Lower panel shows mean (plus standard error of the mean) levels of plasma TSH from 11 healthy young men. the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamicCpituitaryCthyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer. Introduction Thyroid hormones (precursor thyroxine T4 and active T3) are iodine containing compounds (iodothyronines) that are important for metabolism, heat production, proper development and differentiation of cells, and growth. Thyroid hormone synthesis and secretion are primarily regulated by TSH, which is derived from thyrotrophs located in the pars distalis in the anterior pituitary gland. TSH production and secretion are regulated by hypothalamic thyrotropin-releasing hormone (TRH). Circulating thyroid hormones control the synthesis and release of TRH and TSH from pars distalis as part of a classic negative-feedback loop called the hypothalamicCpituitaryCthyroid (HPT) axis1,2(FIG. 1). Open in a separate window Figure 1. HypothalamicCpituitaryCthyroid axis.Thyrotropin-releasing hormone (TRH) produced in the paraventricular nucleus (PVN) is secreted from the median eminence (ME) and transported to the pituitary via the hypothalamusChypophyseal portal system. TRH stimulates thyrotrophs to synthesize TSH in the pars distalis (PD) of the pituitary gland by upregulating mRNA levels of and and and gene expression by binding to some thyroid hormone response elements (sequences containing [A/G]GGT[G/C/A]A) on DNA as either a thyroid hormone receptor monomer, thyroid hormone receptor homodimer, and/or thyroid hormone receptor Cretinoid X receptor heterodimer in the promoter17 or the promoter18,19. In the presence or absence of thyroid hormone, the thyroid hormone receptor complexes regulate positively or negatively target gene expression by interacting with co-activators or co-repressors, respectively2. Circadian clocks and the master pacemaker Circadian clocks are highly conserved, endogenous time-keeping mechanisms present in virtually all living organisms. These clocks generate self-sustained oscillations with an approximately 24-h period, referred to as circadian rhythms3. Circadian rhythms modulate multiple physiological and behavioral processes, including sleepCwake cycles, hormone release and metabolism3. In mammals, these daily rhythms are primarily controlled by a population of neurons and astrocytes in the SCN, a paired structure located in the anterior hypothalamus above the optic chiasm20,21. The SCN, which is considered the master pacemaker, receives direct light IGFBP2 information from the retina through the retinohypothalamic tract (FIG. 2). Within the retina, intrinsically photosensitive ganglion cells are primarily responsible for circadian photoreception and the entrainment of the circadian pacemaker to environmental lightCdark cycles22,23, while classical rod and cone photoreceptors have only a supportive role (of note, more than 50% of people who are totally blind have normal entrainment of the circadian pacemaker because their intrinsically photosensitive retinal ganglion cells are intact). Most peripheral tissues and cells also contain self-sustained circadian oscillators that, under FRAX597 normal conditions, are synchronized with the SCN clock via neural and humoral pathways (that is, the autonomous nervous system and the 24-h rhythms of glucocorticoid and melatonin levels)3,24,25. Open in a separate window Figure 2. The hypothalamicCpituitaryCthyroid axis is under circadian regulation.The suprachiasmatic nuclei (SCN) receives light information from the retina through FRAX597 the retino-hypothalamic tract (RHT) and outputs the circadian signal to hypothalamic paraventricular nucleus (PVN) via neural connections20,21. In humans, thyrotropin-releasing hormone (TRH) and TSH secretions exhibit circadian rhythms34,35. Molecular mechanisms of the clockwork The 2017 Nobel Prize for Physiology or Medicine was awarded for the discovery of FRAX597 the molecular mechanism FRAX597 driving circadian rhythms26. Briefly, circadian rhythms are generated by transcriptionCtranslation feedback loops consisting of circadian clock genes and proteins27 (FIG. 3). The basic helix-loop-helix proteins circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like protein 1 (BMAL1) heterodimerize to form a transcriptional activator complex and activate the period (and genes through ROR elements but exert opposite effects on gene transcription, thus constituting a second important interlocking feedback loop30C32 (FIG. 3). Open in a separate window Figure 3. The circadian transcriptional and translational feedback loop machinery in mammals.In the core loop, the CLOCKCBMAL1 complex binds E-boxes in promoters of target genes.