Serum leptin levels were significantly increased during rat gestation. Our data showed that leptin mRNA levels in both the adipose tissue and placenta were higher as pregnancy progressed, suggesting a role for both tissues in the hyperproduction of leptin. This paradoxical increase in leptin concentration during gestation suggests that a physiological state of leptin resistance may exist at the hypothalamic level that may explain the hyperphagia observed in pregnant rats. In order to study this issue further, levels of the mRNA encoding the different leptin receptor isoforms were determined in the hypothalamus of pregnant and nonpregnant rats. We found a specific reduction of the mRNA levels encoding the leptin receptor isoform Ob-Rb in the hypothalamus of pregnant rats compared to nonpregnant animals, suggesting that during pregnancy the hypothalamus shows a physiological resistance to the high levels of leptin due, at least in part, to a decrease in the expression of the long, biologically active form of the leptin receptor (Ob-Rb). During lactation, serum leptin levels returned to values observed in nonpregnant rats. In the hypothalami of these animals, Ob-Rb mRNA content was similar to that observed in nonpregnant rats, but we found an increased expression of some of the short forms of the leptin receptor (Ob-Re and Ob-Rf). This could contribute to induction of the hyperphagia present during lactation. These data provide new insights into the adaptive mechanisms that take place during pregnancy and lactation in order to meet increased metabolic requirements.