Changes in adrenal status affect hypothalamic thyrotropin-releasing hormone gene expression in parallel with corticotropin-releasing hormone.

Abstract

Glucocorticoids are well known to influence the secretion of TSH from the anterior pituitary gland, although it is uncertain whether its site of action is on the hypothalamus, pituitary, or both. To determine whether glucocorticoids can modulate the concentration of pro-TRH gene expression in hypothalamic hypophysiotropic neurons, we measured the content of pro-TRH messenger RNA (mRNA) in the paraventricular nucleus (PVN) of adrenalectomized and corticosterone- and dexamethasone-treated rats compared to that in control populations using in situ hybridization histochemistry. Adrenalectomy resulted in the expected increase in corticotropin-releasing hormone mRNA in the PVN and was accompanied by a parallel rise in pro-TRH mRNA (68.3%; P < 0.05). Conversely, corticosterone and dexamethasone both resulted in profound reduction in corticotropin-releasing hormone mRNA in the PVN and a parallel reduction in pro-TRH mRNA (43.2% and 73.2% respectively; P < 0.05). No significant differences were observed in pro-TRH mRNA in the lateral hypothalamus in any of the groups. These data suggest that glucocorticoids can influence the concentration of pro-TRH mRNA in a cell-specific manner and thereby could result in changes in the biosynthesis and release of TRH in hypophysiotropic neurons of the PVN.

Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways

“…Adrenalectomy in rats increases pro-TRH mRNA levels in the PVN, whereas administration of exogenous corticosterone or dexamethasone to rats has the opposite effect (Kakucska et al, 1995). Similar effects appear to be at play in humans, since people that had been treated with glucocorticoids until the time of death showed a significant decrease in TRH mRNA levels in the PVN compared to control subjects (Alkemade et al, 2005), and glucocorticoid excess suppresses the secretion of TSH in humans (Nicoloff et al, 1970).…”

“…Additionally, whereas acute or chronic ICV NPY administration induced pronounced hypercorticosteronemia and hyperinsulinemia, HS014 induced a modest rise in corticosteronemia only during the first hour after acute ICV injection. As glucocorticoids inhibit activity of the thyrotropic axis (Kakucska et al, 1995, Alkemade et al, 2005and Nicoloff et al, 1970, this finding may contribute to the observed differences in effects of NPY versus HS014 on plasma TSH and free T4 concentrations. Despite these patent dissimilarities in hormonal responses to central administration of NPY or the MC4 receptor antagonist HS014, both peptides resulted in marked and significant increases in adiposity and leptinemia after chronic infusion, even though pair feeding with vehicle-infused control animals prevented NPY-and HS014-induced hyperphagia.…”

“…Moreover, corticosterone and insulin status can have significant effects on thyroid hormone concentrations (Kakucska et al, 1995, Alkemade et al, 2005, Nicoloff et al, 1970, Gonzalez et al, 1980and Mitsuma and Nogimori, 1982. Therefore, in order to determine whether changes in insulin or corticosterone levels may have contributed to these changes in thyroid hormone concentrations, we investigated circulating insulin and corticosterone concentrations in NPYand HS014-injected rats.…”

“…Acute ICV NPY administration is known to modulate circulating concentrations of corticosterone and insulin (Sainsbury et al, 1996;Wisialowski et al, 2000), both of which -in addition to thyroid hormones -influence energy homoestasis. Moreover, corticosterone and insulin status can have significant effects on thyroid hormone concentrations (Kakucska et al, 1995;Alkemade et al, 2005;Nicoloff et al, 1970;Gonzalez et al, 1980;Mitsuma and Nogimori, 1982). Therefore, in order to determine whether changes in insulin or corticosterone levels may have contributed to these changes in thyroid hormone concentrations, we investigated circulating insulin and corticosterone concentrations in NPY-and uncoupling protein 3 (UCP-3) in this tissue was determined, since the expression and activity of UCP-3 is known to be regulated by thyroid function (Lanni et al, 2003;Flandin et al, 2009).…”

Expression Profiling Identifies the CRH/CRH-R1 System as a Modulator of Neurovascular Gene Activity

“…Different from the HPA axis, the HPT axis is inhibited in depressed patients (Musselman and Nemeroff, 1996). Glucocorticoids repress the HPT axis on the level of the hypothalamus by inhibiting thyrotropin-releasing hormone expression (Kakucska et al, 1995). Activation of the HPA axis has been associated with the decreased production of thyroid-stimulating hormone and inhibition of peripheral conversion of L-thyroxine (T4) to the biologically more active 3,5,3 0 -L-triiodothyronine (T3).…”