Phenotype Of Anorexia Nervosa Research Articles

Unveiling Metabolic Phenotype Alterations in Anorexia Nervosa through Metabolomics

Anorexia nervosa (AN) is a mental disorder characterized by an intense fear of weight gain that affects mainly young women. It courses with a negative body image leading to altered eating behaviors that have devastating physical, metabolic, and psychological consequences for the patients. Although its origin is postulated to be multifactorial, the etiology of AN remains unknown, and this increases the likelihood of chronification and relapsing. Thus, expanding the available knowledge on the pathophysiology of AN is of enormous interest. Metabolomics is proposed as a powerful tool for the elucidation of disease mechanisms and to provide new insights into the diagnosis, treatment, and prognosis of AN. A review of the literature related to studies of AN patients by employing metabolomic strategies to characterize the main alterations associated with the metabolic phenotype of AN during the last 10 years is described. The most common metabolic alterations are derived from chronic starvation, including amino acid, lipid, and carbohydrate disturbances. Nonetheless, recent findings have shifted the attention to gut-microbiota metabolites as possible factors contributing to AN development, progression, and maintenance. We have identified the areas of ongoing research in AN and propose further perspectives to improve our knowledge and understanding of this disease.

Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency

Sirtuin of type 1 (Sirt1), a class III HDAC, is known to be involved in the regulation of differentiation of skeletal stem cells (SSCs) into osteoblasts and adipocytes. In caloric restriction, it has been shown that the expression and activity of Sirt1 is a tissue-dependent regulation. However, at present, no study has focused on the link between Sirt1, bone marrow adiposity (BMA) and osteoporosis related to anorexia nervosa (AN). Thus, the aims of this work were to (i) determine BMA and bone changes in a mouse model replicating the phenotypes of AN (separation-based anorexia model (SBA)); (ii) determine the expression of Sirt1 in bone marrow stromal cells (BMSCs) extracted from these mice and identify their differentiation capacities; (iii) study the effects of pharmacological activation and inhibition of Sirt1 on the osteoblastogenesis and adipogenesis of these cells and (iiii) delineate the molecular mechanism by which Sirt1 could regulate osteogenesis in an SBA model. Our results demonstrated that SBA protocol induces an increase in BMA and alteration of bone architecture. In addition, BMSCs from restricted mice present a down-regulation of Sirt1 which is accompanied by an increase in adipogenesis at expense of osteogenesis. After a 10-day organotypic culture, tibias from SBA mice displayed low levels of Sirt1 mRNA which are restored by resveratrol treatment. Interestingly, this recovery of Sirt1 levels also returned the BMA, BV/TV and Tb.Th in cultured tibias from SBA mice to normal levels. In contrast of down-regulation of Sirt1 expression induced by sirtinol treatment, stimulation of Sirt1 expression by resveratrol lead to a decrease in adipogenesis and increase in osteogenesis. Finally, to investigate the molecular mechanisms by which Sirt1 could regulate osteogenesis in the SBA model, the acetylation levels of Runx2 and Foxo1 transcription factors were determined. Our data show that this chronic energy deficiency in female mice causes a decrease in BMSC activity, resulting in critical changes to Runx2 and Foxo1 acetylation levels and thus to their activity. Altogether, these data suggest that Sirt1 could be considered as a potential therapeutic target in osteoporosis related to AN.

Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency.

