The Central Effects of Orexin‐A in the Hypothalamic‐Pituitary‐Adrenal Axis <i>In Vivo</i> and <i>In Vitro</i> in Male Rats

Russell, S. H.; Small, Caroline J.; Dakin, C. L.; Abbott, Caroline R.; Morgan, David; Ghatei, Mohammad A.; Bloom, Stephen R.

doi:10.1046/j.1365-2826.2001.00672.x

Cited by 127 publications

(83 citation statements)

References 51 publications

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“…This may serve to stimulate food intake. Also, an effect on plasma insulin has been confirmed by several approaches (25)(26)(27)(28); however, a strong link with glucagon secretion and glycemia is suggested by the present findings.…”

Section: Discussionsupporting

confidence: 50%

Glucose Regulates the Release of Orexin-A From the Endocrine Pancreas

2003

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Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about its release or functional significance. In this study, we show that depolarizing stimuli evoke the release of OXA from rat pancreatic islets in a calcium-dependent manner. Moreover, OXA release is stimulated by low glucose (2.8 mmol/l), similar to glucagon secretion, and inhibited by high glucose (16.7 mmol/l). Fasting increases plasma OXA, supporting the idea that orexin is released in response to hypoglycemia. Cells that secrete glucagon and insulin contain OXA and both cell types express orexin receptors. OXA increases glucagon secretion and decreases glucose-stimulated insulin release from isolated islets. OXA infusion increases plasma glucagon and glucose levels and decreases plasma insulin in fasted rats. We conclude that orexin-containing islet cells, like those in the brain and gut, are glucosensitive and part of a network of glucose "sensing" cells that becomes activated when blood glucose levels fall. OXA may modulate islet hormone secretion to maintain blood glucose levels during fasting. Diabetes 52: 111-117, 2003 O rexins (hypocretins) are novel neuropeptides that play a role in arousal and the regulation of energy balances (1-3). Orexin-A (OXA) and -B are 33-and 28-residue peptides, respectively, that are isolated from the rat hypothalamus and named for their ability to stimulate feeding when injected into the brain (2). Their common precursor, prepro-orexin, is expressed in a specific population of neurons in and around the lateral hypothalamic area (LHA) (2), a region classically implicated in the control of mammalian feeding behavior (4). The LHA contains glucosensitive neurons that are stimulated by falls in circulating glucose (5) and inhibited by prandial signals, such as the presence of food in the gut and/or a rise in portal glucose concentration (4). Previous studies have suggested that orexin neurons might correspond to this neuronal population, since orexin neurons are activated by hypoglycemia (6) and increased hypothalamic prepro-orexin mRNA levels are observed in response to fasting (1,7); however, glucosensitive neurons do not contain OXA (8). They are excited by the peptide (8), implying that orexin acts as a neuromodulator at glucosensitive cells, stimulating them under conditions of hunger.Glucosensitive neurons are also found in regions outside the hypothalamus, including the nucleus of the solitary tract (NTS) (9) and enteric nervous system (ENS) (10). The NTS relays visceral afferent signals to the LHA (8). Orexin fibers are distributed extensively in the NTS (11), and glucosensitive neurons are activated by the same conditions that stimulate orexin neurons in the LHA (6). The ENS participates in the regulation of food intake by directly sensing, integrating, and reg...

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Section: Discussionsupporting

confidence: 50%

Glucose Regulates the Release of Orexin-A From the Endocrine Pancreas

2003

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“…Then saline vehicle (2 l of isotonic saline) alone or vehicle containing 3.0 nmol of the OX 1R antagonist was injected via the indwelling lateral ventricular cannula. After 15 min, a second blood sample was collected as described above, and the second intracerebroventricular injection was completed, with all animals receiving 2 l of saline vehicle containing 3.0 nmol orexin A, a dose previously demonstrated to result in ACTH secretion in vivo (27,32). Additional blood samples were removed 30, 45, and 60 min after this second intracerebroventricular injection.…”

Section: Methodsmentioning

confidence: 99%

Hypocretin/orexin type 1 receptor in brain: role in cardiovascular control and the neuroendocrine response to immobilization stress

