Biomedical subjects

C J Small

Publications and source records attributed to C J Small.

At least 37 records · Page 2Linked to original sources

PubMed2002

Appetite control and reproduction: leptin and beyond.

It is now recognized that appropriate regulation of reproduction, energy intake, and energy expenditure, and thus maintenance of body weight and fertility, relies on complex hypothalamic neurocircuitry. Feeding and reproductive function are closely linked. During times of undernourishment and falling body fat the reproductive axis is down-regulated. Circulating factors and hypothalamic circuits coordinate these responses. Leptin has been described to be an important peripheral signal that indicates body fat stores to the hypothalamus and thus links nutrition and reproduction. Leptin acts by altering neuropeptide circuits in the hypothalamus, which alter gonadotropin-releasing hormone release and food intake. The importance of key neuropeptide systems identified in rodents is now being established in man. Notably mutations in the melanocortin MC4 receptor are found in up to 4% of the morbidly obese, and in a proportion of patients with anorexia nervosa mutations have been identified in the agouti-related peptide gene (AgRP), which codes for an endogenous antagonist of this receptor. Intranasal administration of a melanocortin fragment known to activate the MC4 receptor decreases adiposity in humans. The melanocortin system has been shown to influence the reproductive axis in rodents. However, the role of the melanocortin system in the control of reproduction in humans remains to be established. Since the discovery of leptin, attention has also been focused on peripheral signals that regulate reproduction, food intake, and energy expenditure, either directly or via feedback on hypothalamic circuits. Notable new discoveries in this area include the gastric hormone ghrelin. Circulating ghrelin stimulates food intake in rodents and humans, although an influence on the reproductive axis is yet to be reported.

Agouti-Related Protein↗

PubMed2002

Hypothalamic actions of neuromedin U.

The central nervous system and gut peptide neuromedin U (NMU) inhibits feeding after intracerebroventricular injection. This study explored the hypothalamic actions of NMU on feeding and the hypothalamo-pituitary-adrenal axis. Intraparaventricular nucleus (intra-PVN) NMU dose-dependently inhibited food intake, with a minimum effective dose of 0.1 nmol and a robust effect at 0.3 nmol. Feeding inhibition was mapped by NMU injection into eight hypothalamic areas. NMU (0.3 nmol) inhibited food intake in the PVN (0-1 h, 59 +/- 6.9% of the control value; P < 0.001) and arcuate nucleus (0-1 h, 76 +/- 10.4% of the control value; P < 0.05). Intra-PVN NMU markedly increased grooming and locomotor behavior and dose-dependently increased plasma ACTH (0.3 nmol NMU, 24.8 +/- 1.9 pg/ml; saline, 11.4 +/- 1.0; P < 0.001) and corticosterone (0.3 nmol NMU, 275.4 +/- 40.5 ng/ml; saline, 129.4 +/- 25.0; P < 0.01). Using hypothalamic explants in vitro, NMU stimulated CRH (100 nM NMU, 5.9 +/- 0.95 pmol/explant; basal, 3.8 +/- 0.39; P < 0.01) and arginine vasopressin release (100 nM NMU, 124.5 +/- 21.8 fmol/explant; basal, 74.5 +/- 7.6; P < 0.01). Leptin stimulated NMU release (141.9 +/- 20.4 fmol/explant; basal, 92.9 +/- 9.4; P < 0.01). Thus, we describe a novel role for NMU in the PVN to stimulate the hypothalamo-pituitary-adrenal axis and locomotor and grooming behavior and to inhibit feeding.

Adrenal Glands↗

PubMed2001

Actions of cocaine- and amphetamine-regulated transcript (CART) peptide on regulation of appetite and hypothalamo-pituitary axes in vitro and in vivo in male rats.

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.

Animals↗

PubMed2001

The in vitro role of tumour necrosis factor-alpha and interleukin-6 in the hypothalamic-pituitary gonadal axis.

