Araujo RL, Andrade BM, da Silva ML, Ferreira AC, Carvalho DP. Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats. Am J Physiol Endocrinol Metab 296: E1157-E1163, 2009. First published February 10, 2009 doi:10.1152/ajpendo.90869.2008The 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, thyroid-stimulating hormone (TSH), thyroxine (T 4), and triiodothyronine (T3) and increased serum corticosterone, while liver, kidney, and thyroid type I deiodinase (D1) and brown adipose tissue (BAT) type II deiodinase (D2) activities were decreased and hypothalamic D2 was significantly increased. Interestingly, thyroid iodide uptake was unchanged by caloric restriction, but thyroperoxidase (TPO) activity was significantly reduced. Leptin replacement for the last 10 days of caloric restriction normalized serum leptin and TSH levels, but serum T 4 and T3 levels and thyroid D1 and TPO activities were not reestablished. Also, a negative effect of leptin administration on Na ϩ -I Ϫ symporter 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.hypothalamus; pituitary; thyroid; caloric deprivation; thyrotropin MODERATE REDUCTION in caloric intake promotes well-known systemic effects such as body and fat mass reduction; however, homeostatic mechanisms impair further weight loss after longer periods of food restriction (40, 41). Studies in rodents suggest that the reduction in serum leptin levels that occurs during weight loss signals to the central nervous system, leading to decreased energy expenditure (1,2,3,5). This rapid fall in serum leptin in response to starvation also suppresses immunity, reproductive, and thyroid functions through central mechanisms (1,16,21,23,46).It is well documented that food restriction exerts profound effects on the hypothalamic-pituitary-thyroid axis, resulting in low plasma thyroxine (T 4 ) and triiodothyronine (T 3 ) levels that seem to be secondary to decreased thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion (4,29,38). The relationship between thyroid hormon...