Long-Term Physiological Alterations and Recovery in a Mouse Model of Separation Associated with Time-Restricted Feeding: A Tool to Study Anorexia Nervosa Related Consequences

Abstract

BackgroundAnorexia nervosa is a primary psychiatric disorder, with non-negligible rates of mortality and morbidity. Some of the related alterations could participate in a vicious cycle limiting the recovery. Animal models mimicking various physiological alterations related to anorexia nervosa are necessary to provide better strategies of treatment.AimTo explore physiological alterations and recovery in a long-term mouse model mimicking numerous consequences of severe anorexia nervosa.MethodsC57Bl/6 female mice were submitted to a separation-based anorexia protocol combining separation and time-restricted feeding for 10 weeks. Thereafter, mice were housed in standard conditions for 10 weeks. Body weight, food intake, body composition, plasma levels of leptin, adiponectin, IGF-1, blood levels of GH, reproductive function and glucose tolerance were followed. Gene expression of several markers of lipid and energy metabolism was assayed in adipose tissues.ResultsMimicking what is observed in anorexia nervosa patients, and despite a food intake close to that of control mice, separation-based anorexia mice displayed marked alterations in body weight, fat mass, lean mass, bone mass acquisition, reproductive function, GH/IGF-1 axis, and leptinemia. mRNA levels of markers of lipogenesis, lipolysis, and the brown-like adipocyte lineage in subcutaneous adipose tissue were also changed. All these alterations were corrected during the recovery phase, except for the hypoleptinemia that persisted despite the full recovery of fat mass.ConclusionThis study strongly supports the separation-based anorexia protocol as a valuable model of long-term negative energy balance state that closely mimics various symptoms observed in anorexia nervosa, including metabolic adaptations. Interestingly, during a recovery phase, mice showed a high capacity to normalize these parameters with the exception of plasma leptin levels. It will be interesting therefore to explore further the central and peripheral effects of the uncorrected hypoleptinemia during recovery from separation-based anorexia.

Physical activity: benefit or weakness in metabolic adaptations in a mouse model of chronic food restriction?

“…Thus, in FRW mice, physical activity that is usually described to stimulate bone formation did not prevent the termination of bone mass acquisition induced by food restriction. Similar data were also described in female mice subjected to a protocol of chronic stress associated with caloric restriction, the "separation based-anorexia" model (73). This confirmed the absence of the protective effect of activity on BMC in AN.…”

Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery

“…Two groups of mice were used: the SWL group included mice housed in a cage fitted with 6 individual Plexiglas ® partitions and submitted to a food restriction protocol as previously described [1,2] and the control group with mice housed in standard conditions (6 mice per cage, food and water ad libitum). In the first study, SWL mice ( n = 6) were fed daily with an access to food gradually reduced from 6 to 2 h a day for a duration of 10 weeks.…”

“…However, central effects of long-term energy deficit and refeeding remain to be elucidated. We adapted and characterized a long-term mouse model [1] initially developed by van Leeuwen et al [2] that we designated "separation-induced weight loss" model (SWL) initially called "separation-based anorexia." Indeed, these mice did not display voluntary food restriction as described in the "activity-based anorexia" mouse model (ABA), currently used to study anorexia nervosa (AN) [3,4] .…”

“…Indeed, these mice did not display voluntary food restriction as described in the "activity-based anorexia" mouse model (ABA), currently used to study anorexia nervosa (AN) [3,4] . However, we have recently shown that SWL mice display numerous physiological consequences described in restrictive AN patients [1] . In our model, sexually mature young female mice are submitted to time-restricted feeding and separation stress for up to 10 weeks.…”

“…The main described consequences of the SWL protocol are severe body weight loss, disturbance of the reproductive functions, low plasma leptin concentrations and a disruption of the GH/IGF-1 axis that, by 10 weeks, are associated with alterations in bone quality. When SWL mice are renourished (i.e., refed and grouphoused for up to 10 weeks), most of these parameters normalize, including body weight, body composition, food intake behavior, GH/IGF-1 axis, and reproductive functions [1] . One important exception is the low plasma leptin levels and its low mRNA levels in adipose depots that persist during the refeeding period, despite recovery of their body fat mass to a level similar to that of the control mice.…”