin due to loss of the synthetic enzyme tryptophan hydroxylase, show increased foraging (turns and reversals) in response to food deprivation.30, 31 Clozapine and olanzapine, which antagonize serotonin receptors, mimicked the tph-1 phenotype and stimulated foraging in C. elegans.32 By contrast, inhibition of dopamine D2 receptors with raclopride33 or trifluoperazine and fluphenazine32 decreased foraging. These findings suggest that serotonin and dopamine have similar roles in the regulation of appetite in C. elegans as they do in man.34

Drosophila melanogaster (fruitfly)

A critical observation for the thesis developed here is the finding that the overexpression of FOXO equivalent in Drosophila (dFOXO) produced eating disturbances similar to those seen in AN patients.35 Thus, larvae overexpressing dFOXO dispersed from food, ate less and were smaller in size than wild-type animals, yet were otherwise healthy. Similar to anorexic females, they showed a delay in reproductive maturation. Overexpression of PI3K (Dp110 in Drosophila), which is upstream of dFOXO and down-modulates its activity by Akt, also caused animals to stray from food, ingest less and grow more slowly.36 Thus, significant changes in the expression of single genes involved in the starvation response can cause animals to reduce their food intake and suppress foraging, which mimics the eating behavior of patients with AN.

Mouse models

Several observations with genetically altered mice are relevant for AN. The spontaneously-occurring anx/anx mouse strain is anorexic and shows delayed growth and various behavioral abnormalities, including tremors, uncoordination and hyperactivity.37 The nature of the genetic lesion has not been established; however, the eating and behavioral characteristics are consistent with observed hyperinnervation by serotonergic neurons.37 On the other hand, knockout mice lacking the 5-HT2C serotonergic receptor are obese and hyperphagic.38 Anorexia (hypophagia) is observed in dopamine-deficient mice (because of the selective knockout of tyrosine hydroxylase in dopaminergic neurons)39 and in mice lacking the M3 muscarinic acetylcholine receptor.40 It is worth noting that the M3 receptors regulate insulin secretion from β-cells of the pancreas.41 Serotonin is also known to affect insulin secretion and prevents nuclear localization of FOXO in response to starvation.42 A final knockout strain is worth mentioning here. Mice lacking the insulin receptor substrate-2 (IRS-2) protein show various metabolic and developmental defects that are more severe in females than males.43 Female IRS-2/ mice are hyperphagic, obese and infertile. The data suggest that IRS-2 activity is normally involved in the suppression of appetite and feeding. Although studies of knockout mice can shed light on the role of individual genes in the regulation of feeding, there are also limitations to this approach, including compensatory adaptations to gene knockout and altered brain/tissue development because of a lack of the expressed protein.

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Defective regulation of the starvation response and causation in AN

Aberrant regulation of the starvation response in AN may result from primary effects, for example, genetic mutations that alter protein function and/or expression or occur secondary to epigenetic changes induced by environmental conditions (for example, fasting). Insulin/IGF-1 signaling is a critical component of the overall starvation response. In C. elegans, foraging after removal from food is significantly reduced in mutant strains with defects in the DAF-2 insulin/IGF-1 receptor.22 Consistent with this observation, IGF-1 is low in patients with AN.44 Furthermore, children with growth failure due to low levels or absence of IGF-1 routinely have poor appetites.45 However, the effects of insulin and IGF-1 on foraging/feeding in humans appear paradoxical at first glance. Insulin signals satiety and is anorexigenic (catabolic) in the brain,46 whereas it is anabolic at the level of peripheral tissues, such as muscle and fat. Insulin and dietary protein (including amino acids) elicit a slow rise in IGF-1(over more than 3–4h), whereas they suppress the production of IGF-1 binding protein-1.47, 48 The gradual increase in IGF-1 may then help to initiate food-seeking behavior similar to the proposed role of INS-1/DAF-2 in C. elegans. Treatment with IGF-1 often induces a voracious appetite, especially in juvenile patients.49 We speculate that high levels of insulin suppress feeding, consistent with its role as a metabolic signal of energy sufficiency, whereas IGF-1 stimulates feeding to support its activity as a major growth factor.