The adipocyte derived hormone leptin has been implicated as an important nutritional signal to the reproductive system, but the role of other adipocyte related cytokines is not clear. Tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 are present in adipose tissue and released into the circulation where plasma levels correlate positively with body mass index and body fat mass. These cytokines could play a role in signalling nutritional status to the hypothalamic-pituitary-gonadal axis. We investigated the effects of TNF-alpha and IL-6 on basal and luteinizing hormone releasing hormone (LHRH) stimulated luteineizing hormone (LH) release from cultured anterior pituitary cells, harvested from either proestrus female or male Wistar rats. We examined the effects of TNF-alpha and IL-6 on LHRH release from hypothalamic explants harvested from proestrus female and male rats in vitro. IL-6 significantly suppressed LHRH stimulated LH release from male dispersed pituitaries throughout the dose range, but did not influence basal LH release. IL-6 had no effect on basal or LHRH stimulated LH release in dispersed pituitaries from proestrus females. By contrast, TNF-alpha significantly suppressed LHRH stimulated LH release in dispersed pituitaries from proestrus female rats in a dose responsive manner, but did not influence basal LH release. TNF-alpha had no effect on basal or LHRH stimulated LH release in dispersed pituitaries from male rats. TNF-alpha and IL-6 had no effect on LHRH release from male hypothalamic explants in vitro. TNF-alpha and IL-6 had no effect on LHRH release from proestrus female hypothalamic explants in vitro. TNF-alpha and IL-6 have differential effects in dispersed pituitaries harvested from males and proestrus female rats. TNF-alpha and IL-6 may be important in mediating some of the nutritional effects on the reproductive axis by acting at the level of the anterior pituitary rather than the hypothalamus.

Adipose Tissue↗

PubMed2001

The central effects of orexin-A in the hypothalamic-pituitary-adrenal axis in vivo and in vitro in male rats.

Orexin-A is synthesized in the posterolateral hypothalamus and immunoreactive fibres project to many central nervous system structures, including the paraventricular nucleus, which is rich in corticotropin releasing factor (CRF) neurones and neuropeptide Y (NPY) innervation. We investigated the central effects of orexin-A on the hypothalamic-pituitary-adrenal (HPA) axis by measuring plasma concentrations of corticosterone and adrenocorticotropic hormone (ACTH) in vivo. We explored the potential neuropeptide pathways involved by investigating the effects of orexin-A on CRF, NPY, arginine vasopressin (AVP) and noradrenaline release from hypothalamic explants in vitro. Intracerebroventricular (i.c.v.) injection of orexin-A (3 nmol) in male rats stimulated increases in plasma concentrations of corticosterone between 10 and 40 min after injection, and of plasma ACTH at 20 and 90 min after injection. Orexin-A significantly stimulated CRF and NPY release from hypothalamic explants in vitro. Orexin-A did not stimulate CRF release in the presence of the selective NPY Y1 receptor antagonist, BIBP3226. BIBP3226 alone did not alter CRF release from hypothalamic explants. Orexin-A had no effect in vitro on the release of other neuropeptides, AVP and noradrenaline, involved in the central regulation of the HPA axis. These results suggest that orexin-A is involved in activation of the HPA axis, and that these effects could be mediated via the release of NPY.

Adrenal Glands↗

PubMed2001

PRL-releasing peptide inhibits food intake in male rats via the dorsomedial hypothalamic nucleus and not the paraventricular hypothalamic nucleus.

PRL-releasing peptide inhibits food intake after intracerebroventricular injection. PRL-releasing peptide immunoreactivity is found in several hypothalamic nuclei involved in feeding, with highest levels in the paraventricular and dorsomedial hypothalamic nuclei. The aim of this study was to examine the effect of PRL-releasing peptide on food intake after administration into these nuclei. Paraventricular nucleus injection of PRL-releasing peptide did not alter food intake. Dorsomedial hypothalamic nucleus injection of PRL-releasing peptide decreased 1 h food intake [PRL-releasing peptide (1 nmol) 83.4 +/- 6.1% saline all; P < 0.05]; and continued until 8 h postinjection [PRL-releasing peptide (1 nmol) 89.2 +/- 4.1% saline; P < 0.05]. To investigate the mechanism of this inhibition of food intake, we examined PRL-releasing peptide's effect on neuropeptide release from hypothalamic explants. alpha MSH release was increased [PRL-releasing peptide (100 nmol), 5.4 +/- 1.6 pmol/explant; change vs. basal, P < 0.01], whereas agouti-related protein release was unchanged. The release of cocaine- and amphetamine-regulated transcript was inhibited [PRL-releasing peptide (100 nmol), -33.5 +/- 12.6 pmol/explant; change vs. basal, P < 0.01]. PRL-releasing peptide dose-dependently increased neurotensin release [PRL-releasing peptide (1 nmol), 3.7 +/- 2.6 pmol/explant; change vs. basal, P = NS; PRL-releasing peptide (10 nmol), 7.2 +/- 2.7 pmol/explant; change vs. basal, P < 0.01; PRL-releasing peptide (100 nmol), 36.8 +/- 5.4 pmol/explant; change vs. basal, P < 0.001]. Our data suggest that the dorsomedial hypothalamic nucleus is important in the inhibitory effect of PRL-releasing peptide on food intake and that PRL-releasing peptide alters the release of several hypothalamic neuropeptides important in the control of food intake.

