Feedback regulation of thyrotropin-releasing hormone (TRH): mechanisms for the non-thyroidal illness syndrome.
Regulation of the hypothalamic-pituitary-thyroid (HPT) axis is dependent upon the secretion of thyrotropin-releasing hormone (TRH), a tripeptide originating in the hypothalamic paraventricular nucleus (PVN). These so-called hypophysiotropic neurons are under feedback inhibition by circulating levels of thyroid hormone, mediated through interactions with the beta2 thyroid hormone receptor (TRbeta2) and competition with the phosphorylated form of cyclic adenosine 5'-monophosphate response element binding protein (CREB) for a multifunctional binding site in the TRH gene. The non-thyroidal illness syndrome, characterized by low circulating thyroid hormone levels yet suppression of TRH gene expression in hypophysiotropic neurons, is due to alteration in the regulatory factors that modulate TRH gene expression to result in central hypothyroidism. These factors include alpha melanocyte-stimulating hormone (alphaMSH) and cocaine- and amphetamine-regulated transcript (CART), and agouti-related protein (AGRP) and neuropeptide Y (NPY), substances co-produced by distinct populations of leptin-responsive neurons in the hypothalamic arcuate nucleus. Through monosynaptic projections from arcuate nucleus neurons to hypophysiotropic TRH neurons, these factors contribute to suppression of HPT axis during fasting and starvation by exerting opposing actions on the TRH gene, altering the sensitivity for feedback inhibition by thyroid hormone. In contrast, central hypothyroidism associated with infection may be due to upregulation of type 2 deiodinase activity in tanycytes, specialized glial cells that line the infralateral walls and floor of the third ventricle. Through tanycyte-cerebrospinal fluid, -vascular or -neuronal associations, these cells may lead to inhibition of TRH gene expression in hypophysiotropic neurons by increasing local triiodothyronine production.
Lechan
R M
RM
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center and Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. rlechan@tufts-nemc.org
Fekete
C
C
D000818:Animals; D005246:Feedback; D006801:Humans; D007031:Hypothalamus / Q000033:anatomy & histology / Q000503:physiopathology; D007239:Infections / Q000503:physiopathology; D009474:Neurons / Q000502:physiology; D010904:Pituitary Gland, Posterior / Q000503:physiopathology; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D013961:Thyroid Gland / Q000033:anatomy & histology / Q000503:physiopathology*; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*
D011988:Receptors, Thyroid Hormone; D013973:Thyrotropin-Releasing Hormone