Dimorphic Effects of Leptin on the Circadian and Hypocretinergic Systems of Mice

The hormone leptin controls food intake and body weight through its receptor in the hypothalamus, and may modulate physiological functions such as reproduction, sleep or circadian timing. In the present study, the effects of leptin on the resetting of the circadian clock, the hypothalamic suprachiasmatic nucleus (SCN) and on the activity of the hypocretinergic system were examined in vivo, with comparative analysis between male and female mice. A single leptin injection (5 mg/kg) at both the onset and offset of the activity period did not alter locomotion of mice housed under a 12 : 12 h light/dark cycle and did not shift the circadian behavioral rhythm of mice housed in constant darkness. By contrast, leptin potentiated the phase-shifting effect of a 30-min light-pulse on behavioural rhythms during the late subjective night, although only in females. This was accompanied by a higher induction of the clock genes Per1 and Per2 in the SCN. A 2-week chronic exposure to a physiological dose of leptin (100 mu g/kg per day) decreased locomotor activity, expression of hypocretin receptor 1 and 2, as well as the number of hypocretin-immunoreactive neurones only in female mice, whereas the number of c-fos-positive hypocretinergic neurones was reduced in both genders. These results highlight a dimorphic effect of leptin on the hypocretinergic system and on the response of the circadian clock to light. Leptin may thus modulate the sleep/wake cycle and circadian system beside its well-established action on food intake and regulation of body weight.