Animals↗

PubMed2001

Oxyntomodulin inhibits food intake in the rat.

Oxyntomodulin is derived from proglucagon processing in the intestine and the central nervous system. To date, no role in the central nervous system has been demonstrated. We report here that oxyntomodulin inhibits refeeding when injected intracerebroventricularly and into the hypothalamic paraventricular nucleus of 24-h fasted rats [intracerebroventricularly and into the paraventricular nucleus, 1 h, oxyntomodulin (1 nmol), 3.1 +/- 0.5 g; saline, 6.2 +/- 0.4 g; P < 0.005]. In addition, oxyntomodulin inhibits food intake in nonfasted rats injected at the onset of the dark phase (intracerebroventricularly, 1 h: oxyntomodulin, 3 nmol, 1.1 +/- 0.19 g vs. saline, 2.3 +/- 0.2 g; P < 0.05). This effect of oxyntomodulin on feeding is of a similar time course and magnitude as that of an equimolar dose of glucagon-like peptide-1. Other proglucagon-derived products investigated [glucagon, glicentin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol), and spacer peptide-1 (intracerebroventricularly and into the paraventricular nucleus, 3 nmol)] had no effect on feeding at any time point examined. The anorectic effect of oxyntomodulin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol) was blocked when it was coadministered with the glucagon-like peptide-1 receptor antagonist, exendin-(9-39) (intracerebroventricularly, 100 nmol; into the paraventricular nucleus, 10 nmol). However, oxyntomodulin has a lower affinity for the glucagon-like peptide-1 receptor compared with glucagon-like peptide-1 (IC(50): oxyntomodulin, 8.2 nM; glucagon-like peptide-1, 0.16 nM). One explanation for this is that there might be an oxyntomodulin receptor to which exendin-(9-39) can also bind and act as an antagonist.

Animals↗

PubMed2001

Orexin A interactions in the hypothalamo-pituitary gonadal axis.

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.

Animals↗

PubMed2001

Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vivo and in vitro, via the hypothalamus and the pituitary.

Melanin-concentrating hormone (MCH) is an orexigenic peptide encoded in the pre-pro MCH gene. Targeted deletion of MCH causes a phenotype of hypophagia and leanness with an inappropriately high metabolic rate, suggesting a role for MCH in the control of energy balance. In order to further elucidate the mechanism by which MCH controls, energy expenditure, we have investigated the effects of MCH on the hypothalamic pituitary thyroid (HPT) axis. The thyroid axis is important in energy homeostasis and starvation leads to profound suppression of the HPT axis. MCH significantly reduces plasma TSH in vivo at 10 min (0.5 +/- 0.07 ng/ml, p < 0.05, n = 8) and 60 min (0.33 +/- 0.04 ng/ml, p < 0.01, n = 10) compared to saline (0.7 +/- 0.07 ng/ml and 0.69 +/- 0.07 ng/ml respectively) when administered intracerebroventricularly. Release of TRH form hypothalamic explants was significantly reduced in the presence of MCH production (7.1 +/- 0.99 fmol/explant to 2.3 +/- 0.4 fmol/explant p < 0.01, n = 18) and Neuropeptide EI (NEI) (8.47 +/- 1.28 fmol/explant to 4.6 +/- 1.13 p < 0.05, n = 16), a peptide, also encoded in the pre-pro-MCH gene. MCH was also shown to significantly reduce TRH stimulated TSH release from dispersed pituitary cell cultures (basal = 0.5 +/- 0.06 ng/ml, 100 nM TRH = 0.9 +/- 0.2 ng/ml, p < 0.05 0.1 nM MCH = 0.5 +/- 0.1 ng/ml, p < 0.05, 1 nM MCH = 0.3 +/- 0.03 ng/ml, p < 0.01, 10 nM MCH = 0.4 +/- 0.02 ng/ml, p < 0.01, 1000 nM MCH = 0.4 +/- 0.05 ng/ml, P < 0.01, n = 4), although basal release of TSH from these cultures was unaffected. These data suggest a possible role for MCH in the control of energy homeostasis via inhibition of the thyroid axis.

Animals↗

PubMed2001

Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei.

