title: Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin.
abstract: Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275-425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Brittany S
authors.initials: BS
authors.lastname: Luckett
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Frielle
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wolfgang
authors.forename: Sean D
authors.initials: SD
authors.lastname: Stocker
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology*; D003627:Data Interpretation, Statistical; D018756:GABA Antagonists / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000503:physiopathology; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood / Q000502:physiology*; D007329:Insulin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008845:Microinjections; D051058:Oncogene Protein v-akt / Q000502:physiology; D010766:Phosphorylation; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D018756:GABA Antagonists; D007328:Insulin; D007329:Insulin Antagonists; D011724:Pyridazines; C049853:gabazine; D051058:Oncogene Protein v-akt
keywords: blood pressure; lumbar; obesity; renal; sympathetic nerve activity
references.citation: Diabetes. 2010 Jun;59(6):1521-7
references.pmid: 20299468
references.citation: Am J Physiol. 1994 Nov;267(5 Pt 2):R1350-5
references.pmid: 7977864
references.citation: J Clin Invest. 1991 Jun;87(6):2246-52
references.pmid: 2040704
references.citation: J Neurosci. 2010 Feb 17;30(7):2472-9
references.pmid: 20164331
references.citation: Diabetes. 1981 Mar;30(3):219-25
references.pmid: 7009270
references.citation: J Comp Neurol. 2004 Apr 12;471(4):462-81
references.pmid: 15022264
references.citation: Circulation. 1997 Nov 18;96(10):3423-9
references.pmid: 9396437
references.citation: PLoS One. 2012;7(12):e53111
references.pmid: 23300873
references.citation: J Clin Invest. 2008 May;118(5):1796-805
references.pmid: 18382766
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1834-8
references.pmid: 17218435
references.citation: Neuron. 1999 Aug;23(4):775-86
references.pmid: 10482243
references.citation: Hypertension. 1994 Jun;23(6 Pt 2):1059-62
references.pmid: 8206594
references.citation: J Comp Neurol. 2001 Oct 8;439(1):1-18
references.pmid: 11579378
references.citation: J Hypertens. 1996 Mar;14(3):301-8
references.pmid: 8723982
references.citation: Am J Physiol. 1993 Feb;264(2 Pt 2):R423-7
references.pmid: 8447499
references.citation: Endocrinology. 1987 Oct;121(4):1562-70
references.pmid: 3653038
references.citation: Circulation. 1994 Jun;89(6):2634-40
references.pmid: 8205675
references.citation: Cell. 2012 Oct 26;151(3):645-57
references.pmid: 23101631
references.citation: J Pharmacol Exp Ther. 2012 Oct;343(1):206-13
references.pmid: 22815534
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2543-9
references.pmid: 17704284
references.citation: PLoS One. 2012;7(9):e45180
references.pmid: 23028831
references.citation: Metabolism. 1974 Jan;23(1):7-14
references.pmid: 4808514
references.citation: Nat Neurosci. 2008 Sep;11(9):998-1000
references.pmid: 19160495
references.citation: Hypertension. 2006 Nov;48(5):787-96
references.pmid: 17000932
references.citation: Circulation. 1998 May 26;97(20):2037-42
references.pmid: 9610534
references.citation: Blood Press. 1994 Nov;3(6):394-403
references.pmid: 7704288
references.citation: J Hypertens. 2001 Mar;19(3 Pt 2):523-8
references.pmid: 11327624
references.citation: J Comp Neurol. 1998 Dec 28;402(4):442-59
references.pmid: 9862320
references.citation: Diabetologia. 2006 Nov;49(11):2790-2
references.pmid: 16951936
references.citation: Hypertension. 2011 Mar;57(3):435-41
references.pmid: 21263116
references.citation: Hypertension. 2010 Feb;55(2):284-90
references.pmid: 20065145
references.citation: Brain Res. 1997 Aug 22;766(1-2):29-38
references.pmid: 9359584
references.citation: Circulation. 2002 Nov 12;106(20):2533-6
references.pmid: 12427647
references.citation: Hypertension. 2007 Aug;50(2):354-9
references.pmid: 17592069
references.citation: J Physiol. 2011 Apr 1;589(Pt 7):1643-62
references.pmid: 21300750
references.citation: J Hypertens. 2010 Sep;28(9):1913-9
references.pmid: 20577122
references.citation: Brain Res. 1987 Dec 15;436(2):323-38
references.pmid: 2829991
references.citation: J Physiol. 2010 Sep 15;588(Pt 18):3593-603
references.pmid: 20643774
references.citation: J Clin Invest. 1993 Oct;92(4):1824-30
references.pmid: 8408635
references.citation: Int J Obes Relat Metab Disord. 2000 Sep;24(9):1183-7
references.pmid: 11033988
references.citation: Hypertension. 2007 Mar;49(3):640-6
references.pmid: 17190873
references.citation: Hypertension. 2008 Feb;51(2):514-20
references.pmid: 18158342
references.citation: J Neurosci. 2003 Jul 9;23(14):5998-6004
references.pmid: 12853417
references.citation: J Comp Neurol. 2000 Jul 24;423(2):261-81
references.pmid: 10867658
references.citation: Am J Physiol. 1994 Feb;266(2 Pt 2):R481-6
references.pmid: 8141406
references.citation: Endocrinology. 1990 Dec;127(6):3234-6
references.pmid: 2249648
references.citation: Diabetes. 2000 Sep;49(9):1525-33
references.pmid: 10969837
references.citation: J Clin Invest. 2004 Sep;114(5):652-8
references.pmid: 15343383
references.citation: Hypertension. 2013 Mar;61(3):628-34
references.pmid: 23339171
references.citation: J Neurosci. 2006 Mar 29;26(13):3423-33
references.pmid: 16571749