Oxytocin (Oxt) is a hormone produced in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, known to mediate the central anorexigenic effects of the adipokine leptin (Lep), as well as to promote adipose tissue (AT) lipolysis at the periphery. Here, we sought to address whether Oxt neurons could directly respond to Lep, and if any such regulatory cascade would increase Oxt levels in plasma. Adult C57BL/6 mice were intraperitoneally injected with mouse recombinant leptin (0.5 mg/kg) or saline, while others were subjected to standard or high-fat diet (HFD). Hypothalamus, AT and blood were collected and plasma isolated to measure Oxt by mass spectrometry. C57BL/6J-Tg (Pomc-EGFP)1Low/J mice were used for assessing POMC projections. We found that Lep induced c-Fos, but not p-Stat3, activation mainly in SON-Oxytocin neurons. Lep administration resulted in higher Oxt plasma levels, with faster Oxt secretion in males than in females (1.5 vs. 6 hours post-injection) and in increased Oxt receptor (Oxtr) protein levels, paired with decreased Oxtr transcript in AT. Furthermore, only in female mice fed with HFD there was a trend for increased Oxt plasma levels. However, single-nucleus RNA-seq demonstrated that Lep receptor (Lepr) was not expressed by Oxt neurons while proopiomelanocortin neurons of the arcuate nucleus, which are known to express Lepr, abundantly innervated SON-oxytocin neurons. In conclusion, we have characterized a Lep-dependent oxytocin secretory pathway driven in SON neurons which may act in a sexually dimorphic fashion to target AT. Our data reinforce AT-brain crosstalk in the regulation of the energy balance.