Cocaine- and amphetamine-regulated transcript is expressed in hypothalamic regions involved in the central control of food intake. Previous data have implicated cocaine- and amphetamine-regulated transcript as an anorectic peptide. We studied the effect of the active fragment of cocaine- and amphetamine-regulated transcript, cocaine- and amphetamine-regulated transcript-(55-102), on feeding when injected into discrete nuclei of the hypothalamus. Cocaine- and amphetamine-regulated transcript-(55-102) (0.04 nmol) elicited a delayed, but significant, increase in feeding in 24-h fasted rats after injection into the ventromedial nucleus (1-2 h, 261 +/- 60% of control; P < 0.05) and arcuate nucleus (1-2 h, 225 +/- 38% of control; P < 0.05) of the hypothalamus. Administration of a higher dose of cocaine- and amphetamine-regulated transcript-(55-102) (0.2 nmol) elicited a significant increase in feeding after injection into the ventromedial nucleus (1-2 h, 1253 +/- 179% of control; P < 0.001), arcuate nucleus (1-2 h, 265 +/- 43% of control; P < 0.05), paraventricular nucleus (2-4 h food intake, 186 +/- 29% of control; P < 0.05), lateral hypothalamic area (2-4 h, 280 +/- 34% of control; P < 0.001), anterior hypothalamic area (2-4 h, 252 +/- 42% of control; P < 0.01), dorsomedial nucleus (2-4 h, 368 +/- 29% of control;P < 0.001) and supraoptic nucleus (2-4 h, 212 +/- 34% of control; P < 0.05) of the hypothalamus. Administration of cocaine- and amphetamine-regulated transcript-(55-102) into the third ventricle of the hypothalamus resulted in an inhibition in feeding [0-4 h (0.4 nmol), 33 +/- 13% control; P < 0.001], but was associated with marked abnormalities in behavior, which may have interfered with feeding. These behavioral abnormalities were not observed after the administration of cocaine- and amphetamine-regulated transcript-(55-102) directly into the arcuate nucleus. These data suggest that cocaine- and amphetamine-regulated transcript may play an orexigenic role in the hypothalamic feeding circuitry.

Animals↗

PubMed2001

The actions of tuberoinfundibular peptide on the hypothalamo-pituitary axes.

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.

Animals↗

PubMed2001

Ghrelin causes hyperphagia and obesity in rats.

Ghrelin, a circulating growth hormone-releasing peptide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghrelin concentration was compared with that during fasting. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 +/- 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 +/- 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimulated food intake most markedly in the arcuate nucleus (Arc) (0-1 h food intake, 427 +/- 43% of control; P < 0.001 vs. control, P < 0.01 vs. all other nuclei), which is potentially accessible to the circulation. After chronic systemic or intracerebroventricular (ICV) administration of ghrelin for 7 days, cumulative food intake was increased (intraperitoneal ghrelin 13.6 +/- 3.4 g greater than saline-treated, P < 0.01; ICV ghrelin 19.6 +/- 5.5 g greater than saline-treated, P < 0.05). This was associated with excess weight gain (intraperitoneal ghrelin 21.7 +/- 1.4 g vs. saline 10.6 +/- 1.9 g, P < 0.001; ICV ghrelin 15.3 +/- 4.3 g vs. saline 2.2 +/- 3.8 g, P < 0.05) and adiposity. These data provide evidence that ghrelin is important in long-term control of food intake and body weight and that circulating ghrelin at fasting concentrations may stimulate food intake.

Animals↗

PubMed2001

Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals.

The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 +/- 6 [saline] vs. 319 +/- 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 +/- 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 +/- 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3.5 +/- 0.3 [saline] vs. 2.7 +/- 0.4 [AGRP ad libitum fed] vs. 2.1 +/- 0.2 ng/ml [AGRP pair-fed]; P < 0.01). This study demonstrates that independent of its orexigenic effects, chronic AGRP treatment decreased BAT UCP-1, suppressed plasma TSH, and increased fat mass and plasma leptin, suggesting that it may play a role in energy expenditure.

Adipose Tissue↗

PubMed2000

The effects of ciliary neurotrophic factor on the hypothalamo-pituitary gonadal axis in vitro in female rats.

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.

Animals↗

PubMed2000

The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin.

Prolonged fasting is associated with a downregulation of the hypothalamo-pituitary thyroid (H-P-T) axis, which is reversed by administration of leptin. The hypothalamic melanocortin system regulates energy balance and mediates a number of central effects of leptin. In this study, we show that hypothalamic melanocortins can stimulate the thyroid axis and that their antagonist, agouti-related peptide (Agrp), can inhibit it. Intracerebroventricular (ICV) administration of Agrp (83-132) decreased plasma thyroid stimulating hormone (TSH) in fed male rats. Intraparaventricular nuclear administration of Agrp (83-132) produced a long-lasting suppression of plasma TSH, and plasma T4. ICV administration of a stable alpha-MSH analogue increased plasma TSH in 24-hour-fasted rats. In vitro, alpha-MSH increased thyrotropin releasing hormone (TRH) release from hypothalamic explants. Agrp (83-132) alone caused no change in TRH release but antagonized the effect of alpha-MSH on TRH release. Leptin increased TRH release from hypothalami harvested from 48-hour-fasted rats. Agrp (83-132) blocked this effect. These data suggest a role for the hypothalamic melanocortin system in the fasting-induced suppression of the H-P-T axis.