Sirtuin of type 1 (Sirt1), a class III HDAC, is known to be involved in the regulation of differentiation of skeletal stem cells (SSCs) into osteoblasts and adipocytes. In caloric restriction, it has been shown that the expression and activity of Sirt1 is a tissue-dependent regulation. However, at present, no study has focused on the link between Sirt1, bone marrow adiposity (BMA) and osteoporosis related to anorexia nervosa (AN). Thus, the aims of this work were to (i) determine BMA and bone changes in a mouse model replicating the phenotypes of AN (separation-based anorexia model (SBA)); (ii) determine the expression of Sirt1 in bone marrow stromal cells (BMSCs) extracted from these mice and identify their differentiation capacities; (iii) study the effects of pharmacological activation and inhibition of Sirt1 on the osteoblastogenesis and adipogenesis of these cells and (iiii) delineate the molecular mechanism by which Sirt1 could regulate osteogenesis in an SBA model. Our results demonstrated that SBA protocol induces an increase in BMA and alteration of bone architecture. In addition, BMSCs from restricted mice present a down-regulation of Sirt1 which is accompanied by an increase in adipogenesis at expense of osteogenesis. After a 10-day organotypic culture, tibias from SBA mice displayed low levels of Sirt1 mRNA which are restored by resveratrol treatment. Interestingly, this recovery of Sirt1 levels also returned the BMA, BV/TV and Tb.Th in cultured tibias from SBA mice to normal levels. In contrast of down-regulation of Sirt1 expression induced by sirtinol treatment, stimulation of Sirt1 expression by resveratrol lead to a decrease in adipogenesis and increase in osteogenesis. Finally, to investigate the molecular mechanisms by which Sirt1 could regulate osteogenesis in the SBA model, the acetylation levels of Runx2 and Foxo1 transcription factors were determined. Our data show that this chronic energy deficiency in female mice causes a decrease in BMSC activity, resulting in critical changes to Runx2 and Foxo1 acetylation levels and thus to their activity. Altogether, these data suggest that Sirt1 could be considered as a potential therapeutic target in osteoporosis related to AN.

A process approach to verbal memory assessment: Exploratory evidence of inefficient learning in women remitted from anorexia nervosa

ABSTRACTIntroduction: Anorexia nervosa (AN) is associated with deficits in set-shifting and cognitive flexibility, yet less is known about the persistence of these deficits after recovery and how they might contribute to reported difficulties organizing and learning new information. To address this question, the current study applied a process-focused approach, that accounts for errors and strategies by which a score is achieved, to investigate the relationship between verbal memory and executive function in women remitted from AN.Method: Twenty-six women remitted from anorexia nervosa (RAN) and 25 control women (CW) aged 19–45 completed the California Verbal Learning Test, Second edition (CVLT-II) and the Wisconsin Card Sorting Test (WCST). Groups were compared on overall achievement scores, and on repetition, intrusion, and perseverative errors on both tests. Associations between learning and memory performance and WCST errors were also examined.Results: RAN and CW groups did not differ on overall CVLT-II learning and memory performance or errors on the WCST, though the RAN group trended towards greater WCST non-perseverative and total errors. On the CVLT-II, the RAN group made significantly more repetition errors than CW (p = 0.010), and within-trial perseveration (WTP) errors (p = 0.044). For the CW group, CVLT-II learning and memory performance were negatively associated with errors on the WCST, whereas among RAN, primarily delayed memory was negatively correlated with WCST errors. Notably, for RAN, greater WCST perseverative responses were correlated with greater CVLT-II repetition and WTP errors, showing the convergence of perseverative responding across tasks.Conclusions: Despite similar overall learning and memory performance, difficulties with executive control seem to persist even after symptom remission in patients with AN. Results indicate an inefficient learning process in the cognitive phenotype of AN and support the use of process approaches to refine neuropsychological assessment of AN by accounting for strategy use.

Not the Function of Eating, but Spontaneous Activity and Energy Expenditure, Reflected in "Restlessness" and a "Drive for Activity" Appear to Be Dysregulated in Anorexia Nervosa: Treatment Implications.

Anorexia nervosa (AN) is uncommon as a syndrome, despite widespread dieting or voluntary food restriction, especially among female adolescents. This suggests that restriction of caloric intake might not be the only component driving weight loss in AN. Historical observations and experimental evidence from energy expenditure studies and recordings from movement sensors reviewed in this paper reveal that AN is associated with motor activity levels and with an energy output not significantly different from that in normal-weight healthy age-matched controls. By contrast, other conditions of prolonged caloric under-nutrition are typically associated with loss of energy, slowing of movements and a decrease in self-initiated activity and well-being. Several hypotheses can be inferred from the findings: (a) that long term severe caloric restriction fails in downregulating movements and energy expenditure in AN. (b) Clinically and subjectively observable as mental and physical restlessness and continued motor activity, this restless energy, differing in intensity, seems to serve as the permissive factor for and possibly to drive exercise and hyperactivity in AN. (c) Such restless energy and increased arousal, generated sometime in the course of the weight loss process, appear to enhance the person’s self-perception and wellbeing, to heighten proprioception, to intensify body awareness and to improve self-esteem. (d) Restlessness and continued motor activity may constitute a phenotype of AN. The therapeutic value of the concept of an abnormality in the energy regulatory system, likely the result of a host of genetic and epigenetic changes in AN, lies primarily in its heuristic and explanatory power and its potential for disease prevention. Restless energy as a permissive and important component for the development and in the maintenance of AN, does not fundamentally alter treatment, since prolonged food deprivation is the principal causal factor for the development of AN. Re-nutrition within a structured treatment plan, to include individual and family therapy and, if indicated, heat application, remains the most effective symptomatic treatment for AN. Corroboration of the concept of restless activation will require the patient’s cooperation and input to identify and capture more precisely the experiences, sensations, and changes that allow the emaciated patient to remain mobile and active.

