In a previous study, we established that leptin controls food intake and immune responses by acting on intestinal vagal chemosensitive mechanoreceptors via a functional link with interleukin-1β (Il-1β). Since the control of intestinal motility is one of the main roles of the vagal afferent fibres, we investigated the effects of leptin on intestinal electromyographic (EMG) activity which reflects intestinal motility. For this purpose, the effects of locally injected leptin on small intestine spontaneous EMG activity were studied in 23 anaesthetised cats. The EMG activity was recorded using bipolar electrodes implanted in the proximal small intestine. Leptin and Il-1β (0.1, 1 and 10 μg), administered through the artery irrigating the upper part of the intestine 20 min after cholecystokinin (CCK, 10 μg, i.a.), had significant (P < 0.001) excitatory effects on intestinal EMG activity. The effects of both substances were blocked by the endogenous interleukin-1β receptor antagonist (Il-1ra, 250 μg, i.a.), by atropine (250 μg, i.a.) and by vagotomy. In the absence of CCK, leptin and Il-1β had no effect on intestinal electrical activity. It can therefore be concluded that: (1) leptin is effective only after the previous intervention of CCK, (2) the enhancement of the electrical activity induced by leptin involves Il-1β receptors and the cholinergic excitatory pathway, (3) the modes whereby the leptin-induced enhancement of EMG activity occurs strongly suggest that these effects are due to a long-loop reflex involving intestinal vagal afferent fibres and the parasympathetic nervous system.