Insulin/IGF-1 signals through insulin/IGF-1 receptors and downstream receptor substrates (for example, IRS-2 and IRS-4), adapter proteins (Grb2) and effectors, including PI3K, PDK-1 and Akt (see Figure 1). This pathway is regulated or amplified by phosphatases (for example, phosphatase and tensin homolog deleted on chromosome 10 (PTEN)), additional adapters (TRIO; not shown) and by co-activation by G-proteins, Gα and Gβγ. Ultimately, signaling converges on the FOXO (DAF-16) transcription factor, which regulates the expression of genes controlling energy metabolism, resistance to oxidative stress and longevity.16, 17 Akt and serum- and glucocorticoid-inducible kinase-1 phosphorylate FOXO, which causes cytoplasmic retention and inhibits transcriptional activation. By contrast, AMP-kinase α-2 subunit, AMPK activates FOXO by phosphorylating different sites on the protein without affecting its subcellular localization.50 Similar to FOXO, AMPK is activated by starvation, and serves as a fuel gauge in cells.51 It regulates food intake by signaling in hypothalamic neurons that sense nutrient levels.52 Expression of a dominant-negative mutant of AMPK in the hypothalamus significantly reduces spontaneous food intake and causes weight loss53—another anorexic phenotype.

Additional signaling molecules involved in the response to starvation are conserved from yeast to man, including cyclic adenosine monophosphate (and downstream effectors) and target of rapamycin (TOR) and its co-factors, Raptor and Rictor. The TOR pathway integrates signaling from nutrients and growth factors to regulate mRNA translation, ribosome biogenesis, metabolism and cell/organism size.54 As shown in Figure 1, there is extensive crosstalk between TOR, Akt and AMPK.55 A substrate of TOR, S6 kinase (S6K1), has been implicated in life span extension produced by caloric restriction and knockout of S6K1 in mice and C. elegans results in reduced body size, delayed reproductive maturation and changes in FOXO expression.56 Moreover, in C. elegans, DAF-15 (Raptor) expression is regulated by DAF-16.57 Intriguingly, the genes coding for human TOR, Rictor and Raptor are located on chromosomes 1p36, 5p13 and 17q25 (Table 1), respectively. These loci may harbor potential risk factor genes for AN (see the next section).


Overexpression of FOXO (as well as PI3K and IRS-2) may reduce appetite, food-seeking and eating in anorexic patients as it does in Drosophila and even yeast. In addition, FOX genes regulate the expression of enzymes, tryptophan hydroxylase58 and tyrosine hydroxylase,59 which synthesize serotonin and dopamine, respectively. This provides an additional mechanism for regulating appetite and foraging. The role of FOXO is complicated because Kim et al.60 have reported that short-term overexpression of FOXO1 in hypothalamic neurons of mice (8–10 weeks old) increased food intake and body weight. Furthermore, DAF-16 accumulates in the nucleus during acute food deprivation, but returns to the cytoplasm with prolonged starvation.61 Thus, FOXO may increase or decrease appetite and feeding depending on the timing and duration (and possibly location) of its aberrant expression. It is interesting that the binge-purging subtypes of AN patients exhibit both extremes of eating behavior. Taken together, these studies confirm a vital role for FOXO in controlling appetite and feeding across evolution.

The role of other genes depicted in Figire 1 may likewise be complex. For example, TAX-4 (cyclic nucleotide-gated channel) affects the development of sensory neurons.62 Consequently, defects in this gene might impair sensation of food-related cues that normally stimulate eating. Alternatively, cyclic nucleotide-gated channels gated by cyclic guanosine monophosphate may be required for ongoing regulation of feeding mediated by nitric oxide in hypothalamic neurons.63

The net result of deficits in the starvation response is that patients fail to exhibit normal appetite or to properly regulate their response to fasting and fuel shortage. This leads to a vicious cycle. Thus, a bias toward denial of food leads to a reduction in calorie consumption, and weight loss. As weight loss proceeds, production of ancillary signals to initiate feeding, such as IGF-1 and dopamine (controlled by FOXO), is diminished and the starvation response is further activated. However, because this response is defective in AN, counterregulatory (orexigenic) mechanisms are ineffectual, and a persistent catabolic state develops, much like anorexia associated with cancer or infectious diseases. The fact that some anorexic patients literally starve themselves to death attests to the failure of evolutionarily conserved survival strategies in AN.

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Genetic risk factors in AN

AN shows strong familial association and is highly heritable.7, 64 Recent reviews have summarized genetic contributions to the development of eating disorders (for example, see Bulik et al.3). These efforts include mapping genetic loci associated with increased risk for developing AN and BN.3, 65, 66, 67, 68 If our hypothesis about causal factors in AN is correct, then some components of the starvation response should map to these genetic risk loci. Genetic linkage analysis and association studies have identified risk markers at the chromosomal locations listed in Table 1. Identification of the serotonin receptors, 5HTR1D and 5HTR2A, the dopamine D2 receptor, catechol-O-methyltransferase and brain-derived neurotrophic factor as candidate susceptibility genes has been reported previously,3, 68 whereas the others are derived from our own analysis.

