title: Perifornical hypothalamic orexin and serotonin modulate the counterregulatory response to hypoglycemic and glucoprivic stimuli.
abstract: Previous reports suggested an important role for serotonin (5-hydroxytryptamine [5-HT]) in enhancing the counterregulatory response (CRR) to hypoglycemia. To elucidate the sites of action mediating this effect, we initially found that insulin-induced hypoglycemia stimulates 5-HT release in widespread forebrain regions, including the perifornical hypothalamus (PFH; 30%), ventromedial hypothalamus (34%), paraventricular hypothalamus (34%), paraventricular thalamic nucleus (64%), and cerebral cortex (63%). Of these, we focused on the PFH because of its known modulation of diverse neurohumoral and behavioral responses. In awake, behaving rats, bilateral PFH glucoprivation with 5-thioglucose stimulated adrenal medullary epinephrine (Epi) release (3,153%) and feeding (400%), while clamping PFH glucose at postprandial brain levels blunted the Epi response to hypoglycemia by 30%. The PFH contained both glucose-excited (GE) and glucose-inhibited (GI) neurons; GE neurons were primarily excited, while GI neurons were equally excited or inhibited by 5-HT at hypoglycemic glucose levels in vitro. Also, 5-HT stimulated lactate production by cultured hypothalamic astrocytes. Depleting PFH 5-HT blunted the Epi (but not feeding) response to focal PFH (69%) and systemic glucoprivation (39%), while increasing PFH 5-HT levels amplified the Epi response to hypoglycemia by 32%. Finally, the orexin 1 receptor antagonist SB334867A attenuated both the Epi (65%) and feeding (47%) responses to focal PFH glucoprivation. Thus we have identified the PFH as a glucoregulatory region where both 5-HT and orexin modulate the CRR and feeding responses to glucoprivation.
authors.affiliation: Graduate School of Biomedical Sciences, Rutgers, Newark, NJ Department of Neurology and Neurosciences, New Jersey Medical School, Rutgers, Newark, NJ.
authors.forename: Oleg
authors.initials: O
authors.lastname: Otlivanchik
authors.affiliation: Department of Neurology and Neurosciences, New Jersey Medical School, Rutgers, Newark, NJ.
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Foll
authors.affiliation: Department of Neurology and Neurosciences, New Jersey Medical School, Rutgers, Newark, NJ Neurology Service, Veterans Affairs Medical Center, East Orange, NJ levin@njms.rutgers.edu.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001583:Benzoxazoles / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D020712:Fornix, Brain / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D020644:Midline Thalamic Nuclei / Q000378:metabolism; D009287:Naphthyridines; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D001786:Blood Glucose; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D018013:Receptors, Neuropeptide; D012701:Serotonin; D014508:Urea
references.citation: J Clin Invest. 1997 Jan 15;99(2):361-5
references.pmid: 9006005
references.citation: Diabetes. 1999 Mar;48(3):584-7
references.pmid: 10078560
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R572-80
references.pmid: 21697524
references.citation: Diabetes. 2003 Mar;52(3):663-6
references.pmid: 12606506
references.citation: Am J Physiol Endocrinol Metab. 2008 May;294(5):E853-60
references.pmid: 18334609
references.citation: Ann N Y Acad Sci. 1978 Jun 12;305:346-69
references.pmid: 280251
references.citation: Diabetes. 1999 Nov;48(11):2132-7
references.pmid: 10535445
references.citation: Endocr Regul. 2004 Sep;38(3):97-102
references.pmid: 15693287
references.citation: Diabetes. 1991 Feb;40(2):223-6
references.pmid: 1991573
references.citation: Diabetes. 2014 Jun;63(6):1895-906
references.pmid: 24550189
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Nov;287(5):R1110-5
references.pmid: 15475504
references.citation: Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R123-8
references.pmid: 14660476
