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Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nm) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 +/- 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 mug, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 +/- 20, leptin, 135 +/- 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 +/- 39, leptin, 452 +/- 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 +/- 38; NMU IgG, 342 +/- 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation.

Recent studies of transgenic mice and humans have provided compelling evidence for the importance of the hypothalamic melanocortin system in the regulation of energy balance. Energy homeostasis is a balance between food intake (energy input) and energy expenditure. The melanocortin system regulates feeding via effects of the endogenous agonist, alpha-melanocyte stimulating hormone (alpha-MSH) and the endogenous antagonist agouti-related protein (AGRP) on melanocortin 3 and 4 receptors (MC3-Rs and MC4-Rs). It has been demonstrated that the melanocortin system interacts with the hypothalamo-pituitary-thyroid (HPT) axis. Thyroid hormones influence metabolism and hence energy expenditure. Therefore, an interaction between the HPT axis and the melanocortin system would allow control of both sides of the energy balance equation, by the regulation of both energy input and energy expenditure. Here we will discuss the evidence demonstrating interactions between the melanocortin system and the HPT axis.

Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 +/- 0.8 g; 0.3 nmol CGRP, 1.1 +/- 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP(8-37) (a CGRP(1) receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP(8-37) [CGRP(8-37) (10 nmol)/CGRP (0.3 nmol), 3.0 +/- 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nM) stimulated the release of alpha-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 +/- 19%, 148 +/- 10%, 158 +/- 17%, and 198 +/- 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 +/- 8% of control levels [CGRP mRNA (arbitrary units), 4.75 +/- 0.4; controls, 3.65 +/- 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is an agonist, and agouti-related protein (Agrp) an endogenous antagonist at the melanocortin 3 and 4 receptors which are found in the central nervous system (CNS). We have examined the effect of alpha-MSH and Agrp on the hypothalamo-pituitary-adrenal (HPA) axis in vitro and in vivo in male rats. Intraparaventricular nuclear (iPVN) injection of [Nle(4),D-Phe(7)]-alpha-MSH (NDP-MSH) (a long-acting alpha-MSH analogue) increased plasma adrenocorticotropic hormone (ACTH) (10 min post-injection: 25.0 +/- 3.9 vs. saline 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 174.1 +/- 14.2 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05). iPVN injection of Agrp(83-132) increased plasma ACTH (24.2 +/- 4.0 vs. saline 10.1 +/- 1.0 pg/ml, p < 0.01). The combination of NDP-MSH and Agrp(83-132) administered iPVN significantly increased plasma ACTH (10 min post-injection: 21.3 +/- 3.8 vs. 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 169.0 +/- 15.1 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05), but there was no additive effect. Hypothalamic explants treated with alpha-MSH (100 nM) resulted in a 159 +/- 23% increase in corticotropin-releasing hormone (CRH) release (p < 0.01) and 175 +/- 12% increase in arginine vasopressin (AVP) release (p < 0.001) compared to basal. Agrp(83-132) (100 nM) administered to hypothalamic explants resulted in a 161 +/- 20% increase in CRH (p < 0.01) and 174 +/- 13% increase in AVP release (p < 0.001) compared to basal. Hypothalamic explants treated with the combination of alpha-MSH and Agrp(83-132) (100 nM) resulted in a 179 +/- 31% increase in CRH release (p < 0.01) and 130 +/- 9% increase in AVP release (p < 0.01) compared to basal, but there was no additive effect. This is the first report that both alpha-MSH and Agrp(83-132) stimulate the HPA axis. The combination of alpha-MSH and Agrp(83-132) has no additive effect in vitro and in vivo in male rats. These results suggest that there may be another receptor independent of the known melanocortin receptors at which Agrp is acting., (Copyright 2002 S. Karger AG, Basel)

The distribution of orexin A-immunoreactive neurons and orexin type I receptors in the CNS suggests important roles in regulating the hypothalamo-pituitary gonadal (HPG) axis and sexual behaviors. We examined orexin A interactions in the HPG axis in vivo and in vitro. Orexin A stimulated LH-releasing hormone (LHRH) release in hypothalamic explants harvested from male rats (+133%) and from females at proestrus (+233%), with no effect at estrus or metestrus. Orexin A dose dependently inhibited LHRH-stimulated LH release in dispersed pituitaries from proestrous females only. A selective NPY1-receptor antagonist abolished in vitro release of LHRH by orexin A. Hyperestrogenization in female rats reduced orexin A content in hypothalamus (-28%), midbrain (-26%), medulla (-40%), thalamus (-36%), olfactory tubercles (-25%), and cortex (-35%), brain regions that are important in HPG control and sex-cycle specific behaviors. Orexin A content was lower in hypothalamus (-20%) and higher in midbrain (+40%), medulla (+31%), and thalamus (+33%) at late proestrus vs. other cycle stages. Orexin A release after administration of 56 mM KCl was significantly greater in hypothalamic explants harvested on the morning of proestrus than at estrus or metestrus, and orexin A release was stimulated by estradiol (E2) in explants from males. These results reveal important interactions for orexin A in the HPG axis.

