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Seema Bhatnagar - One of the best experts on this subject based on the ideXlab platform.

  • Orexin 2 receptor regulation of the hypothalamic pituitary adrenal hpa response to acute and repeated stress
    Neuroscience, 2017
    Co-Authors: Laura A. Grafe, John J Renger, Christopher J. Winrow, Anthony L. Gotter, Darrell Eacret, Seema Bhatnagar, Sandra Luz
    Abstract:

    Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of Orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid (CSF) were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central Orexin levels and failure to habituate to repeated stress, the effect of activating Orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating Orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of Orexin receptors in acute and repeated stress using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated Orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high Orexin release.

  • Orexins mediate sex differences in the stress response and in cognitive flexibility
    Biological Psychiatry, 2017
    Co-Authors: Laura A. Grafe, Seema Bhatnagar, Amanda D Cornfeld, Rita J Valentino
    Abstract:

    Abstract Background Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether Orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases. Methods Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, Orexin expression and activation were determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the Orexin promoter. Designer receptors exclusively activated by designer drugs were used to inhibit Orexin activation throughout repeated restraint to determine if the stress-related impairments in female rats could be reduced. Results Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared with male rats. Increased Orexin expression and activation were observed in female rats compared with male rats. The higher expression of Orexin messenger RNA in female rats was due to actions of glucocorticoid receptors on the Orexin promoter, as determined by chromatin immunoprecipitation. Inhibition of Orexins using designer receptors exclusively activated by designer drugs in female rats throughout repeated restraint abolished their heightened hypothalamic-pituitary-adrenal responsivity and reduced stress-induced cognitive impairments. Conclusions Orexins mediate the impairments in adaptations to repeated stress and in subsequent cognitive flexibility exhibited by female rats and provide evidence for a broader role for Orexins in mediating functions relevant to stress-related psychiatric diseases.

  • Orexins hypocretins act in the posterior paraventricular thalamic nucleus during repeated stress to regulate facilitation to novel stress
    Endocrinology, 2011
    Co-Authors: Willem Heydendael, Sandra Luz, Kanika Sharma, Vikram Iyer, David A Piel, Sheryl G Beck, Seema Bhatnagar
    Abstract:

    Orexins/hypocretins heavily innervate the posterior division of the paraventricular nucleus of the thalamus (pPVT), which expresses both Orexin receptor types. The pPVT is important for adaptations to repeated stress, particularly the ability to facilitate to novel stress after repeated stress exposure. Here, we examined how Orexins acting in the pPVT regulate facilitation of hypothalamic-pituitary-adrenal (HPA) responses to novel restraint after 4 d of repeated swim stress. Blockade of Orexin receptors in the pPVT with SB334867 before novel restraint did not change the facilitated HPA response. However, blockade of Orexin receptors before each of four daily swim exposures prevented the facilitated ACTH and facilitated hypothalamic c-Fos response to restraint as well as the repeated swim stress-induced increase in CRH mRNA in the paraventricular hypothalamus. These results suggest that Orexin actions in the pPVT during the 4 d of swim, but not during restraint, are necessary for the facilitated HPA response to heterotypic restraint. Exposure to the fourth swim produced a shift in Orexin1 receptors from membrane to cytosolic fractions. OrexinA also changed the firing patterns of pPVT cells to be more responsive in repeatedly swim stressed rats compared with nonstressed rats. Together, the results suggest that Orexin actions in the pPVT, mediated by Orexin1 receptors, are important for the ability to adapt to repeated stress.

