Animal Models for Anorexia Nervosa—A Systematic Review

Anorexia nervosa is an eating disorder characterized by intense fear of gaining weight and a distorted body image which usually leads to low caloric intake and hyperactivity. The underlying mechanism and pathogenesis of anorexia nervosa is still poorly understood. In order to learn more about the underlying pathophysiology of anorexia nervosa and to find further possible treatment options, several animal models mimicking anorexia nervosa have been developed. The aim of this review is to systematically search different databases and provide an overview of existing animal models and to discuss the current knowledge gained from animal models of anorexia nervosa. For the systematic data search, the Pubmed—Medline database, Embase database, and Web of Science database were searched. After removal of duplicates and the systematic process of selection, 108 original research papers were included in this systematic review. One hundred and six studies were performed with rodents and 2 on monkeys. Eighteen different animal models for anorexia nervosa were used in these studies. Parameters assessed in many studies were body weight, food intake, physical activity, cessation of the estrous cycle in female animals, behavioral changes, metabolic and hormonal alterations. The most commonly used animal model (75 of the studies) is the activity-based anorexia model in which typically young rodents are exposed to time-reduced access to food (a certain number of hours a day) with unrestricted access to a running wheel. Of the genetic animal models, one that is of particular interest is the anx/anx mice model. Animal models have so far contributed many findings to the understanding of mechanisms of hunger and satiety, physical activity and cognition in an underweight state and other mechanisms relevant for anorexia nervosa in humans

Activity-Based Anorexia Reduces Body Weight without Inducing a Separate Food Intake Microstructure or Activity Phenotype in Female Rats—Mediation via an Activation of Distinct Brain Nuclei

Anorexia nervosa (AN) is accompanied by severe somatic and psychosocial complications. However, the underlying pathogenesis is poorly understood, treatment is challenging and often hampered by high relapse. Therefore, more basic research is needed to better understand the disease. Since hyperactivity often plays a role in AN, we characterized an animal model to mimic AN using restricted feeding and hyperactivity. Female Sprague-Dawley rats were divided into four groups: no activity/ad libitum feeding (ad libitum, AL, n=9), activity/ad libitum feeding (activity, AC, n=9), no activity/restricted feeding (RF, n=12) and activity/restricted feeding (activity-based anorexia, ABA, n=11). During the first week all rats were fed ad libitum, ABA and AC had access to a running wheel for 24h/d. From week two ABA and RF only had access to food from 9:00-10:30 am. Body weight was assessed daily, activity and food intake monitored electronically, brain activation assessed using Fos immunohistochemistry at the end of the experiment. While during the first week no body weight differences were observed (p>0.05), after food restriction RF rats showed a body weight decrease: -13% vs. day eight (p0.05). Similarly, the daily physical activity was not different between AC and ABA (p>0.05). The investigation of Fos expression in the brain showed neuronal activation in several brain nuclei such as the supraoptic nucleus, arcuate nucleus, locus coeruleus and nucleus of the solitary tract of ABA compared to AL rats. In conclusion, ABA combining physical activity and restricted feeding likely represents a suited animal model for AN to study pathophysiological alterations and pharmacological treatment options. Nonetheless, cautious interpretation of the data is necessary since rats do not voluntarily reduce their body weight as observed in human AN

Aktivitäts-basierte Anorexie ist ein Tiermodell für Anorexia nervosa

Anorexia nervosa (AN) in an eating disorder diagnosed by the occurrence of the ensuing symptoms: a strong wish to lose body weight, restricted caloric intake, a distorted body image, and hyperactivity. Despite the well-defined symptomatology of the disease, the pathophysiology still remains poorly explained. Moreover, a specific pharmacological treatment is lacking. In order to better characterize pathophysiological alterations occurring under disease conditions, animal models can be useful. The activity-based anorexia (ABA) model for rats mimics the disease by combining the two factors of restricted feeding (access to food: 1.5h/day) with the possibility of voluntary exercise in a running wheel installed in the rats’ cage. The aim of the studies was to investigate the modulation of food intake and body weight under conditions of ABA as well as to describe neuronal changes possibly underlying the observed alterations. Female Sprague-Dawley rats were used and randomly assigned to one of four groups: ad libitum (AL, ad libitum food, no running wheel, n=9), activity (AC, ad libitum food and running wheel, n=9), restricted feeding (RF, food restriction, no running wheel, n=12) and activity-based anorexia (ABA, food restriction and running wheel, n=11). Following validation of an automated food intake-monitoring system for the use in rats, food intake microstructure was assessed under conditions of ABA. ABA resulted in a pronounced body weight loss of -22% compared to the first day of food restriction (p0.05). An analysis of the neuronal changes showed that ABA leads to an activation of distinct brain nuclei involved in the regulation of food intake (LS, LHA, Arc, DMH, NTS), gastrointestinal motility (LHA, NTS, 10N), thermoregulation (DMH), circadian rhythm (DMH), stress (PVN, LC), memory (hippocampus) and depressiveness/anxiety (SON, PVN, DR, Rpa). Immunohistochemical doublestaining for c-Fos and the anorexigenic peptide nesfatin-1 -indicated by a significant increase of nesfatin-1 immunoreactive cells in PVN, DMH, Arc, LC and NTS in ABA rats (p0.05), noch in der Laufradaktivität (ABA vs. AC, p>0.05). Die Analyse der neuronalen Veränderungen ergab, dass ABA zu einer Aktivierung von Gehirngebieten führt, die in die Regulation von Nahrungsaufnahme (LS, LHA, Arc, DMH, NTS), gastrointestinaler Motilität (LHA, NTS, 10N), Thermoregulation (DMH), zirkadiane Rhythmen (DMH), Stress (PVN, LC), Gedächtnis (Hippocampus) und Depressivität/Angst (SO, PVN, DR, Rpa) involviert sind. Immunhistochemische Doppelfärbungen von c-Fos und dem anorexigenen Peptid Nesfatin-1 gaben Anlass zu der Vermutung, dass Nesfatin-1 eine Rolle bei ABA und eventuell auch bei Patienten mit AN spielt, denn Nesfatin-1 immunreaktive Zellen waren bei ABA-Tieren im PVN, DMH, Arc, LC und NTS (p<0.05) vermehrt nachweisbar. Zusammengefasst stellt ABA ein potentiell hilfreiches Modell zur Untersuchung von pathophysiologischen Veränderungen bei AN dar, auch wenn die Tiermodell-Daten vorsichtig interpretiert werden sollten