references.citation: Brain Res. 1997 Jan 16;745(1-2):1-9
references.pmid: 9037388
references.citation: Neurosci Lett. 1999 Apr 2;264(1-3):101-4
references.pmid: 10320024
references.citation: Diabetes. 2008 Feb;57(2):470-5
references.pmid: 18003752
references.citation: Am J Physiol Regul Integr Comp Physiol. 2009 Sep;297(3):R655-64
references.pmid: 19535676
references.citation: J Neurosci. 2009 May 27;29(21):7015-22
references.pmid: 19474328
references.citation: Brain Res. 2002 Mar 8;929(2):175-80
references.pmid: 11864622
references.citation: Diabetes. 2008 Sep;57(9):2453-60
references.pmid: 18567822
references.citation: J Comp Neurol. 2006 Feb 10;494(5):845-61
references.pmid: 16374809
references.citation: J Neurosci. 2002 Nov 1;22(21):9453-64
references.pmid: 12417670
references.citation: Neurosci Lett. 2001 Aug 31;309(3):165-8
references.pmid: 11514067
references.citation: Brain Res. 1980 Dec 8;202(2):474-8
references.pmid: 6254614
references.citation: Physiol Behav. 2006 Nov 30;89(4):490-500
references.pmid: 16887153
references.citation: Diabetes. 2014 Apr;63(4):1259-69
references.pmid: 24379353
references.citation: Diabetes. 2008 May;57(5):1371-9
references.pmid: 18292346
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):85-102
references.pmid: 12551730
references.citation: Diabetes. 2000 Nov;49(11):1865-74
references.pmid: 11078453
references.citation: Diabetes Care. 2012 Sep;35(9):1814-6
references.pmid: 22923682
references.citation: Diabetologia. 2002 Jul;45(7):937-48
references.pmid: 12136392
references.citation: Diabetes. 2001 Jan;50(1):105-12
references.pmid: 11147774
references.citation: Physiol Rev. 1992 Jan;72(1):165-229
references.pmid: 1731370
references.citation: Diabetes. 2001 Dec;50(12):2673-81
references.pmid: 11723049
references.citation: Am J Physiol. 1980 Feb;238(2):E141-4
references.pmid: 7361889
references.citation: J Neurosci. 1994 Aug;14(8):5068-76
references.pmid: 8046468
references.citation: J Neurosci. 2005 Mar 2;25(9):2429-33
references.pmid: 15745970
references.citation: Neurosci Lett. 1999 Mar 5;262(2):77-80
references.pmid: 10203235
references.citation: J Pharmacol Exp Ther. 1993 Jun;265(3):1319-24
references.pmid: 7685386
references.citation: Neuroreport. 2001 Mar 5;12(3):531-4
references.pmid: 11234758
references.citation: Diabetes. 2005 Jan;54(1):15-22
references.pmid: 15616006
references.citation: Diabetes. 1992 Mar;41(3):255-60
references.pmid: 1551485
references.citation: Diabetes. 2004 Mar;53(3):549-59
references.pmid: 14988237
references.citation: Diabetes. 2003 Nov;52(11):2767-73
references.pmid: 14578295
references.citation: J Neurosci. 1998 Dec 1;18(23):9996-10015
references.pmid: 9822755
references.citation: Neuroscience. 2003;122(2):541-50
references.pmid: 14614918
references.citation: Am J Physiol. 1989 Dec;257(6 Pt 2):R1345-53
references.pmid: 2690647
references.citation: Diabetes. 2013 Aug;62(8):2709-16
references.pmid: 23557700
references.citation: J Pharmacol Exp Ther. 2002 Jul;302(1):174-9
references.pmid: 12065714
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1792-8
references.pmid: 17218439
references.citation: Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R57-65
references.pmid: 12388440
references.citation: J Clin Invest. 1994 Apr;93(4):1677-82
references.pmid: 8163668
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18976-81
references.pmid: 19033200
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Nov;281(5):R1426-36
references.pmid: 11641112
references.citation: Diabetes. 1995 Feb;44(2):180-4
references.pmid: 7859938
references.citation: Brain Res. 2000 Aug 25;874(2):158-64
references.pmid: 10960600
references.citation: Diabetes Care. 2012 Sep;35(9):1897-901
references.pmid: 22699297
references.citation: Brain Res. 2000 Feb 21;856(1-2):37-47
references.pmid: 10677609
references.citation: J Neurosci. 2010 Jun 16;30(24):8061-70
references.pmid: 20554857
references.citation: Diabetes. 2008 Dec;57(12):3315-22
references.pmid: 18835927