  • Orexins hypocretins act in the posterior paraventricular thalamic nucleus during repeated stress to regulate facilitation to novel stress
    Endocrinology, 2011
    Co-Authors: Willem Heydendael, Kanika Sharma, Vikram Iyer, David A Piel, Sheryl G Beck, Seema Bhatnagar
    Abstract:

    Orexins/hypocretins heavily innervate the posterior division of the paraventricular nucleus of the thalamus (pPVT), which expresses both Orexin receptor types. The pPVT is important for adaptations to repeated stress, particularly the ability to facilitate to novel stress after repeated stress exposure. Here, we examined how Orexins acting in the pPVT regulate facilitation of hypothalamic-pituitary-adrenal (HPA) responses to novel restraint after 4 d of repeated swim stress. Blockade of Orexin receptors in the pPVT with SB334867 before novel restraint did not change the facilitated HPA response. However, blockade of Orexin receptors before each of four daily swim exposures prevented the facilitated ACTH and facilitated hypothalamic c-Fos response to restraint as well as the repeated swim stress-induced increase in CRH mRNA in the paraventricular hypothalamus. These results suggest that Orexin actions in the pPVT during the 4 d of swim, but not during restraint, are necessary for the facilitated HPA respon...

Takeshi Sakurai - One of the best experts on this subject based on the ideXlab platform.

  • connectomics of Orexin producing neurons interface of systems of emotion energy homeostasis and arousal
    Trends in Pharmacological Sciences, 2011
    Co-Authors: Takeshi Sakurai, Michihiro Mieda
    Abstract:

    Avoiding danger and finding food, which are life-sustaining activities that are regulated by emotion, reward and energy balance, require proper wakefulness. The Orexin system controls sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis. Recent findings have brought about the possibility of novel therapies targeting the Orexin system for sleep disorders, including insomnia and narcolepsy–cataplexy, as well as other pathological conditions such as obesity and drug addiction [1]. In this review, we will discuss the current understanding of the integrative physiology and clinical perspectives of the Orexin system. We will briefly review signaling through Orexin A and B receptors and discuss the role of Orexins in the pathophysiology of narcolepsy. We will also examine connections between Orexin neurons and other brain areas involved in feeding behavior, reward and emotion. Finally, we will consider the therapeutic potential of drugs that target Orexin receptors.

  • ectopic overexpression of Orexin alters sleep wakefulness states and muscle tone regulation during rem sleep in mice
    Journal of Molecular Neuroscience, 2011
    Co-Authors: Jon T. Willie, Takeshi Sakurai, Masashi Yanagisawa, Megumi Shibahara, Junko Hara, Hitomi Takahira, Mika Nomiyama
    Abstract:

    Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that Orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased Orexinergic transmission tone, which might be important for understanding the effects of Orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-Orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/Orexin transgenic mice). CAG/Orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous Orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.

  • Orexin neuronal circuitry role in the regulation of sleep and wakefulness
    Frontiers in Neuroendocrinology, 2008
    Co-Authors: Kousaku Ohno, Takeshi Sakurai
    Abstract:

    Orexin A and Orexin B were initially identified as endogenous ligands for two orphan G protein-coupled receptors [104]. They were initially recognized as regulators of feeding behavior in view of their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity [104,30,49,107]. Subsequently, the finding that Orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wake cycle [22,46,71,95,117]. These peptides activate waking-active monoaminergic and cholinergic neurons in the hypothalamus/brain stem regions to maintain a long, consolidated awake period. Recent studies on efferent and afferent systems of Orexin neurons, and phenotypic characterization of genetically modified mice in the Orexin system further suggested roles of Orexin in the coordination of emotion, energy homeostasis, reward system, and arousal [3,80,106,137]. A link between the limbic system and Orexin neurons might be important for increasing vigilance during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states [137]. Recent research has also implicated Orexins in reward systems and the mechanisms of drug addiction [13,48,91]. These observations suggest that Orexin neurons sense the outer and inner environment of the body, and maintain proper wakefulness of animals for survival. This review discusses the mechanism by which Orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis.

  • difference in obesity phenotype between Orexin knockout mice and Orexin neuron deficient mice with same genetic background and environmental conditions
    Neuroscience Letters, 2005
    Co-Authors: Junko Hara, Masashi Yanagisawa, Takeshi Sakurai
    Abstract:

