Leptin-responsive neurons of the hypothalamus constitute a heterogeneous population expressing a vast array of different neuropeptides and neurotransmitters, some of which participate in the regulation of hunger and satiety. Here we report that somatostatin modulates the efficacy of leptin-signalling in the rat hypothalamus. Using a two-pulse paradigm at 30-min intervals, we delivered somatostatin or somatostatin receptor subtype-selective agonists in combination with leptin into the lateral cerebral ventricle of stereotaxically cannulated rats. To monitor the effect of somatostatin on the leptin-signalling pathway, we quantified changes in the leptin-mediated activation of STAT3, the signal transducer and activator of transcription 3. Successive administration of somatostatin and leptin diminished the level of STAT3-phosphorylation and nuclear STAT3 translocation in the ventromedial and dorsomedial hypothalamic nuclei, the lateral hypothalamic area, and the arcuate nucleus by about 40% compared to leptin administration alone. Furthermore, application of subtype-selective somatostatin receptor agonists suggests that the observed reduction in leptin-responsiveness is predominantly mediated by the sst3 receptor-subtype, followed by sst1 and sst2. In addition, the intensity of the negative-regulatory effect of somatostatin on leptin-signalling displayed regional differences for the three receptor-subtypes involved. Addressing the functional consequences of the diminished leptin-signalling, behavioural analyses showed that centrally applied somatostatin counteracts the leptin-mediated suppression of food intake. These results suggest that the pleiotropic effector somatostatin also plays a role in the central regulation of energy homeostasis.