Circulating gonadal steroid levels affect metabolic homeostasis by regulating appetite and food intake. The actions of estrogen are mediated through its two receptors ERalpha and ERbeta. ERalpha expression is necessary to maintain normal food intake, body weight and adiposity. Leptin plays a central role in regulating feeding behavior, homeostasis and reproduction. It is known that there is an effect of estrogen and leptin on feeding behavior. The present study was undertaken 1) to assess the changes in the reproductive cycle in obese, infertile ob/ob mice with no circulating leptin and infertile, obese, agouti (Ay/a) mice with high circulating leptin levels, 2) to evaluate the hypothalamic distribution of ERalpha and ERbeta, and 3) to analyze the differences in expression of ERs related to leptin and beta-estradiol levels in these mouse lines. The results show that the ob/ob and Ay/a mice were acyclic and were at a persistent estrous phase. The beta-estradiol levels were similar between WT, ob/ob and Ay/a mice. Stereologic analysis showed that there were significantly higher numbers of ERalpha-immunoreactive cells in ob/ob mice irrespective of sex when compared to wild-type (WT) in arcuate nucleus (ARH) and no significant change in ERbeta immunoreactive cell numbers in ARH or paraventricular nucleus (PVN). Ovariectomy in female wild-type mice caused a 50% increase of ERalpha-immunoreactive cells. Results suggest that leptin and estrogen act via the same neuronal circuits to affect reproduction, neuroendocrine and behavioral processes. However, estrogen levels and acyclicity have more profound effect on the regulation of ERalpha cell numbers in the ARH than circulating leptin levels.