Samson

Bagley²,

Ferguson³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Samson WK, Bagley SL, Ferguson AV, White MM. Hypocretin/ orexin type 1 receptor in brain: role in cardiovascular control and the neuroendocrine response to immobilization stress. Am J Physiol Regul Integr Comp Physiol 292: R382-R387, 2007. First published August 10, 2006; doi:10.1152/ajpregu.00496.2006.-Hypocretin/orexin acts pharmacologically in the hypothalamus to stimulate stress hormone secretion at least in part by an action in the hypothalamic paraventricular nucleus, where the peptide's receptors have been localized. In addition, orexin acts in the brain to increase sympathetic tone and, therefore, mean arterial pressure and heart rate. We provide evidence for the role of endogenously produced hypocretin/orexin in the physiological response to immobilization stress and identify the receptor subtype responsible for this action of the peptide. Antagonism of the orexin type 1 receptor (OX 1R) in the brain prevented the ACTHstimulating effect of centrally administered hypocretin/orexin. Furthermore, pretreatment of animals with the OX 1R antagonist blocked the ACTH response to immobilization/restraint stress. The OX 1R antagonist did not, however, block the pharmacological or physiological release of prolactin in these two models. Antagonism of the OX 1R also blocked the central action of orexin to elevate mean arterial pressures and heart rates in conscious rats. These data suggest receptor subtype-selective responses to hypocretin/orexin and provide further evidence for the importance of endogenously produced peptide in the physiological control of stress hormone secretion. autonomic function; hypothalamus; adrenocorticotropin; prolactin IN ADDITION TO THE WELL-CHRONICLED pharmacological actions of the hypocretins/orexins on arousal state (6,23,29,36), the peptides (referred to here simply as orexins) exert a variety of behavioral (24), autonomic (7,15,34), and endocrine (1, 5, 7, 13, 22, 26 -28, 31, 32) actions mediated by the two characterized binding proteins, the orexin type 1 (OX 1 R) and the orexin type 2 (OX 2 R) receptors (29). Although orexin A and orexin B have many common pharmacological effects, some actions unique to one and not the other have been reported (7,36). Since orexin A binds with higher affinity to the OX 1 R than orexin B and both isoforms bind with apparently equal affinity to the OX 2 R, many investigators have narrowed their attention to the pharmacological effects of orexin A. Our original studies focused on endocrine, cardiovascular, and behavioral actions of orexin A in the hypothalamus and brain stem (7,32,37,38). We demonstrated direct neuronal actions of orexin in the hypothalamic paraventricular nucleus (PVN) and established that the action of exogenous orexin to stimulate the hypothalamic-pituitary-adrenal (HPA) axis was mediated at least in part by the release of corticotrophin-releasing hormone (CRH) (32). We have attempted to identify the receptor subtype responsible for the cardiovascular and neuroendocrine actions of these peptides and provide evidence for the i...

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“…Recent data show that OXs stimulate the expression of c-Fos in the paraventricular and arcuate nucleus, and peripheral administration of OX inhibited plasma thyrotrophin levels as well as in vitro hypothalamic thyrotrophin-releasing hormone release (12). Furthermore, OX-A and OX-B have been reported to modulate in vivo luteinizing hormone secretion (13,14), the hypothalamic -pituitary-adrenal axis (15) and in vitro GH secretion from porcine somatotrophs. Taken together these data suggest that OXs may play an important neuroendocrine role in anterior pituitary hormone secretion.…”

Section: Introductionmentioning

confidence: 99%

Orexin A suppresses in vivo GH secretion

Seoane

Tovar

Pérez

et al. 2004

European Journal of Endocrinology

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Background/aims: Orexins (OXs) are a newly described family of hypothalamic neuropeptides. Based on the distribution of OX neurons and their receptors in the brain, it has been postulated that they could play a role in the regulation of neuroendocrine function. GH secretion is markedly influenced by nutritional status and body weight. To investigate the role OX-A plays in the neuroregulation of GH secretion we have studied its effect on spontaneous GH secretion as well as GH responses to GHRH and ghrelin in freely moving rats. Finally, we also assessed the effect of OX-A on in vitro GH secretion. Methods: We administered OX-A (10 mg, i.c.v.) or vehicle (10 ml, i.c.v.) to freely moving rats. Spontaneous GH secretion was assessed over 6 h with blood samples taken every 15 min. Results: Administration of OX-A led to a decrease in spontaneous GH secretion in comparison with vehicle-treated rats, as assessed by mean GH levels (means^S.E.M. 4.2^1.7 ng/ml vs 9.4^2.2 ng/ml; P , 0.05), mean GH amplitude (3.6^0.5 ng/ml vs 20.8^5.6 ng/ml; P , 0.01) and area under the curve (848^379 ng/ml per 4 h vs 1957^458 ng/ml per 4 h; P , 0.05). In contrast, OX-A failed to modify in vivo GH responses to GHRH (10 mg/kg, i.v.) although it markedly blunted GH responses to ghrelin (40 mg/kg, i.v.) (mean peak GH levels: 331^71 ng/ml, vehicle, vs 43^11 ng/ml in OX-A-treated rats; P , 0.01). Finally, OX-A infusion (10

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The Central Effects of Orexin‐A in the Hypothalamic‐Pituitary‐Adrenal Axis In Vivo and In Vitro in Male Rats

Cited by 127 publications

References 51 publications

Glucose Regulates the Release of Orexin-A From the Endocrine Pancreas

Glucose Regulates the Release of Orexin-A From the Endocrine Pancreas

Hypocretin/orexin type 1 receptor in brain: role in cardiovascular control and the neuroendocrine response to immobilization stress

Orexin A suppresses in vivo GH secretion

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