Endophenotypes: A conceptual link between anorexia nervosa and autism spectrum disorder

The paper, by translating the concept and the two models of endophenotype (EP), strengthens the hypothesis that there exists a linkage between anorexia nervosa (AN) and autism spectrum disorder (ASD). Specifically, the paper synthesizes empirical research that supported the idea that individuals with AN and individuals with ASD share similarities with respect to their neurocognitive EPs and temperament EPs. The paper then introduces an innovative structure to emphasize the subtle difference between neurocognitive EPs and temperament EPs in relation to AN and ASD. This structure constitutes the categorization of the shared neurocognitive EPs to the liability-index model of EP and the shared temperament EPs to the mediational model of EP. The paper argues that the shared neurocognitive EPs under the liability index model of EP are trait markers signaling the effects of genes on the phenotypes of AN and ASD; whereas, the shared temperament EPs under the mediational model of EP are state markers describing the symptomatic status of AN and ASD. The proposition of the paper suggests clinicians and researchers should target the atypical state markers (i.e., temperament EPs) shared between AN and ASD when tailoring environment-based treatments for individuals with AN who exhibit autistic behaviors and individuals with ASD who display disordered eating behaviors or anorexic symptoms.

Prevalence and characteristics of orthorexia nervosa in a sample of university students in Italy.

Orthorexia nervosa (ON) has been recently defined as a pathological approach to feeding related to healthiness concerns and purity of food and/or feeding habits. This condition recently showed an increasing prevalence particularly among young adults. In order to investigate the prevalence of ON and its relationship with gender and nutritional style among young adults, we explored a sample of students from the University of Pisa, Italy. Assessments included the ORTO-15 questionnaire and a socio-demographic and eating habits form. Subjects were dichotomized for eating habits (i.e. standard vs vegetarian/vegan diet), gender, parents' educational level, type of high school attended, BMI (low vs high vs normal BMI). Chi square tests were performed to compare rates of subjects with overthreshold ORTO-15 scores, and Student's unpaired t test to compare mean scores between groups. Two Classification tree analyses with CHAID growing method were employed to identify the variables best predicting ON and ORTO-15 total score. more than one-third of the sample showed ON symptoms (ORTO-15 ≥ 35), with higher rates among females. Tree analyses showed diet type to predict ON and ORTO-15 total score more than gender. Our results seem to corroborate recent data highlighting similarities between ON and anorexia nervosa (AN). We propose an interpretation of ON as a phenotype of AN in the broader context of Feeding and eating disorders (FEDs) spectrum.

A new phenotype of anorexia nervosa: the changing shape of eating disorders

Background and aims Adolescents are increasingly referred to our specialist eating disorder (ED) program having lost large amounts of weight and having the diagnostic features of anorexia nervosa (AN) with the exception of underweight. Many of these adolescents with EDNOS-AN[wt] were premorbidly overweight. We aimed to identify the changing prevalence of this phenotype from 2005-2010 in an inpatient sample, and compare the associated complications with adolescents with AN.

Excitatory synapses on dendritic shafts of the caudal basal amygdala exhibit elevated levels of GABAA receptor α4 subunits following the induction of activity-based anorexia.