    Orexins are a pair of neuropeptides expressed by a population of neurons located in the lateral hypothalamic area (LHA). Prepro-Orexin- or Orexin receptor type 2-deficient animals exhibit a phenotype remarkably similar to the human sleep disorder, narcolepsy, which is characterized by sleep/wakefulness fragmentation. Human narcolepsy is known to be associated with metabolic abnormalities, including an increased frequency of obesity and non-insulin-dependent diabetes mellitus. Complex disruption of energy homeostasis in Orexin neuron-deficient transgenic mice (Orexin/ataxin-3 mice) is also manifested as late-onset obesity despite eating less. Here, we report that the development of obesity in Orexin neuron-ablated narcoleptic mice is critically dependent on their genetic background and environmental factors, and the phenotype is different from that of prepro-Orexin knockout mice even under the same genetic background and environmental factors, suggesting that factors that co-localize in Orexin neurons might have important roles in the regulation of energy homeostasis. Our observation also suggests that the obesity observed in Orexin neuron-deficient narcolepsy is dependent on the genetic background and environmental factors.

  • reverse pharmacology of Orexin from an orphan gpcr to integrative physiology
    Regulatory Peptides, 2005
    Co-Authors: Takeshi Sakurai
    Abstract:

    Orexins, which were initially identified as endogenous peptide ligands for two orphan G-protein coupled receptors (GPCRs), have been shown to have an important role in the regulation of energy homeostasis. Furthermore, the discovery of Orexin deficiency in narcolepsy patients indicated that Orexins are highly important factors for the sleep/wakefulness regulation. The efferent and afferent systems of Orexinproducing neurons suggest interactions between these cells and arousal centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that Orexin neurons are regulated by humoral factors, including leptin, glucose, and ghrelin as well as monoamines and acetylcholin. Thus, Orexin neurons have functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers to provide a link between peripheral energy balance and the CNS mechanisms that coordinate sleep/ wakefulness states and motivated behavior such as food seeking. D 2004 Elsevier B.V. All rights reserved.

Masashi Yanagisawa - One of the best experts on this subject based on the ideXlab platform.

  • localization of Orexin b and Orexin 2 receptor in the rat epididymis
    Acta Histochemica, 2018
    Co-Authors: Giovanna Liguori, Masashi Yanagisawa, Simona Tafuri, Chika Miyoshi, C Squillacioti, Valeria De Pasquale, N Mirabella, Alfredo Vittoria, Anna Costagliola
    Abstract:

    Abstract The peptides Orexin A (OXA) and Orexin B (OXB) derived from the proteolytic cleavage of a common precursor molecule, prepro-Orexin, were originally described in the rat hypothalamus. Successively, they have been found in many other brain regions as well as in peripheral organs of mammals and other less evolved animals. The widespread localization of Orexins accounts for the multiple activities that they exert in the body, including the regulation of energy homeostasis, feeding, metabolism, sleep and arousal, stress, addiction, and cardiovascular and endocrine functions. Both OXA and OXB peptides bind to two G-coupled receptors, Orexin-1 (OX1R) and Orexin-2 (OX2R) receptor, though with different binding affinity. Altered expression/activity of Orexins and their receptors has been associated with a large number of human diseases. Though at present evidence highlighted a role for Orexins and cognate receptors in mammalian reproduction, their central and/or local effects on gonadal functions remain poorly known. Here, we investigated the localization of OXB and OX2R in the rat epididymis. Immunohistochemical staining of sections from caput, corpus and cauda segments of the organ showed intense signals for both OXB and OX2R in the principal cells of the lining epithelium, while no staining was detected in the other cell types. Negative results were obtained from immunohistochemical analysis of hypothalamic and testicular tissues from OX2R knock-out mice (OX2R −/− ) and OX1R/OX2R double knock-out (OX1R −/− ; OX2R −/− ) mice, thus demonstrating the specificity of the rabbit polyclonal anti-OX2R antibody used in our study. On contrary, the same antibody clearly showed the presence of OX2R in sections from hypothalamus and testis of normal mice and rats which are well known to express the receptor. Thus, our results provide the first definite evidence for the immunohistochemical localization of OXB and OX2R in the principal cells of rat epididymis.

  • ectopic overexpression of Orexin alters sleep wakefulness states and muscle tone regulation during rem sleep in mice
    Journal of Molecular Neuroscience, 2011
    Co-Authors: Jon T. Willie, Takeshi Sakurai, Masashi Yanagisawa, Megumi Shibahara, Junko Hara, Hitomi Takahira, Mika Nomiyama
    Abstract:

    Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that Orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased Orexinergic transmission tone, which might be important for understanding the effects of Orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-Orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/Orexin transgenic mice). CAG/Orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous Orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.