Agouti-Related Protein↗

PubMed2000

The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

Adrenocorticotropic Hormone↗

PubMed2000

Characterization of human and rat glucagon-like peptide-1 receptors in the neurointermediate lobe: lack of coupling to either stimulation or inhibition of adenylyl cyclase.

Glucagon-like peptide-1 (GLP-1) has been shown to bind to the posterior pituitary in the rat. We examined GLP-1 binding sites in human postmortem and rat pituitaries. Dense [125I]GLP-1 binding was seen in both human and rat posterior pituitary. In rat neurointermediate lobe membranes the binding site showed a Kd of 0.2 +/- 0.01 nM and a binding capacity of 600 +/- 33 fmol/mg protein (n = 3). In human pituitary membranes the binding site showed a Kd of 0.82 +/-0.05 nM and a binding capacity of 680 +/- 93 fmol/mg protein (n = 3). Chemical cross-linking showed a relative mol wt for the receptor-ligand complex of 73,100 +/- 1,400 (n = 3) in man and 59,300 +/- 900 (n = 3) in rat. GLP-1 (1 microM) failed to increase cAMP levels measured in rat neurointermediate lobes, whereas pituitary adenylate cyclase-activating polypeptide (100 nM) increased cAMP from a basal level of 14 +/-1 to 80 +/- 4 pmol/neurointermediate lobe 15 min (n = 5; P < 0.01). GLP-1 (up to 1 microM) did not affect the pituitary adenylate cyclase-activating polypeptide-stimulated cAMP levels. GLP-1 (up to 1 microM) also did not stimulate release of vasopressin or oxytocin from isolated rat neurointermediate lobes. The posterior pituitary shows the highest density of GLP-1-binding sites yet seen, but their function and signal transduction mechanism remain unknown.

Adenylyl Cyclase Inhibitors↗

PubMed2000

Prolactin releasing peptide (PrRP) stimulates luteinizing hormone (LH) and follicle stimulating hormone (FSH) via a hypothalamic mechanism in male rats.

Prolactin releasing peptide (PrRP) was originally isolated as an endogenous hypothalamic ligand for the hGR3 orphan receptor. It has been shown to release prolactin from dispersed pituitaries harvested from lactating female rats and only at very high doses in cycling females. PrRP is reported to have no effect on prolactin production from dispersed pituitary cells harvested from males. The CNS distribution of this peptide suggested a role for PrRP in the control of the hypothalamo-pituitary axis. The aim of this study was to examine the actions of PrRP (1-31) on circulating pituitary hormones following intracerebroventricular (ICV) injection in male rats and to investigate the mechanism of PrRP's effect by measurement of hypothalamic releasing factors in vitro. In our experiments, PrRP (1-31) did not release LH, FSH, TSH, growth hormone or prolactin directly from dispersed male pituitary cells in vitro. We have shown for the first time that following ICV injection of PrRP (1-31) 5 nmol there was a highly significant simulation of plasma LH that began at 10 minutes and was maintained over the course of the experiment (at 60 minutes PrRP 5 nmol 2.2 +/- 0.2 vs. saline 0.5 +/- 0.1 ng/ml, p<0.001). Plasma FSH increased at 20 minutes following ICV injection (PrRP 5nmol 10.8 +/- 2.0 ng/ml vs. saline 5.1 +/- 0.5, p<0.01). Total plasma testosterone increased at 60 minutes post injection (PrRP 5nmol 9.2 +/- 1.6 vs. saline 3.5 +/- 0.6 nmol/l, p<0.01). There was no significant alteration in plasma prolactin levels. PrRP significantly increased the release of LHRH from hypothalamic explants in vitro (PrRP 100nmol/l 180.5 +/- 34.5% of the basal secretion, p<0.05). PrRP (100nmol/l) also increased the following hypothalamic peptides involved in the control of pituitary hormone release, vasoactive intestinal peptide (VIP) 188.1 +/- 24.6% and galanin 153.8 +/- 13.0% (both p<0.001 vs. basal secretion) but had no effect on orexin A secretion. These results suggest a role for PrRP in the control of gonadotrophin secretion acting via a hypothalamic mechanism involving the release of LHRH.

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