As seen in Table 1, numerous components of the starvation response are located in the vicinity of the putative AN/BN genetic risk loci discovered in genome-wide linkage analysis,3, 65, 66, 67, 68 which would be consistent with our hypothesis that FOXO1, FOXO3, AKT1, serum- and glucocorticoid-inducible kinase-1, AMPK and IRS4 may constitute risk factors for AN. Despite the fact that some of the linkages are based on behavioral phenotypes (for example, anxiety or obsessionality), it is quite remarkable that so many genes involved in the control of energy metabolism map to these risk loci. Additional components related to this pathway—the IGF-1 receptor and neuropeptide Y—have been implicated by a genome-wide analysis of genes involved in the maintenance of fat-free body mass.69 We consider it highly unlikely that these observations are the result of chance. However, to formally address this issue, we arbitrarily selected 11 genes from similar overall classes as those listed in the table to determine the frequency of ‘hits’ at risk loci. The panel included the α2C adrenergic receptor, β2-adrenergic receptor, cholecystokinin, interleukin-2 receptor, protein kinase A-α, platelet-derived growth factor receptor-β (PDGFRB), glutathione reductase, glutamate dehydrogenase, flavin adenine dinucleotide synthetase (FLAD1) and glucose-dependent insulinotropic polypeptide receptor. None of these genes were close to any of the risk loci listed in Table 1. Furthermore, genes coding for various cytokines that regulate feeding, for example, leptin (7q32.1), ghrelin (3p25.3) and adiponectin (3q27.3) do not map to these regions. Leptin and other hormone regulators of appetite/feeding may indeed have a role in AN, however, as yet, a genetic contribution has not been established.

Genetic models for the etiology of AN should be able to explain gender differences in the relative incidence of eating disorders (that is, females >> males). Signaling by IRS proteins potentially represents one such difference between the sexes. Knockout of the IRS-2 gene had a much greater impact on reproductive maturation and food intake in female than male mice.43 IRS-2 normally suppresses food intake related to insulin signaling in the brain, whereas the closely related protein, IRS-4, signals downstream of leptin.70 The gene for IRS-4 is located on the X chromosome at Xq22.3, which was identified as a possible risk locus for AN by Devlin et al.66 Overexpression of IRS-4 in females, perhaps as the result of escape from X chromosome inactivation, might suppress eating similar to IRS-2. Of course, many other gender differences might contribute to the higher rate of AN in women than men.

The genetic data cited here should be considered preliminary in nature. Although the studies are solid and adequately controlled, many findings have not yet been replicated. Moreover, population size is often limited, some of the linkages are weak, and associations with individual genes remain controversial. Yet, the overall picture emerging from the genetic analysis is consistent with what would be expected for a disorder with a polygenic origin and modest contributions by multiple genes. At this stage, the genetic findings offer attractive candidates for further evaluation rather than definitive causal factors for AN.

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Role of culture and the environment in eating disorders

Although this review is focused on biological factors in AN, it is clear that a culture of thinness and dieting contribute to the prevalence of eating disorders. However, culture and environment may affect the propensity for AN in unsuspected ways. AN occurs throughout the world, not just in western cultures that equate beauty with thinness.6 It has also existed in different historical periods when people had divergent notions of the ideal body shape for women.6 Nevertheless, cultural attitudes and norms may trigger an initial bout of dieting in adolescents concerned about their appearance, and dieting itself is a risk factor for AN.4 A first episode of excessive caloric restriction to induce weight loss appears to cause homeostatic adaptation in the starvation response that may be accompanied by long-term changes in neurotransmitter production mediated by FOXO. Bergh and Södersten71 proposed that self starvation has rewarding properties in anorexic patients. Thus, caloric restriction and weight loss predispose to additional episodes of dieting, especially in susceptible individuals with defective regulation of their starvation response, or with a perseverative bias in behavior, reflected in obsessive thoughts and compulsivity.

Although personality traits and psychological factors modify the course of AN, they may not be fundamental causative agents, and may, in fact, be a response to starvation. This possibility is raised by the pioneering work of Keys and colleagues9 on the effects of semi-starvation in normal college-age males. Male volunteers were subjected to severe caloric restriction over a period of 24 weeks, followed by gradual restoration of calories over a 12–week rehabilitation phase. Over the course of these studies, subjects lost an average of 37 pounds or nearly 25% of their starting weight. They became progressively anxious, irritable, depressed, preoccupied with food and exhibited obsessive ideations. These psychological changes persisted in many subjects even after refeeding. During the rehabilitation phase, many expressed concerns about gaining too much weight and ‘becoming flabby.’ Most subjects did not return to their pre-study weights even after 12 weeks of free access to food; environmental factors (fasting) appear to have altered metabolic set points, such as baseline body weight. From case reports and diary entries during natural periods of food shortage in wars and famine, Keys et al.9 found numerous examples where starvation was accompanied by mental illness, including depression, anxiety, psychosis and even suicide. Thus, in normal individuals, starvation elicits the same type of psychopathology seen in patients with AN, as observed previously by Bergh, Södersten and colleagues.4, 71 In this context, it is noteworthy that prolonged voluntary starvation (for example, a hunger strike) is associated with a reduction in sense of harm and significant loss of appetite, even after the self-imposed fast has ended.72, 73