  • difference in obesity phenotype between Orexin knockout mice and Orexin neuron deficient mice with same genetic background and environmental conditions
    Neuroscience Letters, 2005
    Co-Authors: Junko Hara, Masashi Yanagisawa, Takeshi Sakurai
    Abstract:

    Orexins are a pair of neuropeptides expressed by a population of neurons located in the lateral hypothalamic area (LHA). Prepro-Orexin- or Orexin receptor type 2-deficient animals exhibit a phenotype remarkably similar to the human sleep disorder, narcolepsy, which is characterized by sleep/wakefulness fragmentation. Human narcolepsy is known to be associated with metabolic abnormalities, including an increased frequency of obesity and non-insulin-dependent diabetes mellitus. Complex disruption of energy homeostasis in Orexin neuron-deficient transgenic mice (Orexin/ataxin-3 mice) is also manifested as late-onset obesity despite eating less. Here, we report that the development of obesity in Orexin neuron-ablated narcoleptic mice is critically dependent on their genetic background and environmental factors, and the phenotype is different from that of prepro-Orexin knockout mice even under the same genetic background and environmental factors, suggesting that factors that co-localize in Orexin neurons might have important roles in the regulation of energy homeostasis. Our observation also suggests that the obesity observed in Orexin neuron-deficient narcolepsy is dependent on the genetic background and environmental factors.

  • Orexins acting at native ox1 receptor in colon cancer and neuroblastoma cells or at recombinant ox1 receptor suppress cell growth by inducing apoptosis
    Journal of Biological Chemistry, 2004
    Co-Authors: Patricia Rouetbenzineb, Masashi Yanagisawa, Virgile Avondo, Marc Laburthe, C Rouyerfessard, Anne Jarry, Cecile Pouzet, Christian L Laboisse, Thierry Voisin
    Abstract:

    Screening of 26 gut peptides for their ability to inhibit growth of human colon cancer HT29-D4 cells grown in 10% fetal calf serum identified Orexin-A and Orexin-B as anti-growth factors. Upon addition of either Orexin (1 microM), suppression of cell growth was total after 24 h and >70% after 48 or 72 h, with an EC(50) of 5 nm peptide. Orexins did not alter proliferation but promoted apoptosis as demonstrated by morphological changes in cell shape, DNA fragmentation, chromatin condensation, cytochrome c release into cytosol, and activation of caspase-3 and caspase-7. The serpentine G protein-coupled Orexin receptor OX(1)R but not OX(2)R was expressed in HT29-D4 cells and mediated Orexin-induced Ca(2+) transients in HT29-D4 cells. The expression of OX(1)R and the pro-apoptotic effects of Orexins were also indicated in other colon cancer cell lines including Caco-2, SW480, and LoVo but, most interestingly, not in normal colonic epithelial cells. The role of OX(1)R in mediating apoptosis was further demonstrated by transfecting Chinese hamster ovary cells with OX(1)R cDNA, which conferred the ability of Orexins to promote apoptosis. A neuroblastoma cell line SK-N-MC, which expresses OX(1)R, also underwent growth suppression and apoptosis upon treatment with Orexins. Promotion of apoptosis appears to be an intrinsic property of OX(1)R regardless of the cell type where it is expressed. In conclusion, Orexins, acting at native or recombinant OX(1)R, are pro-apoptotic peptides. These findings add a new dimension to the biological activities of these neuropeptides, which may have important implications in health and disease, in particular colon cancer.

  • Orexin peptides prevent cataplexy and improve wakefulness in an Orexin neuron ablated model of narcolepsy in mice
    Proceedings of the National Academy of Sciences of the United States of America, 2004
    Co-Authors: Michihiro Mieda, Takeshi Sakurai, Junko Hara, Jon T. Willie, Christopher M Sinton, Masashi Yanagisawa
    Abstract:

    Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of Orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic Orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of Orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-Orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous Orexin neurons. Central administration of Orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that Orexin neuron-ablated mice retain the ability to respond to Orexin neuropeptides and that a temporally regulated and spatially targeted secretion of Orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.

