Nutritional Neuroscience, Volume 6 Number 3 (June 2003), pp. 197–199
Short Communication
Does Short-term Diet Restriction in Mice Precipitate the Development of Anorexia? OMER BONNEa,*, YOSEPHA AVRAHAMb, EITAN BACHARa, MAOR KATZa and ELLIOT M. BERRYb a Department of Psychiatry, Hebrew University-Hadassah Medical School, P.O.BOX 12000, Jerusalem 91120, Israel; bDepartment of Human Nutrition and Metabolism, Hebrew University-Hadassah Medical School, P.O.BOX 12000, Jerusalem 91120, Israel
(Received 21 May 2002; Revised 7 August 2002; In final form 27 January 2003)
Anorexia nervosa (AN) inevitably begins with dieting. Yet, it is unknown whether anyone who will ultimately suffer from anorexia is already ill upon “going on a diet”, or whether disease begins during, and is perhaps triggered by, dieting. The objective of the following study was to precipitate anorexia by imposing diet restriction on animals, as a model for generating AN in humans. Three hundred young female Sabra mice were diet restricted to 40% of daily nutrient requirements for 12 days, lost 17% of body weight and were then re-fed ad-lib. All mice regained appetite and weight. Our conclusions are that diet restriction does not precipitate anorexia in mice. Our findings do not support a role for diet restriction per se in triggering AN. Keywords: Short term diet restriction; Anorexia; Mice; Serotonin
Anorexia nervosa (AN) is a common, severe and often fatal illness, with an overall prevalence of between 0.5 and 1% and a higher rate among adolescent females. It is characterized by morbid fear of fatness, extreme self-induced weight loss, excessive exercise and secondary endocrine disturbances such as amenorrhoea, and increased levels of growth hormone and cortisol. Full-blown AN is very easily recognized. A more challenging task is the recognition of this disorder in its initial phase. In certain young women, somewhere along the course of a seemingly benign weight reduction a “malignant” turn will occur, leading to emaciation and full blown manifestation of AN.
Clinical impression, backed by empirical research (Cooper, 1995) indicates that upon “going on a diet”, girls who will ultimately develop AN seem no different than those who will stop weight control. However, dieting has been determined as the most important predictor of new eating disorders (Patton et al., 1999). Diverse risk factors for AN have been identified. These include personality traits such as rigidity, obsessional behavior, low self-esteem (Casper, 1990) and family history of AN (Lilenfeld et al., 1998). Involvement of biological mediators in the etiology of AN, particularly serotonin, has been frequently suggested (Mauri et al., 1996). Serotonin (5-HT) suppresses food consumption, specifically carbohydrates. 5-HT levels rise following a carbohydraterich meal while starvation brings about a decrease in 5-HT, stimulating appetite and carbohydrate consumption (Mauri et al., 1996; Leibowitz and Alexander, 1998). Studies have shown alterations in 5-HT activity in the ill AN state as well as after weight restoration (Kaye et al., 1998; Ward et al., 1998). 5-HT gene polymorphism has also been demonstrated in studies of eating disorders (Fumeron et al., 2001). In animal studies performed by our group (Hao et al., 2000, and unpublished data), hypothalamic 5-HT concentrations of diet-restricted (DR) mice were reduced. However, occasionally, increased 5-HT values were observed in DR mice (5HT level . 5 standard deviations above
*Corresponding author. Mood and Anxiety Disorders Program, National Institute of Mental Health, 15K North Drive, Room 200, Bethesda, MD 20892-2670, USA. Tel.: þ1-301-496-2399. Fax þ 1-301-402-6100. E-mail:
[email protected] ISSN 1028-415X print/ISSN 1476-8305 online q 2003 Taylor & Francis Ltd DOI: 10.1080/1028415031000094282
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the mean; data available on request). Such values were considered “outliers”. Given the observation associating diet and new onset anorexia in humans (Patton et al., 1999) and considering 5-HT regulation of appetite, we wondered whether the presence of these rare outlier mice with high 5-HT levels could be understood differently. Perhaps, the increased 5-HT indicates that such a mouse had undergone an “anorectic” transformation, and would have abstained from eating and continued to lose weight had it been provided with food instead of being sacrificed at the end of the weight-loss period? We, therefore, put forward the following hypothesis: in a minority of mice, diet restriction leads to an increase in serotonin levels and a decrease in appetite. In these mice, anorexia and weight loss would continue even after free access to food is provided. If confirmed, this hypothesis could provide new insight into the understanding of AN. The following preliminary experiment was performed to test this hypothesis. Three hundred female Sabra mice, aged 9 weeks, weighing 30:8 þ 2:3 g (range 27 – 34 g) were housed (10 each) in 40 £ 60 £ 40 cm3 cages containing wood chip bedding and placed in a temperature-controlled room of 228C on a 12 h light/dark cycle (lights on at 7:00 a.m.). Body weight was recorded to the nearest gram two times a week, beginning one week before diet restriction until 10 days after re-feeding. Mice received a diet of 40 kcal/week/mouse (1.44 g/day/mouse), calculated to be 40% of the daily requirements (Ingram et al., 1987). Food (Purina chow) was provided once every 24 h, containing carbohydrate 54.9%, protein 21.1%, fat 4.7%, humidity 12.0% and ash 5.6% and given between 10:00 and 11:00 a.m. Mice had free access to water the whole 24 h. Mice were re-fed after 12 days, after they had reached an average weight of 25:6 þ 2:3 g: For re-feeding, animals were given ad-libitum nutrition of the same composition, while conditions were kept as similar as possible to those in the diet restriction phase. All mice regained weight, and averaged 30:5 ^ 2:6 g at the end of this period. How can these results be understood? The prevalence of AN in human population is around 1%, and is higher among adolescent females. It may be that the number of animals used in this study was too small to reliably exclude the possibility of voluntary anorexia occurring after diet restriction, particularly since we are only looking at a limited period of time and a certain animal age. In addition, since these animals were not sacrificed, brain receptor density measures were not conducted, and the presence or absence of “outliers” in 5-HT concentrations in this cohort was not documented. The decision to restrict food intake in humans is voluntary. In diet restriction, as implemented in
this study, animals were forced to reduce caloric intake. It may be that AN follows self-induced but not obligatory food restriction. In rodents diet restriction models of “activity-based anorexia” (Routtenberg and Kuznesof, 1967) or “separation” (van Leeuwen et al., 1997) have been considered more “voluntary”. However, both models are not truly voluntary, and both models may introduce a confound which will obscure the major question of this study, the effect of diet restriction in triggering anorexia. A look at animal behavior in the wild reveals that unconstrained animal anorexia has been documented in various species during hibernation, incubation, migration and defense of territory (Mrosovsky and Sherry, 1980). “Voluntary” anorexia thus exists in nature and even has an important evolutionary role. However, the equivalent of human AN, representing pathological, self-harmful behavior is not encountered. Consequently, diet restriction per se may not be a suitable animal model for studying AN. We have examined a hypothesis whereby diet restriction initiates an irreversible process of reduction in food intake in a small minority of animals, as a model for the events occurring at the onset of AN in humans. This hypothesis postulates a major role for a biologic predisposition in the generation of the disease. Our results suggest that biological predisposing factors may not be sufficient for the development of AN.
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