Leptin suppresses semi-starvation induced hyperactivity in rats: implications for anorexia nervosa

Abstract

Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa. Molecular Psychiatry (2000) 5, 476-481.Keywords: food intake; food restriction; energy metabolism; neuroendocrine control of appetite; locomotor activity; running wheels Hyperactivity is observed in 40-80% of patients with anorexia nervosa (AN). 1,2 Caloric deprivation severe enough to result in significant weight loss possibly provokes sensations of behavioral arousal and activation in individuals with an innate vulnerability to develop AN. 3 Indeed, reduced food intake and enhanced activity have been viewed as the core symptomatology in AN, because only these behavioral measures consistently distinguish AN from other disorders. 4 Semi-starvation induced hyperactivity (SIH) is a well characterized phenomenon in laboratory animals. 5,6 Rats supplied with food for only 1 h per day manage to survive, but die within a short period of time when exposed to a running wheel. The enhancement of activity is related to the severity of food restriction; total food deprivation results in a disruption of the nocturnal activity pattern. 6 Leptin is assumed to be the major hormone underlying the regulatory phenomena that lead to an adaptation of an organism to reduced energy supplies. 7 Thus, in mice exogenously applied leptin has been shown to blunt the semi-starvation-induced downregulation of the hypothalamic-pituitary gonadal and thyroid axes as well as the upregulation of the hypothalamic-pituitary adrenal axis. 7 The rapid decline in leptin secretion associated with caloric restriction and weight loss 7,8 could represent the initial trigger underlying the hyperactivity observed in SIH and AN. As an initial step towards testing this hypothesis we investigated the effect of continuous leptin treatment via minipum...

Voluntary access to a warm plate reduces hyperactivity in activity-based anorexia

“…This body weight loss itself might also trigger hyperactivity. Indeed, it was hypothesized before that a decrease in plasma leptin levels associated with body weight loss might trigger hyperactivity [8]. In the present experiment it was observed that body weight loss was correlated with RWA in rats without a plate and that the presence of a warm plate reduced body weight loss.…”

“…However, although body weight loss was significantly affected by access to a warm plate, plasma leptin levels were still undetectable and no differences in leptin expression levels in WAT were observed. This suggests that heat treatment in ABA overrules the putative role of decreased leptin levels in triggering hyperactivity [8].…”

“…Indeed, substantial activity takes place prior to food access (independent of light or dark phase), which is also known as foodanticipatory activity (FAA). Wheel running is also considered as foraging behavior and has rewarding properties [6,7] and recently it was hypothesized that reduced plasma leptin levels associated with body weight loss might trigger hyperactivity [8]. Furthermore, hyperactivity might be explained as a thermoregulatory behavior to prevent starvation-induced hypothermia [9], since activity levels of ABA rats are inversely related to core body temperature [10].…”

Olanzapine Reduces Physical Activity in Rats Exposed to Activity-Based Anorexia: Possible Implications for Treatment of Anorexia Nervosa?

“…Basal body temperature of ad libitum-fed rats was not altered following chronic olanzapine treatment, which is in contrast with another study reporting dose-dependent hypothermia following acute olanzapine treatment in ad libitum-fed rats (Oerther and Ahlenius 2000). It has previously been shown that peripheral leptin treatment reduced hyperactivity of rats exposed to the semistarvation-induced hyperactivity model (Exner et al 2000), and it was proposed that decreases in leptin signaling might trigger hyperactivity in rats, as well as in AN patients (Hebebrand et al 1997). In our study, plasma leptin levels were undetectable in both vehicle-and olanzapine-treated ABA rats.…”

Genetic epidemiology, endophenotypes, and eating disorder classification

“…Animal models of ''anorexia based activity'' exist 54 and both rodent and human studies indicate that hypoleptinemia is associated with hyperactivity and motor restlessness. 55,56 In food restricted rats, exogenous leptin suppresses the development of semi-starvation induced hyperactivity 57 ; in AN patients leptin levels are inversely correlated with motor restlessness. 58 The optional inclusion of symptoms of elevated activity would allow reference to a biologically based phenomenon, which appears rather specific to AN.…”