Research Article| Volume 226, 102670, July 2020

Download started.


Intracerebroventricularly injected nesfatin-1 activates central cyclooxygenase and lipoxygenase pathways


      • ICV injected nesfatin-1 increases the immunoreactivities of the hypothalamic COXs and LOX.
      • Centrally administrated nesfatin-1 augments hypothalamic COXs and LOX protein expression
      • ICV injection of nesfatin-1 causes an increase in posterior hypothalamic extracellular total prostaglandin level.


      Nesfatin-1 is a multifunctional neuropeptide having crucial autonomic roles. It is well known that nesfatin-1 collaborates with other central neuromodulatory systems, such as central corticotropin-releasing hormone, melanocortin, oxytocin, and cholinergic systems to show its autonomic effects. Central arachidonic acid cascade plays an important role to provide the homeostasis by exhibiting similar autonomic effects to nesfatin-1. Based on these similarities, the current study was designed to show the effects of intracerebroventricularly (ICV) injected nesfatin-1 on the hypothalamic arachidonic acid (AA) cascade.
      Immunochemistry and western blot approaches demonstrated that ICV administration of nesfatin-1 provokes an increase in the hypothalamic cyclooxygenase (COX) -1, -2 and lipoxygenase (LOX) protein expression. Moreover, the microdialysis study demonstrated that centrally injected nesfatin-1 increased the posterior hypothalamic extracellular AA products.
      In conclusion, these findings report that while nesfatin-1 is generating its autonomic effects, it also might be using central prostaglandins and leukotrienes by activating central COX and LOX pathways.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Adams E.J.
        • et al.
        Comparision of different scoring systems for immunohistochemical staining.
        J. Clin. Pathol. 1999; 52: 75-77
        • Altinbas B.
        • et al.
        The mediation of the central histaminergic system in the pressor effect of intracerebroventricularly injected melittin, a phospholipase A2 activator, in normotensive rats.
        Prostaglandins Leukot. Essent. Fatty Acids. 2012; 87: 153-158
        • Altinbas B.
        • et al.
        Activation of the central histaminergic system mediates arachidonic-acid-induced cardiovascular effects.
        Can. J. Physiol. Pharmacol. 2014; 92: 645-654
        • Aydin B.
        • et al.
        Modulation of nesfatin-1-induced cardiovascular effects by the central cholinergic system.
        Neuropeptides. 2018; 70: 9-15
        • Aydin C.
        • Yalcin M.
        Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid.
        Prostag. Leukotr. Ess. Fatty Acids. 2008; 78: 361-368
        • Bosetti F.
        Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models.
        J. Neurochem. 2007; 102: 577-586
        • Ciftci K.
        • et al.
        Effect of central and peripheral injected nesfatin-1 on electrocardiography in rats.
        J. Res. Vet. Med. 2019; 38: 10-17
        • Ciftci K.
        • et al.
        Centrally and peripherally injected nesfatin-1-evoked respiratory responses.
        Respir. Physiol. Neurobiol. 2019; 267: 6-11
        • Emmerzaal T.L.
        • Kozicz T.
        Nesfatin-1; implication in stress and stress-associated anxiety and depression.
        Curr. Pharm. Des. 2013; 19: 6941-6948
        • Erkan L.G.
        • et al.
        Brain thromboxane A2 via arachidonic acid cascade induces the hypothalamic-pituitary-gonadal axis activation in rats.
        Auton. Neurosci. 2015; 189: 50-55
        • Erkan L.G.
        • et al.
        The effects of centrally injected arachidonic acid on respiratory system: involvement of cyclooxygenase to thromboxane signaling pathway.
        Respir. Physiol. Neurobiol. 2016; 225: 1-7
        • Erkan L.G.
        • et al.
        The acute cardiorespiratory effects of centrally injected arachidonic acid; the mediation of prostaglandin E, D and F2α.
        Respir. Physiol. Neurobiol. 2017; 242: 117-124
        • Gadek-Michalska A.
        • et al.
        Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.
        Pharmacol. Rep. 2013; 65: 1655-1662
        • Garcia-Galiano D.
        • et al.
        Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation.
        J. Mol. Endocrinol. 2010; 45: 281-290
        • Garcia-Galiano D.
        • et al.
        The anorexigenic neuropeptide, nesfatin-1, is indispensable for normal puberty onset in the female rat.
        J. Neurosci. 2010; 30: 7783-7792
        • Goebel M.
        • et al.
        Nesfatin-1 immunoreactivity in rat brain and spinal cord autonomic nuclei.
        Neurosci. Lett. 2009; 452: 241-246
        • Goebel-Stengel M.
        • Wang L.
        Central and peripheral expression and distribution of NUCB2/nesfatin-1.
        Curr. Pharm. Des. 2013; 19: 6935-6940
        • Goebel-Stengel M.
        • et al.
        Localization of nesfatin-1 neurons in the mouse brain and functional implication.
        Brain Res. 2011; 1396: 20-34
        • Guvenc G.
        • et al.
        Contingent role of phoenixin and nesfatin-1 on secretions of the male reproductive hormones.
        Andrologia. 2019; 51e13410
        • Heidarzadeh H.
        • et al.
        The effect of nesfatin-1 on food intake in neonatal chicks: role of CRF1/CRF2 and H1/H3 receptors.
        Vet. Res. Commun. 2018; 42: 39-47
        • Hsu S.
        • Raine M.L.
        • Fanger H.
        Use of avidin–biotin peroxidase complex (ABC) in immunoperoxidase techniques. A comparision between ABC and unlabelled antibody (PAP) procedures.
        J. Histochem. Cytochem. 1981; 29: 557-580
        • Jochem J.
        Involvement of the sympathetic nervous system in the reversal of critical haemorrhagic hypotension by endogenous central histamine in rats.
        Naunyn Schmiedeberg’s Arch. Pharmacol. 2004; 369: 418-427
        • Jochem J.
        Involvement of arginine vasopressin in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.
        Inflamm. Res. 2004; 53: 269-276
        • Katsuki H.
        • Okuda S.
        Arachidonic acid as a neurotoxic and neurotrophic substance.
        Prog. Neurobiol. 1995; 46: 607-636
        • Kawashima S.
        • et al.
        Corticotropin-releasing factor (CRF) is involved in the acute anorexic effect of alpha-melanocyte–stimulating hormone: a study using CRF deficient mice.
        Peptides. 2008; 29: 2169-2174
        • Kolgazi M.
        • et al.
        Anti-inflammatory effects of nesfatin-1 on acetic acid-induced gastric ulcer in rats: involvement of cyclo-oxygenase pathway.
        J. Physiol. Pharmacol. 2017; 68: 765-777
        • Maejima Y.
        • et al.
        Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway.
        Cell Metab. 2009; 10: 355-365
        • NAC (National Academy of Sciences)
        Guide for the Care and Use of Laboratory Animals.
        8th ed. National Academy Press, Washington, D.C2011 (Available from)
        • Oh-I S.
        • et al.
        Identification of nesfatin-1 as a satiety molecule in the hypothalamus.
        Nature. 2006; 443: 709-712
        • Pan W.
        • Hsuchou H.
        • Kastin A.J.
        Nesfatin-1 crosses the blood–brain barrier without saturation.
        Peptides. 2007; 28: 2223-2228
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates.
        Fourth edition. Academic Press, New York2005
        • Prinz P.
        • et al.
        Peripheral and central localization of the nesfatin-1 receptor using autoradiography in rats.
        Biochem. Biophys. Res. Commun. 2016; 470: 521-527
        • Rapoport S.I.
        In vivo approaches to quantifying and imaging brain arachidonic and docosahexaenoic acid metabolism.
        J. Pediatr. 2003; 143: 26-34
        • Rapoport S.I.
        Arachidonic acid and the brain.
        J. Nutr. 2008; 138: 2515-2520
        • Schalla M.A.
        • Stengel A.
        Current understanding of the role of nesfatin-1.
        J. Endocr. Soc. 2018; 2: 1188-1206
        • Scotece M.
        • et al.
        NUCB2/nesfatin-1: a new adipokine expressed in human and murine chondrocytes with pro-inflammatory properties, an in vitro study.