Anorexia nervosa (AN) is an eating disorder characterized by self-imposed severe starvation, excessive exercise, and anxiety. The onset of AN is most often at puberty, suggesting that gonadal hormonal fluctuations may contribute to AN vulnerability. Activity-based anorexia (ABA) is an animal model that reproduces some of the behavioral phenotypes of AN, including the paradoxical increase in voluntary exercise following food restriction. The basal amygdala as well as the GABAergic system regulate trait anxiety. We therefore examined the subcellular distribution of GABA receptors (GABARs) in the basal amygdala of female pubertal rats and specifically of their α4 subunits, because expression of α4-containing GABARs is regulated by gonadal hormone fluctuations. Moreover, because these GABARs reduce neuronal excitability through shunting of EPSPs, we quantified the frequency of occurrence of these GABARs adjacent to excitatory synapses. Electron microscopic immunoctychemistry revealed no change in the frequency of association of α4 subunits with excitatory synapses on dendritic spines, whether in the anterior (Bregma -2.8 mm) or caudal (Bregma -3.8 mm) portion of the basal amygdala. Sholl analysis of golgi-stained neurons also revealed no change in the extent of dendritic branching by these densely spiny, pyramidal-like neurons. However, there was an increase of membranous α4 subunits near excitatory synapses on dendritic shafts, specifically in the caudal basal amygdala, and this was accompanied by a rise of α4 subunits intracellularly. Because most dendritic shafts exhibiting excitatory synapses are GABAergic interneurons, the results predict disinhibition, which would increase excitability of the amygdaloid network, in turn augmenting ABA animals' anxiety.

Adolescent female C57BL/6 mice with vulnerability to activity-based anorexia exhibit weak inhibitory input onto hippocampal CA1 pyramidal cells

Anorexia nervosa (AN) is an eating disorder characterized by self-imposed severe starvation and often linked with excessive exercise. Activity-based anorexia (ABA) is an animal model that reproduces some of the behavioral phenotypes of AN, including the paradoxical increase in voluntary exercise following food restriction (FR). Although certain rodents have been used successfully in this animal model, C57BL/6 mice are reported to be less susceptible to ABA. We re-examined the possibility that female C57BL/6 mice might exhibit ABA vulnerability during adolescence, the developmental stage/sex among the human population with particularly high AN vulnerability. After introducing the running wheel to the cage for 3days, ABA was induced by restricting food access to 1h per day (ABA1, N=13) or 2h per day (ABA2, N=10). All 23 exhibited increased voluntary wheel running (p<0.005) and perturbed circadian rhythm within 2days. Only one out of five survived ABA1 for 3days, while 10 out of 10 survived ABA2 for 3days and could subsequently restore their body weight and circadian rhythm. Exposure of recovered animals to a second ABA2 induction revealed a large range of vulnerability, even within littermates. To look for the cellular substrate of differences in vulnerability, we began by examining synaptic patterns in the hippocampus, a brain region that regulates anxiety as well as plasticity throughout life. Quantitative EM analysis revealed that CA1 pyramidal cells of animals vulnerable to the second ABA2 exhibit less GABAergic innervation on cell bodies and dendrites, relative to the animals resilient to the second ABA (p<0.001) or controls (p<0.05). These findings reveal that C57BL/6J adolescent females can be used to capture brain changes underlying ABA vulnerability, and that GABAergic innervation of hippocampal pyramidal neurons is one important cellular substrate to consider for understanding the progression of and resilience to AN.

Emotional intelligence in anorexia nervosa: Is anxiety a missing piece of the puzzle?

Problematic emotional processing has been implicated in the genesis and maintenance of anorexia nervosa (AN). This study built on existing research and explored performance-based emotional intelligence (EI) in people with AN. The Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT) was administered to 32 women diagnosed with AN and 32 female healthy controls (HC). Compared to HC women, the AN group demonstrated significantly lower total EI scores and poorer ability to understand how emotions can progress and change over time. Despite scores within the broadly average range compared to published EI norms, there was a general pattern of poorer performance in the AN sample. Self-reported anxiety symptoms were the strongest predictor of EI, over and above a diagnosis of AN. This study adds to the literature documenting the socioemotional phenotype of AN, suggesting this group of individuals may find it relatively difficult to carry out accurate reasoning about emotions, and to use emotions and emotional knowledge to enhance thought. Anxiety was highlighted as a putative variable partially explaining why people with AN demonstrated lower EI compared to controls. Implications for further research are discussed, including the need to explore the specificity of EI difficulties in AN using larger samples and additional control groups.

