The relationship between thyroid function and leptin has been extensively studied; however the mechanisms underlying the changes in thyroid hormone economy that occur during caloric deprivation remain elusive. Our goal was to evaluate the thyroid function of rats submitted to 40% food restriction after chronic leptin replacement. Caloric restriction for 25 days led to significantly reduced serum leptin, thyrotropin (TSH), T4, T3 and increased serum corticosterone, while liver, kidney and thyroid type 1 deiodinase (D1) and brown adipose tissue type 2 deiodinase (D2) activities were decreased, and hypothalamic D2 was significantly increased. Interestingly, thyroid iodide uptake was unchanged by caloric restriction, but thyroperoxidase activity was significantly reduced. Leptin replacement for the last 10 days of caloric restriction normalized serum leptin and TSH levels, but serum T4 and T3 levels, and thyroid D1 and thyroperoxidase (TPO) activities were not reestablished. Also, a negative effect of leptin administration on sodium/iodide symporter (NIS) function was detected. Liver and kidney D1 and hypothalamic and BAT D2 were normalized by leptin, while pituitary D2 was significantly decreased. In conclusion, a tissue-specific modulation of deiodinases might be implicated in the normalization of thyroid function during leptin replacement in food-restricted rats. Although leptin restores the hypothalamus-pituitary axis during food restriction, it exerts a direct negative effect on the thyroid gland, thus normalization of serum thyroid hormones might depend on changes in deiodinase activities and the long-term thyroid stimulation by TSH to counterbalance the direct negative effects of leptin on the thyroid gland.