Prolonged fasting is associated with a number of changes in the thyroid axis manifested by low serum T₃ and T₄ levels and, paradoxically, low or normal TSH. This response is, at least partly, caused by suppression of proTRH gene expression in neurons of the hypothalamic paraventricular nucleus (PVN) and reduced hypothalamic TRH release. Because the fall in thyroid hormone levels can be blunted in mice by the systemic administration of leptin, we raised the possibility that leptin may have an important role in the neuroendocrine regulation of the thyroid axis, through effects on hypophysiotropic neurons producing proTRH. Adult male, Sprague-Dawley rats were either fed normally, fasted for 3 days, or fasted and administered leptin at a dose of 0.5 μg/gm BW ip every 6 h. Fasted animals showed significant reduction in plasma total and free T₄ and T₃ levels compared with controls, that were restored toward normal by the administration of leptin. Percent free T₄, but not percent free T₃, increased during fasting, further suggesting a reduction in plasma transthyretin levels that did not return to fed levels after leptin administration. By semiquantitative analysis of in situ hybridization autoradiograms, proTRH messenger RNA in medial parvocellular PVN neurons was markedly suppressed in the fasting animals but was restored to normal by leptin administration [fed vs. fast vs. fast/leptin (density units × 10⁸): 8.5 ± 0.4, 3.2 ± 0.2, 8.1 ± 0.8]. In contrast, proTRH messenger RNA in adjacent neurons in the lateral hypothalamus that do not have a hypophysiotropic function remained unchanged by any of the experimental manipulations. These findings indicate that leptin has a selective, central action to modulate the hypothalamic-pituitary-thyroid axis by regulating proTRH gene expression in the PVN but does not have peripheral effects on thyroid-binding proteins. We propose that the fall in circulating leptin levels during fasting resets the set point for feedback inhibition by thyroid hormones on the biosynthesis of hypophysiotropic proTRH, thereby allowing adaptation to starvation.