        J. Orthop. Res. 2014; 32: 653-660
        • Stengel A.
        • et al.
        Identification and characterization of nesfatin-1immunoreactivity in endocrine cell types of the rat gastric oxyntic mucosa.
        Endocrinology. 2009; 150: 232-238
        • Stengel A.
        • Goebel M.
        • Tache Y.
        Nesfatin-1: a novel inhibitory regulator of food intake and body weight.
        Obes. Rev. 2011; 12: 261-271
        • Szlachcic A.
        • et al.
        New satiety hormone nesfatin-1 protects gastric mucosa against stress-induced injury: mechanistic roles of prostaglandins, nitric oxide, sensory nerves and vanilloid receptors.
        Peptides. 2013; 49: 9-20
        • Tanida M.
        • Mori M.
        Nesfatin-1 stimulates renal sympathetic nerve activity in rats.
        Neuroreport. 2011; 22: 309-312
        • Ward K.R.
        • et al.
        Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus.
        Hypertension. 2011; 57: 435-441
        • Xiao M.M.
        • et al.
        Plasma nesfatin-1 level is associated with severity of depression in Chinese depressive patients.
        BMC Psychiatry. 2018; 18: 88
        • Yalcin M.
        Central mechanism underlying pressor and bradycardic effect of intracerebroventricularly injected arachidonic acid.
        Can. J. Physiol. Pharmacol. 2011; 89: 127-133
        • Yalcin M.
        • Aydin C.
        Cardiovascular effects of centrally administered arachidonic acid in haemorrhage-induced hypotensive rats: investigation of a peripheral mechanism.
        Clin. Exp. Pharmacol. Physiol. 2009; 36: 447-453
        • Yalcin M.
        • Savci V.
        Restoration of blood pressure by centrally injected U-46619, a thromboxane A2 analog, in haemorhaged hypotensive rats: investigation of different brain areas.
        Pharmacology. 2004; 70: 177-187
        • Yalcin M.
        • Savci V.
        Cardiovascular effects of centrally injected melittin in hemorrhaged hypotensive rats: the investigation of peripheral mechanisms.
        Neuropeptides. 2007; 41: 465-475
        • Yalcin M.
        • et al.
        Involvement of brain thromboxane A2 in hypotension induced by haemorrhage in rats.
        Clin. Exp. Pharmcol. Physiol. 2005; 32: 960-967
        • Yalcin M.
        • Ak F.
        • Erturk M.
        The role of the central thromboxane A2 in cardiovascular effects of a phospholipase A2 activator melittin administrated intracerebroventricularly in normotensive conscious rats.
        Neuropetides. 2006; 40: 207-212
        • Yalcin M.
        • Aydin C.
        • Savci V.
        Cardiovascular effect of peripheral injected melittin in normotensive conscious rats: mediation of the central cholinergic system.
        Prostag. Leukotr. Ess. Fatty Acids. 2009; 81: 341-347
        • Yilmaz M.S.
        • et al.
        The role of centrally injected nesfatin-1 on cardiovascular regulation in normotensive and hypotensive rats.
        Auton. Neurosci. 2015; 193: 63-68
        • Ying J.
        • et al.
        Nesfatin-1 suppresses cardiac L-type Ca2+ channels through melanocortin type 4 receptor and the novel protein kinase C theta isoform pathway.
        Cell. Physiol. Biochem. 2015; 36: 555-568
        • Yokotani K.
        • et al.
        Brain phospholipase A2-arachidonic acid cascade is involved in the activation of central sympatho-adrenomedullary outflow in rats.
        Eur. J. Pharmacol. 2000; 398: 341-347
        • Yosten G.L.
        • Samson W.K.
        Nesfatin-1 exerts cardiovascular actions in brain: possible interaction with the central melanocortin system.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 297: R330-R336
        • Yosten G.L.
        • Samson W.K.
        The anorexigenic and hypertensive effects of nesfatin-1 are reversed by pretreatment with an oxytocin receptor antagonist.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 298: R1642-R1647
        • Yosten G.L.
        • Samson W.K.
        Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014; 306: R722-R727