The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing particularly in the CNS is only poorly defined. The consequences of hypothyroidism on leptin production as well as leptin sensing were analyzed in TRH receptor 1 (Trhr1) knockout mice that exhibit congenital hypothyroidism due to a diminished TRH stimulation of pituitary thyrotrophs. The hypothyroid mice exhibited a 50% reduction in white adipose tissue compared to euthyroid controls. Moreover, the animals showed a decrease in leptin transcript levels as well as strongly reduced leptin serum levels. The finding that murine 3T3-L1 adipocytes responded to T3 with a rise in leptin transcript levels suggests that TH indeed may regulate leptin expression in a cell-autonomous manner. The transcript levels of leptin receptor were altered under hypothyroid conditions as well. The hypothyroid Trhr1 ko mice showed an increase in LepR mRNA expression specifically in neurons of the hypothalamic arcuate nucleus, an important target of leptin action. Likewise, the transcript levels of SOCS3, a potent negative regulator of LepR signaling, were strongly decreased in these neurons. In order to eliminate any effects of the different circulating leptin levels in the analysis, hypothyroid and leptin-deficient animals were generated by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob mice and their response to leptin substitution was analyzed. In comparison to euthyroid ob animals, hypothyroid Trhr1/ob dko mice showed decreased body weight and appetite loss following three days of leptin treatment. Moreover, phospho-Stat3 immunoreactivity in the arcuate nucleus was strongly reduced in Trhr1/ob dko mice compared to euthyroid controls. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism.