EBM Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ueta, Y.
Right arrow Articles by Onaka, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ueta, Y.
Right arrow Articles by Onaka, T.
Experimental Biology and Medicine 228:1168-1174 (2003)
© 2003 Society for Experimental Biology and Medicine

OBESITY AND DIABETES: PATHOPHYSIOLOGICAL MECHANISMS AND THERAPEUTIC APPROACHES

Involvement of Novel Feeding-Related Peptides in Neuroendocrine Response to Stress

Yoichi Ueta*,1, Yumi Ozaki*, Jun Saito* and Tatsushi Onaka{dagger}

* Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan, and
{dagger} Department of Physiology, Jichi Medical School, Tochigi 329-0498, Japan

Abstract

Various stressors are known to cause eating disorders. However, it is not known in detail about the neural network and molecular mechanism that are involved in the stress-induced changes of feeding behavior in the central nervous system. Many novel feeding-regulated peptides such as orexins/hypocretins and ghrelin have been discovered since the discovery of leptin derived from adipocytes as a product of the ob gene. These novel peptides were identified as endogenous ligands of orphan G protein–coupled receptors. The accumulating evidence reveals that these peptides may be involved in stress responses via the central nervous system, as well as feeding behavior. The possible involvement of novel feeding-related peptides in neuroendocrine responses to stress is reviewed here.

Key Words: stress; peptides • G protein–coupled receptor • feeding

Experience has shown that stress is an inducing factor in transient loss of appetite or bulimia and chronic anorexia or overeating. Physiological reactions induced by stress include autonomic nervous responses such as elevated blood pressure, increase of heart rate, or decrease of gastrointestinal motion; endocrine responses such as activation of hypothalamopituitary adrenal (HPA) axis; emotional changes; and behavioral changes such as anorexia or bulimia.

Considerable studies have shown that classic neurotransmitters such as noradrenaline (NA), dopamine, and serotonin and stress hormones (corticotropin-releasing hormone [CRH]) have a contributory role. Recently, many peptides have been termed feeding-related peptides (Table IGo), and it is currently believed that these peptides, acting as feeding regulatory factors, contribute to various physiological stress reactions (Table IIGo).


View this table:
[in this window]
[in a new window]
  		Table I. Feeding Related Peptides
 

View this table:
[in this window]
[in a new window]
  		Table II. Contribution of Peptides to Physiological Stress Reactions
 
G protein–coupled receptors for unknown endogenous ligands are called "orphan receptors." The method for finding endogenous ligand of an orphan receptor is called "reverse pharmacology" because its sequence is reversed from the conventional one in which a physiologically active substance is discovered and its receptor is then identified. Recently a series of novel endogenous ligands have been discovered using this method. Among the feeding-related peptides we discuss, orexins/hypocretins (1), galanin-like peptide (GALP) (2), prolactin-releasing peptide (PrRP) (3), and ghrelin (4) are peptides discovered by this method.

Feeding Regulation by Neuropeptides

Our primitive "appetite" is controlled by a feeding center and a satiety center in the hypothalamus (5). The classic neurotransmitters such as NA, dopamine, and serotonin as well as many neuropeptides play a role in the neural network at these sites. The medial part of the arcuate nucleus (Arc) of the hypothalamus includes numerous neurons that contain neuropeptide Y (NPY), a peptide that powerfully evokes feeding. NPY and agouti-related protein (AgRP) are both present in these neurons. The lateral part of the Arc includes neurons containing pro-opiomelanocortin (POMC) and functions as a feeding inhibition system. The lateral hypothalamic area, known as the feeding center, includes separate neurons containing orexins/hypocretins and melanin-concentrating hormone, respectively, and functions as a feeding stimulation system. The ventromedial nucleus of the hypothalamus is not known to include many neurons containing neuropeptides, but glucose-receptive neurons demonstrate leptin receptors. The hypothalamic paraventricular nucleus (PVN) comprises magnocellular and parvocellular neurons; the magnocellular neurons produce arginine vasopressin and oxytocin (OXT), project their axons into the posterior pituitary, and secrete them into the systemic circulation. The parvocellular neurons in the PVN produce peptides such as CRH and thyrotropin-releasing hormone (TRH) and project their axons into the median eminence, and the peptides they secrete into the hypophysial portal bloodstream control secretion of anterior pituitary hormones. The parvocellular neurons in the PVN also include autonomic neurons with axons projecting to sympathetic preganglionic neurons of the intermediolateral spinal columns.

Feeding Regulation by Peripheral Peptides

After eating, digestive hormones such as cholecystokinin (CCK) transmit neural information regarding satiety to the hypothalamus. This information travels through the abdominal afferent vagus nerves distributed to the stomach and duodenum and is relayed through the nucleus of the tractus solitarius (NTS) and an intracranial neural circuit. Regulation of OXT secretion by CCK is a well-investigated response.

Leptin is produced by adipocytes and secreted into the systemic circulation. Leptin is believed to act on the satiety center in the hypothalamus to suppress feeding (6). Specifically, it functions as a feeding inhibition system by suppressing the neuronal activity of the Arc containing NPY and triggering accelerated activity of neurons containing POMC. It also promotes energy metabolism by stimulating the sympathetic nervous system.

Ghrelin is a peptide identified recently as an endogenous ligand of growth hormone secretagogue (GHS) analog receptors, and it is produced in large quantities by the stomach (7). Ghrelin in the systemic circulation not only brings about secretion of GH from the anterior pituitary, it also stimulates neuronal activity of the Arc containing NPY/AgRP and otherwise activates the feeding center in the hypothalamus.

Stress Responses and Feeding-Related Peptides

CRH and Urocortin.
The center of the physiological endocrine response to stress is the HPA axis. CRH produced in the PVN triggers secretion of ACTH from the anterior pituitary, and ACTH released into the systemic circulation causes secretion of adrenocortical hormones (glucocorticoids) from the adrenal cortex. The fact that central administration of CRH causes various stress-induced stress responses in animal experiments indicates that CRH is a stress hormone in the central nervous system (CNS). Intracerebroventricular administration of CRH in rats also inhibits feeding behavior (8). There are two types of CRH receptors, termed type 1 receptors (CRHR-1) and type 2 receptors (CRHR-2). Endogenous ligands with high affinity for the CRHR-1 and CRHR-2 receptors have been investigated, and peptides identified as demonstrating high affinity to CRHR-2 receptors are urocortin (9), urocortin II (10), (stresscopin-related peptide) (11), and urocortin III (12) (stresscopin) (11). Urocortins II and III demonstrate more selective high affinity to CRHR-2 receptors than urocortin. Recent studies about CRH receptor knockout mice (13, 14) have shown that, in urocortin-induced feeding inhibition, the first half is mediated by CRHR-1 receptors, and the second half is mediated by CRHR-2 receptors. Urocortin II (stresscopin-related peptide) and urocortin III (stresscopin) have also been proven to have a feeding inhibition effect (10, 11).

Orexins/Hypocretins.
Orexin-A and -B were discovered as endogenous ligands of G protein–coupled receptors, and hypocretin-1 and -2 were identified through a cDNA library search by a completely separate group. These were identical genetic products (1, 15). Since the discovery of orexins, a great deal of feeding-related research has been carried out on the basis of the localization of orexin-containing neurons in the lateral hypothalamic area and its surrounding area, the lateral hypothalamic area being known as the feeding center. Intracerebroventricular administration of orexins in the rat and mouse (1, 16) stimulates feeding, and fasting causes increase of orexin mRNA levels (1). It has been also reported that dietary intake is decreased in orexin gene knockout mice (17). However, the effect of intracerebroventricular administration of orexins on feeding is short term and does not change 24-hr total dietary intake or body weight (18, 19). The effect of orexins on feeding is currently attributed to evocation by orexin-induced stimulation of NPY-producing neuron activity in the Arc, where the axons of orexin-producing neurons project (20–25). Many orexin-producing neurons express leptin receptors, and leptin may also regulate the activity of orexin-producing neurons (26, 27).

The parvocellular neurons in the PVN producing CRH have demonstrated abundant expression of the orexin type-2 receptor gene, as well as projection of axons from orexin-producing neurons (28). Intracerebroventricular administration of orexins in the rat has produced the expression of the c-fos gene in the parvocellular neurons of the PVN (28–30), secretion of ACTH (29), and elevation of plasma concentration of corticosterone (29–32). The reaction of the secretions of ACTH and corticosterone is completely eliminated by preadministration of the CRH antagonist, {alpha}-helical CRH9-41 (32). It is also attenuated by preadministration of NPY antagonists and anti-NPY antibodies (7, 33). Intracerebroventricular administration of orexins in conscious rats increases face-washing behavior, grooming behavior, and exploratory behavior, and these behaviors are inhibited significantly by preadministration of {alpha}-helical CRH9-41 (31, 34). Northern blot analysis has demonstrated an increase in the orexin mRNA due to restraint stress and cold stress (31). These results continue to show that the central orexin system is related to physiological stress responses.

Neuromedin U.
Neuromedin U (NMU), which is a 23-amino-acid neuropeptide, was discovered from the porcine spinal cord and other tissues (35–37). NMU is widely distributed in the peripheral organs and the CNS (38, 39). Peripheral administration of NMU causes elevation of blood pressure (35), alternation of ion transport (40), and regulation of the adrenocortical function (41). Intracerebroventricular administration of NMU suppresses food intake and heat production (42, 43).

Recent studies have demonstrated that NMU is an endogenous ligand of G protein–coupled receptors, NMU1R, and NMU2R (previously called as FM-3 and FM-4, respectively) (42, 44–45). NMU1R is expressed abundantly in the peripheral organs (42, 44–46), and the expression of NMU2R is mostly restricted to specific regions in the rat brain, in particular the PVN, the wall of the third ventricle in the hypothalamus, and the CA1 region of the hippocampus (42). Ozaki et al. demonstrated that intracerebroventricular administration of NMU caused activation of HPA axis and OXT release in rats (47). NMU may be involved in neuroendocrine responses to stress.

Galanin and Galanin-Like Peptide.
Galanin is a 29-amino-acid peptide present in the hypothalamus in high concentrations (48). Intracerebroventricular administration or microinjection of galanin in rats evokes feeding and elevates fat feeding in particular (49). Galanin coexists with arginine vasopressin and CRH in the PVN. Microinjection of galanin in the rat PVN is reported to attenuate ACTH secretion elicited by stress (50). Galanin is known to coexist in the great number of NA-producing neurons in the locus ceruleus, and restraint stress is reported to increase the increase of the expression of the galanin gene (51). Galanin-containing neurons express glucocorticoid receptors, suggesting the relationship with the HPA axis.

GALP was recently identified among galanin receptor subtypes (GALR 1, 2, 3) as an endogenous ligand of GALR2 (2). A recent study demonstrated that dehydration and salt loading markedly increased in the expression of the GALP gene in the pituicytes of rat posterior pituitary (52). Recently, Saito et al. demonstrated that the expression of the GALP gene in the posterior pituitary is upregulated during nonosmotic stimuli such as endotoxin shock and chronic inflammatory stress (53).

Oxytocin.
Intracerebroventricular administration of OXT inhibits feeding. Treatments intended to promote OXT secretion from the posterior pituitary (e.g., stress, peripheral administration of LiCl and CCK, and gastric distension) also inhibit feeding. CCK is regarded as the physiological satiety signal (54) and the pathway from CCK to OXT secretion is well investigated. First, CCKA receptors in the stomach are stimulated, the abdominal vagus nerve is activated, NA neurons in the A2 region of the NTS are excited, and NA is released in the hypothalamus, which activates magnacellular OXT neurons (55–57). In addition to the A2 NA neurons (58), NA neurons in the medullary ventrolateral A1 region also play an important role in OXT secretion after stressful stimuli such as noxious stimuli (59). It is unlikely that OXT in the peripheral blood controls feeding directly. At the time when OXT secretion from the posterior pituitary is promoted, OXT release within the hypothalamus has also been shown to be increased, and OXT in the CNS has been shown to inhibit feeding (60). Intracerebroventricular administration of an OXT receptor antagonist attenuates feeding reduction in response to LiCl or CCK (61, 62) and blocks feeding reduction in response to CRH (63). These data suggest that intrinsic OXT may play an important physiological role in inhibition of feeding during satiety and stress. Studies with light microscopy have shown that nerve fibers containing the feeding-inhibition peptides, cocaine-amphetamine-regulated transcript (CART) (64) and PrRP (65), have synaptic contact with hypothalamic OXT neurons. OXT neurons are activated by CART or PrRP administration (66). It has also been suggested that {alpha}-melanocyte-stimulating hormone ({alpha}-MSH), a feeding inhibition factor released by POMC neurons, activates OXT neurons (67). It is therefore possible that OXT contributes to feeding inhibition by CART, PrRP, and {alpha}-MSH. The inhibitory effect of OXT on feeding is blocked by a GLP-1 receptor antagonist. OXT activates GLP-1 neurons in the brain stem. GLP-1 decreases food intake. It is thus possible that GLP-1 is a downstream mediator after activation of OXT neurons (68).

OXT has a short-term feeding inhibition effect. However, when OXT is administered for a long period, it has been reported that food intake becomes increased after an initial decrease in feeding (69). There are no reports that OXT knockout mice get fat. In addition, OXT receptor antagonists also do not block feeding inhibition by {alpha}1NA receptor agonists (70).

The site of OXT action upon the feeding inhibition is not fully understood. Anatomically, OXT neurons in the PVN project to the medullary dorsal nucleus of the vagus nerve, and microinjection of OXT into the dorsal nucleus of the vagus nerve inhibits gastric motility, suggesting that OXT neurons of the PVN projecting to the medulla oblongata may act to inhibit feeding (60). OXT neurons in the PVN also project to sympathetic preganglionic neurons of intermediolateral nuclei in the spinal columns. OXT has been suggested to excite these neurons. Consequently, it is possible that activation of the sympathetic nervous system is a cause of feeding inhibition. OXT reduces binding affinity in the hypothalamus of {alpha}2NA receptor agonists that have a feeding promotion effect (71). Thus, modification of NA receptors may also contribute to feeding inhibition by OXT. In addition to feeding inhibition, OXT released in the CNS after various stress stimuli has been proposed to modify neuroendocrine stress responses, such as ACTH secretion, and to affect anxiety behaviors (72).

Prolactin-Releasing Peptide.
PrRP was identified as a factor causing release of prolactin from the anterior pituitary in vitro (3). PrRP-producing neurons are present in the NTS, the medullary ventrolateral areas, and the hypothalamic ventromedial and dorsomedial areas. The medullary PrRP-producing neurons are A2 or A1 NA neurons producing NA (73). Anatomic data suggest that PrRP fibers have synaptic contact with hypothalamic CRH neurons and OXT neurons (65). Intracerebroventricular administration of PrRP elicits ACTH release and OXT release from the anterior and posterior pituitary (66, 74). Stress activates medullary and hypothalamic PrRP neurons (75, 76). It has been suggested that PrRP and NA may both function cooperatively in neuroendocrine responses to stress (75). Intracerebroventricular administration of anti-PrRP antibodies to rats attenuates OXT secretion in response to conditioned fear (76).

The satiety factor, CCK, activates PrRP neurons. Intracerebroventricular or hypothalamic microinjection of PrRP inhibits feeding (77, 78) but does not induce nausea (conditioned taste aversion) (79). PrRP also increases body temperature. From these data, PrRP has been proposed to mediate satiety signaling (79). PrRP neurons express leptin receptors and PrRP mRNA is reduced when leptin signaling is defective (e.g., fasting, Zucker rats) (80). Thus PrRP is regulated by leptin. PrRP promotes release of the feeding inhibition factors, {alpha}-MSH and neurotensin (78). It is thus possible that {alpha}-MSH and neurotensin contribute to the inhibitory effect of PrRP. The action of PrRP on feeding inhibition during stress requires further investigation.

Leptin.
Leptin synthesized by adipocytes acts on the brain to inhibit feeding (6). The targets of leptin in the brain are believed to be the Arc, the hypothalamic ventromedial nucleus, and the hypothalamic dorsomedial nucleus. Leptin receptors are present in these regions. For example, leptin receptors (OB-Rb) are present in NPY neurons of the Arc, which have a feeding promotion effect, and in POMC neurons of the Arc, which have a feeding inhibition effect. Leptin inhibits NPY neurons and activates POMC neurons. When leptin signaling is deficient, hypothalamic NPY and AgRP mRNA levels are increased, and POMC and CART mRNA levels are decreased. Leptin also raises energy consumption. This is partly due to the fact that leptin activates hypothalamic neurons projecting to sympathetic preganglionic neurons of intermediolateral nuclei in the spinal columns.

Leptin concentration in the blood decreases during hunger. In the state of hunger, the HPA system is activated, whereas thyroid, reproductive, and growth hormone systems are suppressed. Body temperature and energy metabolism decline. At such time, immune function is depressed. These responses are attributed to physiological adaptive phenomena responding to hunger (6). Decrease in leptin concentration may contribute to these responses. The HPA system is the primary system responding to stress, and the effect of leptin on the HPA system is deemed inhibitory. Intracerebroventricular administration of leptin attenuates stress-induced responses in hypothalamic CRH mRNA increase and ACTH release from the pituitary. Leptin has been suggested to inhibit activity of NPY neurons and NA release within the PVN (81), and NPY and NA have been shown to activate CRH neurons. Leptin may also reinforce glucocorticoid feedback inhibition by increasing the expression of PVN and hippocampal glucocorticoid receptors (82). It has also been suggested that leptin acts on adrenal cortex levels and inhibits glucocorticoid release (83, 84). On the contrary, some studies report that leptin activates the HPA axis (85, 86). Meanwhile, leptin production is stimulated by glucocorticoids, insulin, adrenocortical hormones, estrogen, and cytokines, whereas it is inhibited by adrenalin and testosterone.

Ghrelin.
Ghrelin was discovered as an intrinsic ligand of GHS receptors (GHS-R) (4). Ghrelin is produced primarily in the stomach, but production in the colon, pituitary, kidneys, placenta, and hypothalamus has also been discovered. Ghrelin acts on the pituitary or the hypothalamus to bring about release of GHRH or an unknown factor (U-factor) and thereby promote GH secretion from the pituitary (87). Ghrelin also evokes a hunger sensation in the human and promotes feeding, perhaps via activation of GHS-R in a separate system. The blood concentration of ghrelin is decreased by satiation or feeding and is conversely increased during fasting or hunger or in anorexia nervosa. There is evidence that ghrelin acts on the hypothalamus to promote feeding. Microinjection of ghrelin to the Arc, the PVN, the hypothalamic dorsomedial nucleus, and the hypothalamic ventromedial nucleus promotes feeding (88). Ghrelin neurons have been shown to lie in the space between the lateral hypothalamus, arcuate, ventromedial, dorsomedial, and paraventricular hypothalamic nuclei (89). Ghrelin administration activates NPY/AgRP neurons in the Arc (90), and the feeding promotion effect of ghrelin has been shown to be blocked by NPY Y1 receptor antagonists, antibodies to NPY, antibodies to AgRP, and antibodies to orexin (91); it is therefore possible that the feeding-promotive effect of ghrelin is mediated by NPY/AgRP neurons in the Arc and orexin neurons in the lateral hypothalamic area. However, the action of ghrelin has also been observed in NPY knockout mice. It also has been suggested that ghrelin stimulates the hypothalamic feeding center via activation of the vagus nerve (92).

Ghrelin receptors are distributed widely within the brain: the hypothalamus, hippocampus, substantia nigra, ventral tegmental area, and raphe nuclei. Ghrelin may therefore have physiological functions other than feeding. Ghrelin has the opposite effect of leptin in metabolism. Ghrelin decreases oxidation of fats and causes fat accumulation. The function of ghrelin during stress remains to be determined. A recent report states that ghrelin augments ACTH release in response to stress secretion-inhibiting effect of leptin (81). In this respect, it is interesting to point out that ghrelin reduces {gamma}-aminobutyric acid release presynaptically in the PVN (89).

Conclusion

We summarize the topic of stress and feeding-related peptides with emphasis on recently discovered novel peptides. Future understanding of the contribution of feeding-related peptides to physiological stress responses holds the key to prevention and treatment of various stress-induced illnesses.

Footnotes

1 To whom requests for reprints should be addressed at Department of Physiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail: yoichi{at}med.uoeh-u.ac.jp Back

References

  1. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585, 1998.[Medline]
  2. Ohtaki T, Kumano S, Ishibashi Y, Ogi K, Matsui H, Harada M, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus. J Biol Chem 274:37041–37045, 1999.[Abstract/Free Full Text]
  3. Hinuma S, Habata Y, Fujii R, Hosoya M, Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H, Sekiguchi M, Kurokawa T, Nishimura O, Onda H, Fujino M. A prolactin-releasing peptide in the brain. Nature 393:272–276, 1998.[Medline]
  4. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-releasing acylated peptide from stomach. Nature 402:656–660, 1999.[Medline]
  5. Oomura Y. Input-output organization in the hypothalamus relating to food intake behavior. Handbook of the Hypothalamus (Vol. 2). New York: Marcel Dekker, p557–620, 1980.
  6. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 21:263–307, 2000.[Medline]
  7. Jaszberenyi M, Bujdoso E, Pataki I, Telegdy G. Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 12:1174–1178, 2000.[Medline]
  8. Le Feuvre RA, Aisenthal L, Rothwell NJ. Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds. Brain Res 555:245–250, 1991.[Medline]
  9. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C, et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:287–292, 1995.[Medline]
  10. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE. Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA 98:2843–2848, 2001.[Abstract/Free Full Text]
  11. Hsu SY, Hsueh AJW. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 7:605–611, 2001.[Medline]
  12. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian, Rivier J, Sawchenko PE, Vale WW. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci USA 98:7570–7575, 2001.[Abstract/Free Full Text]
  13. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale WW, Lee KF. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102, 1998.[Medline]
  14. Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH, Murray SE, Hill JK, Pantely GA, Hohimer AR, Hatton DC, Phillips TJ, Finn DA, Low MJ, Rittenberg MB, Stenzel P, Stenzel-Poore MP. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 24:403–409, 2000.[Medline]
  15. Gautvik KM, de Lecea L, Gautvik VT, Danielson PE, Tranque P, Dopazo A, Bloom FE, Sutcliffe JG. Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc Natl Acad Sci USA 93:8733–8738, 1996.[Abstract/Free Full Text]
  16. Lubkin M, Stricker-Krongrad A. Independent feeding and metabolic actions of orexin in mice. Biochem Biophys Res Commun 253:241–245, 1998.[Medline]
  17. Chemelli RM, Wille JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: Molecular genetic sleep regulation. Cell 98:437–451, 1999.[Medline]
  18. Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K. Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849:248–252, 1999.[Medline]
  19. Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR. Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20:1099–1105, 1999.[Medline]
  20. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, Miwa Y, Goto K, Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 859:404–409, 2000.[Medline]
  21. Ida T, Nakahara K, Kuroiwa T, Fukui K, Nakazato M, Murakami T, Murakami N. Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats. Neurosci Lett 293:119–122, 2000.[Medline]
  22. Jain MR, Horvath TL, Kalra PS, Kalra SP. Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats. Regul Pept 87:19–24, 2000.[Medline]
  23. Dube MG, Horvath TL, Kalra PS, Kalra SP. Evidence of NPY Y5 receptor involvement in food intake elicited by orexin A in sated rats. Peptides 21:1557–1560, 2000.[Medline]
  24. Broberger C, de Lecea L, Sutcliffe JG, Hokfelt T. Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402:460–474, 1998.[Medline]
  25. Horvath TL, Diano S, van den Pol AN. Synaptic interaction between hypocretin (orexin) and neuropetide Y cells in the rodent and primate hypothalamus: A novel circuit implicated in metabolic and endocrine regulations. J Neurosci 19:1072–1087, 1999.[Abstract/Free Full Text]
  26. Beck B, Richy S. Hypothalamic hypocretin/orexin and neuropeptide Y: Divergent interaction with energy depletion and leptin. Biochem Biophys Res Commun 258:119–122, 1999.[Medline]
  27. Funahashi H, Hori T, Shimoda Y, Mizushima H, Ryushi T, Katoh S, Shioda S. Morphological evidence for neural interactions between leptin and orexin in the hypothalamus. Regul Pept 92:31–35, 2000.[Medline]
  28. Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753, 1999.[Abstract/Free Full Text]
  29. Kuru M, Ueta Y, Serino R, Nakazato M, Yamamoto Y, Shibuya I, Yamashita H. Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11:1977–1980, 2000.[Medline]
  30. Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR. The effect of the orexins on food intake: Comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 160:R7–R12, 1999.[Abstract]
  31. Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N. Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 270:318–323, 2000.[Medline]
  32. Jaszberenyi M, Bujdoso E, Pataki I, Telegdy G. Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 12:1174–1178, 2000.
  33. Jaszberenyi M, Bujdoso E, Telegdy G. The role of neuropeptide Y in orexin-induced hypothalamic-pituitary-adrenal activation. J Neuroendocrinol 13:438–441, 2001.[Medline]
  34. Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M. Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 821:526–529, 1999.[Medline]
  35. Minamino N, Kangawa K, Matsuo H. Neuromedin U-8 and U-25: Novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. Biochem Biophys Res Commun 130:1078–1085, 1985.[Medline]
  36. Domin J, Ghatei MA, Chohan P, Bloom SR. Characterization of neuromedin U like immunoreactivity in rat, porcine, guinea-pig and human tissue extracts using a specific radioimmunoassay. Biochem Biophys Res Commun 140:1127–1134, 1986.[Medline]
  37. O’Harte F, Bockman CS, Zeng W, Abel PW, Harvey S, Conlon JM. Primary structure and pharmacological activity of a nonapeptide related to neuromedin U isolated from chicken intestine. Peptides 12:809–812, 1991.[Medline]
  38. Honzawa M, Sudoh T, Minamino N, Tohyama M, Matsuo H. Topographic localization of neuromedin U-like structures in the rat brain: An immunohistochemical study. Neuroscience 23:1103–1122, 1987.[Medline]
  39. Ballesta J, Carlei F, Bishop AE, Steel JH, Gibson SJ, Fahey M, Hennessey R, Domin J, Bloom SR, Polak JM. Occurrence and developmental pattern of neuromedin U-immunoreactive nerves in the gastrointestinal tract and brain of the rat. Neuroscience 25:797–816, 1988.[Medline]
  40. Brown DR, Quito FL. Neuromedin U octapeptide alters ion transport in porcine jejunum. Eur J Pharmacol 155:159–162, 1988.[Medline]
  41. Malendowicz LK, Nussdorfer GG, Markowska A, Tortorella C, Nowak M, Warchol JB. Effects of neuromedin U (NMU) -8 on the rat hypothalamo-pituitary-adrenal axis: Evidence of a direct effect of NMU-8 on the adrenal gland. Neuropeptides 26:47–53, 1994.[Medline]
  42. Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM, Zeng Z, Williams DL Jr, Feighner SD, Nunes CN, Murphy B, Stair JN, Yu H, Jiang O, Clements MK, Tan CP, McKee KK, Hreniuk DL, McDonald TP, Lynch KR, Evans JF, Austin CP, Caskey CT, Van der Ploeg LH, Liu O. Identification of receptors for neuromedin U and its role in feeding. Nature 406:70–74, 2000.[Medline]
  43. Nakazato M, Hanada R, Murakami N, Date Y, Mondal MS, Kojima M, Yoshimatsu H, Kangawa K, Matsukura S. Central effects of neuromedin U in the regulation of energy homeostasis. Biochem Biophys Res Commun 277:191–194, 2000.[Medline]
  44. Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Habata Y, Hinuma S, Onda H, Nishimura O, Fujino M. Identification of neuromedin U as the cognate ligand of the orphan G protein-coupled receptor FM-3. J Biol Chem 275:21068–21074, 2000.[Abstract/Free Full Text]
  45. Szekeres PG, Muir AI, Spinage LD, Miller JE, Butler SI, Smith A, Rennie GI, Murdock PR, Fitzgerald LR, Wu H, McMillan LJ, Guerrera S, Vawter L, Elshourbagy NA, Mooney JL, Bergsma DJ, Wilson S, Chambers JK. Neuromedin U is a potent agonist at the orphan G protein-coupled receptor FM3. J Biol Chem 275:20247–20250, 2000.[Abstract/Free Full Text]
  46. Kojima M, Haruno R, Nakazato M, Date Y, Murakami N, Hanada R, Matsuo H, Kangawa K. Purification and identification of neuromedin U as an endogenous ligand for an orphan receptor GPR66 (FM3). Biochem Biophys Res Commun 276:435–438, 2000.[Medline]
  47. Ozaki Y, Onaka T, Nakazato M, Saito J, Kanemoto K, Matsumoto T, Ueta Y. Centrally administered neuromedin U activates neurosecretion and induction of c-fos messenger ribonucleic acid in the paraventricular and supraoptic nuclei of rat. Endocrinology 143:4320–4329, 2002.[Abstract/Free Full Text]
  48. Tatemoto K, Rokaeus A, Jornvall H, McDonald TJ, Mutt V. Galanin: A novel biologically active peptide from porcine intestine. FEBS Lett 164:124–128, 1983.[Medline]
  49. Tempel DL, Leibowitz KJ, Leibowitz SF. Effects of PVN galanin on macronutrient selection. Peptides 9:309–314, 1988.[Medline]
  50. Hooi SC, Maiter DM, Martin JB, Koenig JI. Galaninergic mechanisms are involved in the regulation of corticotropin and thyrotropin secretion in the rat. Endocrinology 127:2281–2289, 1990.[Abstract]
  51. Sweerts BW, Jarrott B, Lawrence AJ. Expression of preprogalanin mRNA following acute and chronic restraint stress in brains of normotensive and hypertensive rats. Mol Brain Res 69:113–123, 1999.[Medline]
  52. Shen J, Larm JA, Gundlach AL. Galanin-like peptide mRNA in neural lobe of rat pituitary. Neuroendocrinology 73:2–11, 2001.[Medline]
  53. Saito J, Ozaki Y, Ohnishi H, Nakamura T, Ueta Y. Induction of galanin-like peptide gene expression in the rat posterior pituitary gland during endotoxin shock and adjuvant arthritis. Mol Brain Res 113:124–132, 2003.[Medline]
  54. Moran TH. Cholecystokinin and satiety: Current perspectives. Nutrition 16:858–865, 2000.[Medline]
  55. Leng G, Brown CH, Russel JA. Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog Neurobiol 57:625–655, 1999.[Medline]
  56. Onaka T. Catecholaminergic mechanisms underlying neurohypophysial hormone responses to unconditioned or conditioned aversive stimuli in rats. Exp Physiol 85S:101S–110S, 2000.[Abstract]
  57. Ueta Y, Kannan H, Higuchi T, Negoro H, Yamashita H. CCK-8 excites oxytocin-secreting neurons in the paraventricular nucleus in rats: Possible involvement of noradrenergic pathway. Brain Res Bull 32:453–459, 1993.[Medline]
  58. Zhu L, Onaka T. Involvement of medullary A2 noradrenergic neurons in the activation of oxytocin neurons after conditioned fear stimuli. Eur J Neurosci 16:2186–2198, 2002.[Medline]
  59. Onaka T, Yamashita T, Liu X Honda K, Saito T, Yagi K. Medullary A1 noradrenergic neurons may mediate oxytocin release after noxious stimuli. Neuroreport 12:2499–2502, 2001.[Medline]
  60. Verbalis JG, Blackburn RE, Hoffman GE, Stricker EM. Establishing behavioral and physiological functions of central oxytocin: Insights from studies of oxytocin and ingestive behaviors. Adv Exp Med Biol 395:209–225, 1995.[Medline]
  61. Olson BR, Drutarosky MD, Stricker EM, Verbalis JG. Oxytocin and oxytocin agonist administered centrally decrease food intake in rats. Peptides 12:113–118, 1991.[Medline]
  62. Olson BR, Drutarosky MD, Stricker EM, Verbalis JG. Brain oxytocin-receptor antagonism blunts the effects of anorexigenic treatments in rats: Evidence for central oxytocin inhibition of food intake. Endocrinology 129:785–791, 1991.[Abstract]
  63. Olson BR, Drutarosky MD, Stricker EM, Vebalis JG. Brain oxytocin receptors mediate corticotropin-releasing hormone-induced anorexia. Am J Physiol 260:R448–R452, 1991.
  64. Vrang N, Larsen PJ, Kristensen P, Tang-Christensen M. Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat. Endocrinology 141:794–801, 2000.[Abstract/Free Full Text]
  65. Maruyama M, Matsumoto H, Fujisawa K, Kitada C, Hinuma S, Onda H, Fujino M, Inoue K. Imunocytochemical localization of prolactin-releasing peptide in the rat brain. Endocrinology 140:2326–2333, 1999.[Abstract/Free Full Text]
  66. Maruyama M, Matsumoto H, Fujisawa K, Noguchi J, Kitada C, Hinuma S, Onda H, Nishimura O, Fujino M, Higuchi T, Inoue K. Central administration of prolactin-releasing peptide stimulates oxytocin release in rats. Neurosci Lett 276:193–196, 1999.[Medline]
  67. Olszewski PK, Wirth MM, Shaw TJ, Grace MK, Billington CJ, Giraudo SQ, Levine AS. Role of a-MSH in the regulation of consummatory behavior: Immunohistochemical evidence. Am J Physiol 281:R673–R680, 2001.
  68. Rinaman L, Rothe EE. GLP-1 receptor signalling contributes to anorexigenic effect of centrally administered oxytocin in rats. Am J Physiol 283:R99–R106, 2002.
  69. Bjkstrand E, Uvn-Moberg K. Central oxytocin increases food intake and daily weight gain in rats. Physiol Behav 59:947–952, 1996.[Medline]