Lifetime anorexia nervosa in young men in the community: Five cases and their co‐twins

To describe patterns, comorbidity, and outcomes from a case series of anorexia nervosa (AN) among young men from the general population and their co-twins. Men (N = 2,122) born between 1975 and 1979 from Finnish twin cohorts were screened for lifetime eating disorders by questionnaire. The administration of the short version of the Structured Clinical Interview for DSM-IV for screen positives led to a lifetime AN diagnosis in five participants, described here with their co-twins. In males, overweight commonly predated AN, and symptoms of body dysmorphic disorder, particularly of muscle dysmorphia, were common among the anorexia-discordant co-twins. Affective and anxiety disorders were present in both the probands and their co-twins. We found a strong familial clustering of AN, affective and anxiety disorders, and symptoms of muscle dysmorphia among men in the general population. In men, muscle dysmorphia may represent an alternative phenotype of AN.

Anorexia nervosa and autism spectrum disorders: Guided investigation of social cognitive endophenotypes.

Death by suicide occurs in a disproportionate percentage of individuals with anorexia nervosa (AN), with a standardized mortality ratio indicating a 57-fold greater risk of death from suicide relative to an age-matched cohort. Longitudinal studies indicate impaired social functioning increases risk for fatal outcomes, while social impairment persists following recovery. Study of social cognition in AN may elucidate impaired processes that may influence therapeutic efficacy. Symptoms of autism spectrum disorders (ASD) are overrepresented in those who evidence a chronic course. Relative to that in AN, social information processing in ASD is well characterized and may inform systematic study in AN. This article (a) reviews impaired interpersonal processes in AN, (b) compares the phenotype of AN with that of ASD, (c) highlights deficits of social cognitive disturbance in ASD relative to AN, and (d) proposes a new framework to understand the interaction of individuals with AN with their social context.

Getting beneath the Phenotype of Anorexia Nervosa: The Search for Viable Endophenotypes and Genotypes

Treatment for anorexia nervosa has changed little from that described by Gull over a century ago. To focus merely on symptomatic relief from "not eating," as occurs with some forms of hospital care, is primitive. The evidence base to guide treatment is thin. Nevertheless, there is hope that better understanding of the causes and maintaining factors may translate into more sophisticated treatments. This review aims to look beyond the overt and startling "not eating" phenotype of anorexia nervosa and consider eating disorder endophenotypes. The first part of the review sets the eating behaviour, clinical, and psychopathological features into the context of what is now understood about the central control of appetite. The evidence base for a framework of potential eating disorder endophenotypes follows. Finally, ideas about how to translate endophenotypes into treatment are introduced.

Self-Regulatory Control and Habit Learning in the Development of Eating Disorders

Clinical evidence suggests that initial attempts to regulate weight gain quickly become habit-like in individuals with eating disorders. These behaviors are controlled excessively in patients with Anorexia Nervosa (AN) and are controlled more intermittently, with periods of lost control, in patients with Bulimia Nervosa (BN). We suspect that abnormalities in frontostriatal systems that subserve self-regulatory control and habit learning may contribute to the development and perpetuation of AN and BN. We summarize previous findings and present a pathophysiological model that provides a framework for understanding the shared and non-shared clinical phenotypes of AN and BN. Whereas dysregulated control systems produce heightened self-regulatory control, permitting individuals with AN to sustain excessive dietary restriction, dysregulated control systems likely result in impaired self-regulatory control in patients with BN, releasing feelings of hunger and urges to binge, thereby resulting in overeating. Interactions with cultural ideals of thinness and impaired habit learning systems may then allow the dieting behaviors of individuals with restricting-type AN to spiral into the habitual and restrictive eating behaviors that typify the disorder. Although these cultural factors likely contribute to the compensatory purging behaviors in BN, interactions with normal habit learning systems may explain the higher recovery rate of BN relative to AN, in which habit learning may be impaired. We describe neuroimaging methods that we are using to test these hypotheses and emphasize the potential utility of studying AN and BN early in the course of illness, to disentangle their causes from epiphenomena or compensatory responses. We believe that this innovative approach to studying eating disorders will lend explanation to the perplexing fact that although many young people diet and overeat at some point in time, only some go on to develop eating disorders.