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Implications for treatment

Psychotherapy and behavior-based therapies

Eating disorders are notoriously difficult to treat, and noncompliance is a major issue, which arises in part because of denial of the seriousness of the condition. Therapy for AN consists mainly of behavioral cognitive approaches and psychotherapy.74, 75

The first concern for clinicians treating eating-disordered patients is to identify and manage any physical complications of the eating disorder. Patients are often fearful of treatment that will result in weight gain. Therefore, even at the initial stages of treatment, psychotherapeutic techniques are begun in an effort to engage reluctant patients as participants in their own care. Cognitive-behavioral therapy techniques have been helpful in managing eating-disordered patients. Cognitive restructuring is used to help patients correct cognitive distortions, including a distorted body image.

In addition, family therapy addresses the family interactions and relationships, and helps family members gain a better understanding of the disorder. Common goals in family therapy include improving communication, minimizing conflicts and allowing the patient to feel supported, while retaining some independence. Randomized controlled trials of family-based therapies have shown significant positive effects on clinical outcomes in adolescent patients.76, 77 A recent meta-analysis of controlled studies of family therapy supported the main conclusion that this approach is effective in adolescents over the short term, however, long-term advantages were less clear, and some trials found no significant benefit.78 More research is needed to determine whether family therapy, combined with biological approaches, represents a superior strategy for treatment.

Efforts to treat AN solely with behavioral approaches may have had limited success because they target the sequelae of the disorder rather than the etiology, and rely on ‘will power’ when the real culprit may be a metabolic defect akin to the situation in diabetes mellitus.

Pharmacotherapy

There is no recognized drug treatment for AN. Anti-depressants have been used, but the results have largely been disappointing.1, 79 Anxiolytics are prescribed to reduce anxiety in AN patients, whereas anti-psychotic drugs are indicated when delusions or psychotic features are present. In general, drugs are used to treat co-morbid conditions associated with AN.

Although there is an urgent need to develop new drugs for the effective treatment of AN, several current medications warrant further evaluation as interim therapeutic agents. Olanzapine is an atypical anti-psychotic drug that causes significant weight gain, especially in adolescents.80 In C. elegans, it blocks the starvation response (nuclear localization of FOXO/DAF-16),81 stimulates foraging,32 and induces significant lipid accumulation.82 This profile of biological activity appears to be well suited for addressing the main deficits in AN. Small open-label studies of olanzapine in adolescent patients yielded positive results.83 More recently, a placebo-controlled trial showed that olanzapine induced significant weight gain in anorexic patients and reduced obsessive symptoms in comparison to control subjects.84

IGF-1 (Mecasermin) has increasingly been used to reduce the bone density loss that accompanies chronic starvation in anorexic patients.85, 86 Moreover, IGF-1 stimulates appetite in children treated for growth deficiency.49, 87 Perhaps, the combined administration of olanzapine (at reduced doses) and IGF-1 during an acute rehabilitative phase of treatment would be beneficial in AN. Long-term treatment with IGF-1 may not be desirable in view of the side effect profile, which includes lymphoid hyperplasia, accumulation of fat tissue and potential tumor promotion.88

Xanomeline, or similar drugs, may represent a future approach to the treatment of AN. Xanomeline is a selective muscarinic agonist that showed anti-psychotic properties in a recent clinical trial,89 and also improved cognitive function in Alzheimer's patients.90 Muscarinic cholinergic function is reduced in anorexic patients.91 Furthermore, muscarinic receptors modulate insulin release by the pancreas,41 and regulate the starvation response of C. elegans, including dauer formation.92, 93 Muscarinic agonists also mimic certain effects of insulin and IGF-1 in neuroblastoma cells.94

The medications discussed here should be considered experimental drugs that require further testing to demonstrate their utility and safety in treating AN. They also represent a shift in therapeutic strategy toward the management of AN as a metabolic disorder. According to this approach, the goal of therapy would be to interrupt the starvation response, correct or compensate for defective counterregulation, stimulate appetite and normalize eating habits. In our view, a combination of pharmacotherapy and behavior-based strategies will be required to accomplish this challenging task.

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Conflict of interest

Dr Dwyer's and Dr Aamodt's research has been funded by the NIH. Dr Dwyer has previously consulted for Eli Lilly and Co. and received compensation. Drs Aamodt and Horton declare no conflict of interest.

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Acknowledgements

This work was supported by a grant from the Edward P Stiles Trust Fund (LSUHSC) and Biomedical Research Foundation of Northwest Louisiana.