Stephen R. Bloom - One of the best experts on this subject based on the ideXlab platform.

  • Orexins effects on behavior and localisation of Orexin receptor 2 messenger ribonucleic acid in the rat brainstem
    Brain Research, 2001
    Co-Authors: D Sunter, Shahrad Taheri, C. L. Dakin, Irene Morgan, Mark C B Edwards, Kevin Murphy, James V Gardiner, Esraa Rayes, Stephen R. Bloom
    Abstract:

    The Orexins are neuropeptides originally reported to be involved in the stimulation of food intake. However, analysis of Orexin immunoreactive fibres have revealed the densest innervation in brain sites involved in arousal and sleep-wake control, notably the noradrenergic locus coeruleus, an area that also expresses Orexin receptor 1 (OX1R) messenger RNA (mRNA). We report here that, in the rat, a single intracerebroventricular injection of Orexin A (1 and 3 nmol) or Orexin B (3 nmol), during the early light phase, did not increase food intake over the first 4 h postinjection. However, the frequency of active behaviors such as grooming, rearing, burrowing and locomotion increased. Feeding behavior and food intake subsequently decreased over the following 20 h (4-24 h postinjection period) in the Orexin A 3 nmol injected group whilst the frequency of inactive behavior (still or asleep) in this group increased. Using riboprobes, we performed in situ hybridization histochemistry to map the distribution of Orexin receptor 2 (OX2R) mRNA within the rat brainstem. We report here, for the first time, the presence of OX2R mRNA in the nucleus of the solitary tract and the lateral reticular field (LRt). The LRt is a brainstem site that, amongst other functions, is implicated in attention and wakefulness. This distribution of OX2R and the effects on behavior support recent reports that the Orexins might modulate central nervous system arousal and sleep-wake mechanisms rather than exclusively being involved in the control of food intake.

  • diurnal variation in Orexin a immunoreactivity and prepro Orexin mrna in the rat central nervous system
    Neuroscience Letters, 2000
    Co-Authors: Shahrad Taheri, James Gardiner, C. L. Dakin, Leighton J. Seal, Mohammad A. Ghatei, D Sunter, Sasha Moyes, Michela Rossi, Stephen R. Bloom
    Abstract:

    Orexins are a family of neuropeptides originally believed to be important mediators of food intake. The wide distribution of Orexins and their receptors, however, has suggested other regulatory functions for these peptides including involvement in sleep and arousal mechanisms. In this study, we have demonstrated diurnal variation in Orexin A immunoreactivity in the pons, from where locus coeruleus noradrenergic neurones innervate other brain areas to stimulate arousal, and in the preoptic/anterior hypothalamic region, an area implicated in the regulation of sleep and circadian rhythms. Orexin A immunoreactivity decreased by 50% in the preoptic/anterior hypothalamus from 09:00 to 21:00 h (P < 0.0001), whilst in the pons, it increased by over 30% from 09:00 to 01:00 h (P = 0.02). Prepro-Orexin mRNA also displayed diurnal variation. This further suggests that Orexins are involved in the regulation of the sleep/wake cycle.

  • the effect of the Orexins on food intake comparison with neuropeptide y melanin concentrating hormone and galanin
    Journal of Endocrinology, 1999
    Co-Authors: C M B Edwards, Mohammad A. Ghatei, D Sunter, S Abusnana, K G Murphy, Stephen R. Bloom
    Abstract:

    Orexin-A and Orexin-B (the hypocretins) are recently described neuropeptides suggested to have a physiological role in the regulation of food intake in the rat. We compared the orexigenic effect of the Orexins administered intracerebroventricular (ICV) with other known stimulants of food intake, one strong, neuropeptide Y (NPY), and two weaker, melanin-concentrating hormone (MCH) and galanin. Orexin-A consistently stimulated food intake, but Orexin-B only on occasions. Both peptides stimulated food intake significantly less than NPY, but to a similar extent to MCH (2 h food intake: NPY 3 nmol, 7.2+/-0.9 g vs saline, 1.5+/-0.2 g, P<0.001, MCH 3 nmol, 3.2+/-0.8 g vs saline, P<0.01, Orexin-B 30 nmol, 2. 6+/-0.5 g vs saline, P=0.11) and to galanin (1 h food intake: galanin 3 nmol, 2.0+/-0.4 g vs saline, 0.8+/-0.2 g, P<0.05, Orexin-A 3 nmol 2.2+/-0.4 g vs saline, P<0.01; 2 hour food intake: Orexin-B 3 nmol, 2.4+/-0.3 g vs saline, 1.3+/-0.2 g, P<0.05). Following ICV Orexin-A, hypothalamic c-fos, a maker of neuronal activation, was highly expressed in the paraventricular nucleus (PVN), and the arcuate nucleus (P<0.005 for both). IntraPVN injection of Orexin-A stimulated 2 h food intake by one gram (Orexin-A 0.03 nmol, 1.6+/-0. 3 g vs saline, 0.5+/-0.3 g, P<0.005). These findings support the suggestion that the Orexins stimulate food intake. However, this effect is weak and may cast doubt upon their physiological importance in appetite regulation in the rat.

Akihiro Yamanaka - One of the best experts on this subject based on the ideXlab platform.

  • The regulation of sleep and wakefulness by the hypothalamic neuropeptide Orexin/hypocretin
    2020
    Co-Authors: Ayumu Inutsuka, Akihiro Yamanaka
    Abstract:

    ABSTRACT Orexins, also known as hypocretins, are neuropeptides that are exclusively expressed by neurons in the lateral hypothalamic area. Although originally recognized as regulators of feeding behavior, Orexins are now mainly regarded as key modulators of the sleep/wakefulness cycle. In addition, anatomical studies of neural networks and analyses of transgenic mice have revealed integrated roles for Orexin neurons in the coordination of emotion, energy homeostasis, and the reward system. A functional link between the limbic system and Orexin neurons may be important for increasing vigilance in response to emotional stimuli. These findings suggest that Orexin neurons relay information about an organism's environment to maintain the proper amount of sleep and wakefulness in animals

  • the physiological role of Orexin hypocretin neurons in the regulation of sleep wakefulness and neuroendocrine functions
    Frontiers in Endocrinology, 2013
    Co-Authors: Ayumu Inutsuka, Akihiro Yamanaka
    Abstract:

    The hypothalamus monitors body homeostasis and regulates various behaviors such as feeding, thermogenesis, and sleeping. Orexins (also known as hypocretins) were identified as endogenous ligands for two orphan G-protein-coupled receptors in the lateral hypothalamic area. They were initially recognized as regulators of feeding behavior, but they are mainly regarded as key modulators of the sleep/wakefulness cycle. Orexins activate Orexin neurons, monoaminergic and cholinergic neurons in the hypothalamus/brainstem regions, to maintain a long, consolidated awake period. Anatomical studies of neural projections from/to Orexin neurons and phenotypic characterization of transgenic mice revealed various roles for Orexin neurons in the coordination of emotion, energy homeostasis, reward system, and arousal. For example, Orexin neurons are regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose concentration. This suggests that they may provide a link between energy homeostasis and arousal states. A link between the limbic system and Orexin neurons might be important for increasing vigilance during emotional stimuli. Orexins are also involved in reward systems and the mechanisms of drug addiction. These findings suggest that Orexin neurons sense the outer and inner environment of the body and maintain the proper wakefulness level of animals for survival. This review discusses the mechanism by which Orexins maintain sleep/wakefulness states and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis.

