Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats

Abstract

Nemoto T, Iwasaki-Sekino A, Yamauchi N, Shibasaki T. Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats. Am J Physiol Endocrinol Metab 299: E567-E575, 2010. First published July 27, 2010; doi:10.1152/ajpendo.00163.2010.-We have previously shown that urocortin 2 (Ucn 2), a member of the corticotropinreleasing factor (CRF) peptide family that binds to CRF type 2 receptor, is expressed in proopiomelanocortin (POMC) cells of rat pituitary and that its secretion and expression are increased by CRF in both the anterior and intermediate lobes and suppressed by glucocorticoids in the anterior lobe. We have also shown that Ucn 2 secreted by POMC cells acts on gonadotrophs expressing CRF type 2 receptors and inhibits the expression and secretion of gonadotropins. In the present study, we examined whether pituitary Ucn 2 is involved in stress-induced inhibition of gonadotropin secretion. A 90-min period of immobilization stress increased POMC mRNA expression without influencing Ucn 2 mRNA expression and suppressed luteinizing hormone (LH) ␤-subunit mRNA expression in the anterior lobe and plasma LH levels, while it increased both POMC and Ucn 2 mRNA expression in the intermediate lobe of the pituitary. Pretreatment with anti-CRF IgG blocked immobilization-induced increases in plasma ACTH and corticosterone and in POMC mRNA expression in both pituitary lobes and Ucn 2 mRNA expression in the intermediate pituitary. It also blocked immobilization-induced suppression of plasma LH and LH ␤-subunit mRNA expression. Pretreatment with anti-Ucn 2 IgG blocked immobilization-induced suppression of plasma LH and LH ␤-subunit expression without affecting immobilization-induced ACTH and corticosterone release and POMC or Ucn 2 mRNA expression. These results suggest that CRF suppresses the secretion and expression of LH probably through pituitary Ucn 2 in stress. luteinizing hormone; corticotropin-releasing factor; pituitary STRESS INHIBITS REPRODUCTIVE function (12,13,23). The hormones composing the hypothalamic-pituitary-adrenal (HPA) axis such as corticotropin-releasing factor (CRF), adrenocorticotropin (ACTH), ␤-endorphin, and corticosteroids reportedly play important roles in the suppressive influence of stress on reproductive function (41-43). CRF is a key stress mediator in the endocrine system, autonomic nervous system, emotion, and behavior (4,19,46). The various actions of CRF are mediated through two subtypes of CRF receptors (CRF-R), CRF-R1 and CRF-R2. CRF binds with a higher affinity to CRF-R1 than to CRF-R2 (4, 18). Urocortin 2 (Ucn 2) is a CRF peptide family and shows higher affinities to both CRF-R1 and CRF-R2 compared with CRF, in particular to CRF-R2 (40). Hypothalamic CRF inhibits gonadotropin-releasing hormone (GnRH) neuron activity either directly or indirectly through ␤-endorphin in the arcuate nucleus (42, 43). Intracerebroventricular infusion of CRF in the third ventricle inhibits the estrous cycle and ovulation and reduces immunoreactive GnRH s...

Estrogens downregulate urocortin 2 expression in rat uterus

“…Others and we previously demonstrated that Ucn2 is expressed in both the brain and peripheral tissues, including the lung, adrenal, uterus, ovary, and testis (Hsu & Hsueh 2001, Yamauchi et al 2005, Lee et al 2011. It has been reported that expression of Ucn2 mRNA in various tissues is controlled by stress, inflammation, and hypoxia (Tanaka et al 2003, Tao et al 2006, Chang et al 2007, Buhler et al 2009, Imperatore et al 2010, Nemoto et al 2010 and that factors involved in the regulation of Ucn2 mRNA expression are CRF, glucocorticoids, and endotoxins (Chen et al 2003(Chen et al , 2004mechanisms of Ucn2 expression in reproductive organs are not well understood.…”

Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary

“…Twenty male rats were administrated antiserum IgG to Ucn2 or normal rabbit serum (NRS) IgG (1 mg/kg body wt ip) dissolved in 1 ml normal saline. Two hours later, they were exposed to 90 min of immobilization stress (21). Rats were then killed immediately, and their trunk blood and pituitaries were collected.…”

“…Twenty male rats (7 wk old) were wrapped in a flexible wire mesh and kept for 90 min between 1300 and 1500 in an isolated room (1,21). Rats were killed in the adjacent room immediately after immobilization, and their pituitaries were collected for RNA expression analysis.…”

“…A possible explanation for the inconsistency of effects between Ucn2 and its blockades on LH ␤-subunit mRNA expression is proposed; the expression level of LH ␤-subunit mRNA is already suppressed by endogenous Ucn2 secreted by POMC cells into the culture medium, and exogenous Ucn2 could not induce further suppression of LH ␤-subunit mRNA expression (6). Furthermore, we have shown that anti-Ucn2 IgG partially blocks immobilization-induced suppression of LH secretion and LH ␤-subunit mRNA expression (21). Considered together, these findings suggest that pituitary Ucn2 inhibits LH secretion and LH ␤-subunit mRNA expression and is involved in immobilization-induced suppression of reproductive function, although the details of the mechanism remain unclear.…”

Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats

“…Anterior pituitary cells were cultured as described previously (Nemoto et al 2009(Nemoto et al , 2010. Cells were allowed to attach to the plating surfaces at 37 8C in a humidified 5% CO 2 -95% air incubator for 4 days.…”