Tuberoinfundibular peptide is a recently discovered agonist for the PTH receptor-2; the latter has a wide distribution including the external zone of the median eminence of the hypothalamus, suggesting a role in neuroendocrine function. We have investigated the effects of tuberoinfundibular peptide on the hypothalamo-pituitary axes in vitro and in vivo. Tuberoinfundibular peptide had effects on the hypothalamo-pituitary-adrenal axis with increased release of ACTH-releasing factor (tuberoinfundibular peptide 100 nM 4.4 +/- 0.6 pmol/explant vs. control 2.9 +/- 0.4 pmol/explant, P < 0.001) and increased release of arginine vasopressin (tuberoinfundibular peptide 100 nM 563.5 +/- 55.5 fmol/explant vs. control 73.4 +/- 9.6 fmol/explant, P < 0.01) from in vitro hypothalamic explants. Intracerebroventricular administration of tuberoinfundibular peptide and PTH((1-34)) resulted in elevated plasma ACTH at 10 min post injection (saline 13.5 +/- 2.1 pg/ml, tuberoinfundibular peptide 3 nmol 32.3 +/- 4.0 pg/ml; P < 0.01 to saline: PTH((1-34)) 10 nmol 28.9 +/- 3.2 pg/ml: P < 0.05 to saline). Tuberoinfundibular peptide also had both in vitro and in vivo effects on the hypothalamo-pituitary-gonadal axis with increased release of LH-releasing hormone (tuberoinfundibular peptide 100 nM 28.5 +/- 5.1 fmol/explant vs. control 19.3 +/- 2.5 fmol/explant, P < 0.05) from in vitro hypothalamic explants. Both intracerebroventricular and peripheral administration of tuberoinfundibular peptide had effects on the hypothalamo-pituitary-gonadal axis. Intracerebroventricular injection of tuberoinfundibular peptide increased plasma LH (tuberoinfundibular peptide 10 nmol 0.70 +/- 0.09 ng/ml vs. saline 0.42 +/- 0.04 ng/ml at 10 min, P < 0.05). Intraperitoneal administration of tuberoinfundibular peptide also increased plasma LH (tuberoinfundibular peptide 30 nmol 0.53 +/- 0.09 ng/ml vs. saline 0.21 +/- 0.04 ng/ml at 10 min, P < 0.05). In addition to these actions on the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes, an increased release of GH-releasing factor (GRF) from hypothalamic explants (tuberoinfundibular peptide 100 nM 770.9 +/- 90.7 pg/explant vs. control 657.8 +/- 77.7 pg/explant, P < 0.01) was observed. Overall, these data show the actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes and suggest that it may play a role in the control of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes.

Cocaine- and amphetamine-regulated transcript (CART) and CART peptide are abundant in hypothalamic nuclei controlling anterior pituitary function. Intracerebroventricular (ICV) injection of CART peptide results in neuronal activation in the paraventricular nucleus (PVN), rich in corticotrophin-releasing factor (CRH) and thyrotrophin-releasing factor (TRH) immunoreactive neurons. The aims of this study were three-fold. Firstly, to examine the effects of CART peptide on hypothalamic releasing factors in vitro, secondly, to examine the effect of ICV injection of CART peptide on plasma pituitary hormones and finally to examine the effect of PVN injection of CART peptide on food intake and circulating pituitary hormones. CART(55-102) (100 nM) peptide significantly stimulated the release of CRH, TRH and neuropeptide Y from hypothalamic explants but significantly reduced alpha melanocyte stimulating hormone release in vitro. Following ICV injection of 0.2 nmol CART(55-102), a dose which significantly reduces food intake, plasma prolactin (PRL), growth hormone (GH) and adrenocorticotrophin hormone (ACTH) and corticosterone increased significantly. Following PVN injection of CART(55-102), food intake was significantly reduced only at 0.2 and 0.6 nmol. However, PVN injection of 0.02 nmol CART(55-102) produced a significant increase in plasma ACTH. ICV injection of CART peptide significantly reduces food intake. Unlike many anorexigenic peptides, there is no increased sensitivity to PVN injection of CART(55-102). In contrast, both ICV and PVN injection of CART(55-102) significantly increased plasma ACTH and release of hypothalamic CRH is significantly increased by CART peptide in vitro. This suggests that CART peptide may play a role in the control of pituitary function and in particular the hypothalamo-pituitary adrenal axis.

Ciliary neurotrophic factor (CNTF) is a member of the neuropoietic family of cytokines. CNTF exerts its actions through activation of a receptor complex, which shows similarity of sequence, second messenger systems and distribution to the leptin receptor. Leptin has been demonstrated to exert profound effects on the hypothalamo-pituitary gonadal axis. This study examines the in vitro effects of CNTF on hypothalamic luteinizing hormone releasing hormone release (LHRH) and pituitary luteinizing hormone (LH) release compared to those of leptin in the female. We report that CNTF stimulates LHRH release from medial basal hypothalamic explants harvested from proestrous female rats and this effect is of similar magnitude to that seen with leptin. In contrast, CNTF suppresses LHRH-stimulated LH release from dispersed anterior pituitary cells harvested from proestrous female rats but has no effect on basal LH release. Leptin stimulates basal LH release but has no effect on LHRH-stimulated LH release. The suppressive effect of CNTF on LHRH-stimulated LH release has been confirmed in perifused anterior hemipituitaries. These results suggest a differential effect of CNTF on the hypothalamo-pituitary gonadal axis and a possible role in the modulation of pituitary gonadal function.