Despite elevated plasma leptin, food intake is increased during pregnancy leading to fat deposition. We have demonstrated that intracerebroventricular (icv) leptin is unable to suppress food intake in pregnant rats, as it does in non-pregnant animals. Hence, central leptin resistance develops during pregnancy. These changes are physiologically appropriate, providing increased energy reserves to help meet the high metabolic demands of fetal development and lactation. To characterise this central leptin resistance, we have measured levels of leptin receptor (Ob-Rb) mRNA in the hypothalamus, and examined leptin-induced phosphorylation of STAT3 (pSTAT3) in specific regions of the hypothalamus. In addition, to investigate the mechanism underlying pregnancy-induced leptin resistance, we have investigated effects of hormone treatments on hypothalamic responses to leptin in a pseudopregnant rat model. We observed a significant reduction of Ob-Rb mRNA levels in the ventromedial hypothalamic nucleus (VMH) during pregnancy, with no changes detected in other hypothalamic nuclei. Levels of leptin-induced pSTAT3 were specifically suppressed in the VMH and arcuate nucleus of pregnant rats compared to non-pregnant rats. Pseudopregnant rats were hyperphagic but did not become leptin resistant, suggesting that fetal or placental factors are required for the induction of leptin resistance. These data implicate the VMH as a key hypothalamic site involved in hormone-induced leptin resistance during pregnancy, and suggest that placental hormone secretion may mediate the hormone-induced loss of response to leptin.