FASTING-INDUCED INCREASE IN TYPE-II IODOTHYRONINE DEIODINASE ACTIVITYAND MESSENGER-RIBONUCLEIC-ACID LEVELS IS NOT REVERSED BY THYROXINE INTHE RAT HYPOTHALAMUS

The importance of local formation of T-3 in the feedback effect of the thyroid gland on hypothalamic TRH-producing cells has been establishe d. Primary failure of the thyroid gland results in a fall in circulati ng T-4 and T-3 levels, leading to an elevation in the production and r elease of TRH in the hypothalamic paraventricular nucleus. In contrast , during short term fasting, declining plasma levels of thyroid hormon es coincide with suppressed TRK production and release. In the brain, the prevalent enzyme that converts T-4 to T-3 is type II iodothyronine deiodinase (DII). The present study was undertaken to determine wheth er a differential hypothalamic expression of type II deiodinase may ex ist in fasted rats and in animals that are hypothyroid due to the fail ure of the thyroid gland. Using in situ hybridization, we assessed typ e II deiodinase messenger RNA (mRNA) levels in the hypothalamus of rat s that were control euthyroid, hyperthyroid (T-4), hypothyroid induced by propylthiouracil (PTU), and fasted. A group of fasted rats also re ceived exogenous T-4. DII mRNA was detected around the third ventricle , including the ependymal layer and adjacent periventricular regions a s well as in the arcuate nucleus and the external layer of the median eminence. Quantitative in situ hybridization analysis demonstrated tha t PTU treatment and short term fasting resulted in significant elevati ons in DII messenger levels compared with those in euthyroid controls. Three weeks of PTU administration induced a consistent decline in cir culating T-3 and undetectable T-4 levels, whereas 3 days of fasting re sulted in only a 50% fall in the concentration of serum thyroid hormon es. Interestingly, however, the expression of the DII mRNA was more th an a-fold higher in fasted animals compared with the values in PTU-tre ated rats. Furthermore, although T-4 administration repressed DII mRNA expression in euthyroid animals, the same treatment had no effect on the fasting-induced elevations of DII message. To assess whether DII e nzymatic activity is also affected during food deprivation, hypothalam i were dissected out, and DII activity was measured in control euthyro id, fasted, and fasted plus T-4-treated rats. To determine whether com parable changes in plasma thyroid hormone levels induced by fasting an d PTU treatment could have affected DII enzymatic activity in a simila r manner, animals were injected ip with PTU for 5 days to decrease pla sma thyroid hormones to levels similar to those caused by fasting. DII enzymatic assay showed a significant increase in DII activity in fast ed and fasted plus T-4-treated animals compared with those in euthyroi d controls and PTU-treated rats. No significant changes were found in PTU-treated rats compared with euthyroid animals. These data indicate that during short term fasting, a signal of nonthyroid origin underlie s the robust elevation of DII production and activity in the hypothala mus. Thus, we propose that during the initial phase of food deprivatio n, an increased negative thyroid feedback exists on the hypothalamus d ue to locally formed T-3. This local hyperthyroidism may, in turn, ind uce the suppression of TRH under these conditions.