  • Orexins hypocretins directly interact with neuropeptide y pomc and glucose responsive neurons to regulate ca2 signaling in a reciprocal manner to leptin orexigenic neuronal pathways in the mediobasal hypothalamus
    European Journal of Neuroscience, 2004
    Co-Authors: Hisayuki Funahashi, Akihiro Yamanaka, Shinji Muroya, Daisuke Kohno, Kazuhide Uramura, Tadahiro Nambu, Megumi Shibahara, Motoki Kuramochi
    Abstract:

    Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of Orexins in rats. Immunohistochemical methods showed that Orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of Orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca 2 + concentration ([Ca 2 + ] i ) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca 2 + ] i were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca 2 + uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca 2 + ] i in NPY neurons were greater with Orexin-A than with Orexin-B, indicative of involvement of the Orexin-1 receptor (OX 1 R). In contrast, Orexin-A and -B equipotently attenuated [Ca 2 + ] i oscillations and decreased [Ca 2 + ] i levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the Orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca 2 + ] i levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that Orexins directly regulate NPY, POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca 2 + signaling in NPY neurons via OX 1 R-PLC-PKC and IP 3 pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of Orexins.

  • Orexins activate histaminergic neurons via the Orexin 2 receptor
    Biochemical and Biophysical Research Communications, 2002
    Co-Authors: Akihiro Yamanaka, Natsuko Tsujino, Hisayuki Funahashi, Kazuki Honda, Jianlian Guan, Quingping Wang, Seiji Shioda, Katsutoshi Goto, Makoto Tominaga, Takeshi Sakurai
    Abstract:

    Orexins (Orexin A and B) are recently identified neuropeptides implicated in the regulation of vigilance states and energy homeostasis. We have shown here the physiological significance of histaminergic neurons in the Orexin-induced arousal responses. Immunohistochemical and electron microscopic techniques revealed direct synaptic interaction between Orexin-immunoreactive nerve terminals and histidine decarboxylase-immunoreactive neurons in the TMN. Electrophysiological study revealed that Orexins dose-dependently activate histaminergic neurons, which were freshly isolated from rats TMN region. To further evaluate, we examined the effect of pyrilamine, an H1 receptor antagonist, on Orexin-induced arousal response in rats. Simultaneously recordings of electroencephalograph and electromyograph showed that intracerebroventricular infusion of Orexin A significantly increased the awake state in the light phase. Central application of pyrilamine significantly inhibited this response. These results strongly suggest that activation of histaminergic neurons by Orexins might be important for modulation of the arousal.

  • Orexins suppress catecholamine synthesis and secretion in cultured pc12 cells
    Biochemical and Biophysical Research Communications, 2000
    Co-Authors: Toru Nanmoku, Yasushi Kawakami, Katsutoshi Goto, Kazuhiro Takekoshi, Kazumasa Isobe, Kiyoaki Ishii, Takeshi Sakurai, Akihiro Yamanaka, Toshiaki Nakai
    Abstract:

    Abstract New orexigenic peptides called Orexin-A and -B have recently been described in neurons of the lateral hypothalamus and perifornical area. No Orexins have been found in adipose tissues or visceral organs, including the adrenal gland. However, expression of the Orexin-receptor 2 (OX2R) in the rat adrenal gland has been reported. To test the effects of Orexins on peripheral organs, we investigated their effects on catecholamine synthesis and secretion in the rat pheochromocytoma cell line PC12. Orexin-A and -B (100 nM) significantly reduced basal and PACAP-induced tyrosine hydroxylase (TH) (the rate-limiting enzyme in the biosynthesis of catecholamines) mRNA levels. Orexin-A and -B (100 nM) also significantly inhibited the PACAP-induced increase in the cAMP level, suggesting that the suppressive effect on TH mRNA is mediated, at least in part, by the cAMP/protein kinase A pathway. Furthermore, Orexin-A and -B (100 nM) significantly suppressed basal and PACAP-induced dopamine secretion from PC12 cells. Next, we examined whether Orexin receptors (OX1R, OX2R) were present in the rat adrenal gland and PC12 cells. In the adrenal glands, OX2R was as strongly expressed as in the hypothalamus, but OX1R was not detected. On the other hand, neither OX1R nor OX2R was expressed in PC12 cells. However, binding assays showed equal binding of Orexin-A and -B to PC12 cells, suggesting the existence in these cells of some receptors for Orexins. These results indicate that Orexins suppress catecholamine release and synthesis, and that the inhibitory effect is mediated by the cAMP/protein kinase A pathway.