  70. McMahon LR, Wellman PJ. Assessment of the role of oxytocin receptors in phenylpropanolamine-induced anorexia in rats. Pharmacol Biochem Behav 57:767–770, 1997.[Medline]
  71. Diaz-Cabiale Z, Narvaez JA, Petersson M, Uvnas-Moberg K, Fuxe K. Oxytocin/alpha2-adrenoceptor interactions in feeding responses. Neuroendocrinology 71:209–218, 2000.[Medline]
  72. Gimpl G, Fahrenholz F. The oxytocin receptor system: Structure, function, and regulation. Physiol Rev 81:629–683, 2001.[Abstract/Free Full Text]
  73. Ibata Y, Iijima N, Kataoka Y, Kakihara K, Tanaka M, Hosoya M, Hinuma S. Morphological survey of prolactin-releasing peptide and its receptor with special reference to their functional roles in the brain. Neurosci Res 38:223–230, 2000.[Medline]
  74. Matsumoto H, Maruyama M, Noguchi J, Horikoshi Y, Fujisawa K, Kitada C, Hinuma S, Onda H, Nishimura O, Inoue K, Fujino M. Stimulation of corticotropin-releasing hormone-mediated adrenocorticotropin secretion by central administration of prolactin-releasing peptide in rats. Neurosci Lett 285:234–238, 2000.[Medline]
  75. Maruyama M, Matsumoto H, Fujisawa K, Noguchi J, Kitada C, Fujino M, Inoue K. Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology 142:2032–2038, 2001.[Abstract/Free Full Text]
  76. Zhu L, Onaka T. Facilitative role of prolactin-releasing peptide neurons in oxytocin cell activation after conditioned fear stimuli. Neuroscience 118:1045–1053, 2003.[Medline]
  77. Lawrence CB, Celsi F, Brennand J, Luckman SM. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nat Neurosci 3:645–646, 2000.[Medline]
  78. Seal LJ, Small CJ, Dhillo WS, Stanley SA, Abbott CR, Ghatei MA, Bloom SR. PRL-releasing peptide inhibits food intake in male rats via the dorsomedial hypothalamic nucleus and not the paraventricular hypothalamic nucleus. Endocrinology 142:4236–4243, 2001.[Abstract/Free Full Text]
  79. Lawrence CB, Ellacott KLJ, Luckman SM. PRL-releasing peptide reduces food intake and may mediate satiety signalling. Endocrinology 143:360–367, 2002.[Abstract/Free Full Text]
  80. Ellacott KLJ, Lawrence CB, Rothwell NJ, Luckman SM. PRL-releasing peptide interacts with leptin to reduce food intake and body weight. Endocrinology 143:368–374, 2002.[Abstract/Free Full Text]
  81. Honda K, Onaka T, Kawakami A, Rokkaku K, Ideno J, Ishibashi S. Role of leptin and ghrelin in the regulation of adrenocorticotropin release in fasting. Neurosci Res 25:S8, 2001.
  82. Proulx K, Clavel S, Nault G, Richard D, Walker CD. High neonatal leptin exposure enhances brain GR expression and feedback efficiency on the adrenocortical axis of developing rats. Endocrinology 142:4607–4616, 2001.[Abstract/Free Full Text]
  83. Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, Gaillard RC. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology 139:4264–4268, 1998.[Abstract/Free Full Text]
  84. Spinedi E, Gaillard RC. A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: A physiological role of ACTH. Endocrinology 139:4016–4020, 1998.[Abstract/Free Full Text]
  85. Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroendocrinology 71:366–374, 1997.
  86. Morimoto I, Yamamoto S, Kai K, Hujihira T, Morita E, Eto S. Centrally administered murine-leptin stimulates the hypothalamus-pituitary-adrenal axis through arginine-vasopressin. Neuroendocrinology 71:366–374, 2000.[Medline]
  87. Horvath TL, Diano S, Sotonyi P, Heiman M. Tschop M. Ghrelin and the regulation of energy balance: A hypothalamic perspective. Endocrinology 142:4163–4169, 2001.[Abstract/Free Full Text]
  88. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR. Ghrelin causes hyperphagia and obesity in rats. Diabetes 50:2540–2547, 2001.[Abstract/Free Full Text]
  89. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661, 2003.[Medline]
  90. Seoane LM, Lopez M, Tovar S, Casanueva FF, Senaris R, Dieguez C. Agouti-related peptide, neuropeptide Y and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology 144:544–551, 2003.[Abstract/Free Full Text]
  91. Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, Guan JL, Wang QP, Funahashi H, Sakurai T, Shioda S, Matsukura S, Kangawa K, Nakazato M. Ghrelin-induced food intake is mdiated via the orexin pathway. Endocrinology 144:1506–1512, 2003.[Abstract/Free Full Text]
  92. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120:337–345, 2001.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ueta, Y.
Right arrow Articles by Onaka, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ueta, Y.
Right arrow Articles by Onaka, T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS