Vaspin/SERPIN12 has been identified as a visceral adipose tissue-derived adipokine having glucose-lowering and insulin-sensitizing effects. Here we report that vaspin is also expressed in the hypothalamic nuclei, which are involved in body weight homeostasis. In addition, vaspin has potent weight-reducing effects when administered intracerebroventricularly in normal C57BL6 mice. These effects were mediated through a reduction in food intake and an enhancement in energy expenditure. Interestingly, leptin deficient ob/ob mice have reduced hypothalamic vaspin expression whereas leptin administration increased hypothalamic vaspin expression. Moreover, like leptin, vaspin activates hypothalamic Stat3 signaling pathways and regulates expression of appetite regulating neuropeptides, proopiomelanocortin, neuropeptide Y and agouti related protein. Conversely, reduced hypothalamic vaspin expression using small inhibitory RNA inhibited hypothalamic leptin signaling and its anorexigenic action, suggesting that vaspin is an anorexigenic molecule that constitutes hypothalamic leptin signaling pathway. Further investigation of the molecular mechanism of vaspin actions revealed that NMDA receptor-mediated calcium influx induced by vaspin activated Stat3 signaling cascades. Importantly, the central metabolic effects of vaspin were much reduced when serpin domain was mutated, indicating that serpin activity is important for central vaspin actions. In summary, we firstly describe vaspin as a novel anorexigenic peptide that conveys hypothalamic leptin actions.