Effects of leptin administration on starvation-induced alterations in hepatic thyroid hormone metabolism in mice
Anita Boelen, Mieke Van Beeren, Xander Vos, Olga Surovtseva, Joan Kwakkel & Eric Fliers
Fasting induces profound metabolic changes in order to decrease energy expenditure and to conserve energy. One of the major adaptations is downregulation of the hypothalamuspituitarythyroid (HPT) axis, characterized by decreased serum thyroid hormone levels without an increase in serum TSH or in TRH expression in the hypothalamic paraventricular nucleus (PVN). Leptin has been proposed as a critical signal initiating the neuroendocrine response to fasting as it decreases dramatically during fasting, while the fasting-induced suppression of the HPT axis at the central level can be restored by leptin administration. It is, however, unknown to what extent leptin affects peripheral thyroid hormone metabolism in this setting.
The aim of this study was to evaluate the effect of leptin on starvation-induced alterations of peripheral thyroid hormone metabolism in mice. We therefore performed two experiments: 1) mice were fasted for 24 h while leptin was administered twice (at 0 and 8 h, 1 μg/g BW i.p.), 2) mice were fasted for 24 h and subsequently, leptin was given once (i.p.) at 24 h († at 28 and 32 h). All groups had appropriate controls. Liver thyroid hormone receptor (TR)β1, TRα1, TRα2, type 1deiodinase (D1) and type 3 deiodinase (D3) mRNA expression was measured by qPCR. Liver D3 activity was measured using HPLC and serum T3 and T4 levels were measured by RIA.
Starvation for 24 h decreased serum T3 and T4 levels and liver TRβ1 mRNA expression while liver TRα1 and TRα2 mRNA expression did not change. Liver D1 mRNA decreased only after 28 and 32 h starvation while liver D3 mRNA and activity increased upon 24 h starvation, indicating increased inactivation of thyroid hormone. The observed changes are in keeping with decreased thyroid hormone action in the liver during fasting. Leptin administration after 24 h fasting restored liver D3 expression at 28 and 32 h (mice continued fasting) while serum thyroid hormone levels and liver TRβ1 expression remained low. Liver D1 expression was not affected by leptin administration at any time point.
In conclusion, leptin plays a role in fasting-induced alterations in peripheral thyroid hormone metabolism by selectively affecting liver D3 mRNA expression and activity. The fasting-induced decrease in liver D1 expression, however, is not modulated by leptin.