Interaction between thyroid hormones and circadian clock genes: consequences on anterior pituitary hormones secretion

Abstract

The anterior pituitary gland occupies a central position in the hypothalamus-pituitary-gland/tissues axes, regulating the synthesis/secretion of hormones related to reproduction, growth and metabolism. The plasma concentration of pituitary hormones fluctuates over 24 h. The generation/maintenance of circadian rhythmicity, central or peripheral, is determined by a set of genes called clock genes involved in an auto-regulatory transcriptional-(post)translational-based feedback loop within a 24 h period and in the regulation of several genes related to rhythmicity, hormonal response, growth regulation and cell death in anterior pituitary cells. It is known that GH, TSHB and LH secretions are altered in hypo and hyperthyroidism and that the triiodothyronine (T3) availability in peripheral tissues is controlled by the activity of Deiodinase 2, which in turn, presents a circadian rhythm. All these data suggest that the anterior pituitary cells present an intrinsic circadian clock and that clock genes expression might be altered in different thyroidal states, direct or indirectly, altering the synthesis/secretion pattern of anterior pituitary hormones. To investigate this hypothesis, an evaluation of the synthesis/secretion of pituitary hormones and the expression of clock genes will be performed in two models: a) the double knockout mice for Cry1 and 2 (global disrupted clock) and b) the specific Tshb-cre mice crossed with floxed Bmal1 (cell-specific clock disruption). Both models will be subjected to hypo and hyperthyroidism in adult age. In these conditions, the clock genes mRNA content in pituitary will be assayed by RT-qPCR, the circadian secretion of pituitary hormones (every 3h for 24h) will be evaluated using ELISA assay, the distribution of BMAL1 in pituitary cell types by immunohistochemistry and the locomotor-activity rhythm by running wheel performance analysis. Thus, the goal of this project is to correlate the alterations observed in the different hypothalamic-pituitary-gland axes during the hypo- and hyperthyroidism with the major role of the circadian clock within pituitary gland. (AU)