title: Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production.
abstract: Diabetes is characterized by hyperglycemia due partly to increased hepatic glucose production. The hypothalamus regulates hepatic glucose production in rodents. However, it is currently unknown whether other regions of the brain are sufficient in glucose production regulation. The N-methyl-D-aspartate (NMDA) receptor is composed of NR1 and NR2 subunits, which are activated by co-agonist glycine and glutamate or aspartate, respectively. Here we report that direct administration of either co-agonist glycine or NMDA into the dorsal vagal complex (DVC), targeting the nucleus of the solitary tract, lowered glucose production in vivo. Direct infusion of the NMDA receptor blocker MK-801 into the DVC negated the metabolic effect of glycine. To evaluate whether NR1 subunit of the NMDA receptor mediates the effect of glycine, NR1 in the DVC was inhibited by DVC NR1 antagonist 7-chlorokynurenic acid or DVC shRNA-NR1. Pharmacological and molecular inhibition of DVC NR1 negated the metabolic effect of glycine. To evaluate whether the NMDA receptors mediate the effects of NR2 agonist NMDA, DVC NMDA receptors were inhibited by antagonist D-2-amino-5-phosphonovaleric acid (D-APV). DVC D-APV fully negated the ability of DVC NMDA to lower glucose production. Finally, hepatic vagotomy negated the DVC glycine ability to lower glucose production. These findings demonstrate that activation of NR1 and NR2 subunits of the NMDA receptors in the DVC is sufficient to trigger a brain-liver axis to lower glucose production, and suggest that DVC NMDA receptors serve as a therapeutic target for diabetes and obesity.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto M5G 1L7, Canada.
authors.forename: Carol K L
authors.initials: CK
authors.lastname: Lam
authors.forename: Madhu
authors.initials: M
authors.lastname: Chari
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Su
authors.forename: Grace W C
authors.initials: GW
authors.lastname: Cheung
authors.forename: Andrea
authors.initials: A
authors.lastname: Kokorovic
authors.forename: Clair S
authors.initials: CS
authors.lastname: Yang
authors.forename: Penny Y T
authors.initials: PY
authors.lastname: Wang
authors.forename: Teresa Y Y
authors.initials: TY
authors.lastname: Lai
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000096:biosynthesis*; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*
chemical_list: C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D005947:Glucose; C057013:7-chlorokynurenic acid; D005998:Glycine
references.citation: Nat Neurosci. 2002 Nov;5 Suppl:1039-42
references.pmid: 12403981
references.citation: Physiol Rev. 1994 Jul;74(3):723-60
references.pmid: 8036251
references.citation: Science. 2005 Jan 21;307(5708):375-9
references.pmid: 15662002
references.citation: Nature. 2002 Feb 14;415(6873):793-8
references.pmid: 11823786
references.citation: Neurosci Lett. 1992 Feb 3;135(2):265-8
references.pmid: 1625808
references.citation: Nature. 2001 May 31;411(6837):587-90
references.pmid: 11385573
references.citation: J Neurosci. 2003 Jun 15;23(12):5031-40
references.pmid: 12832526
references.citation: Cell. 2007 Apr 20;129(2):251-62
references.pmid: 17448988
references.citation: Cell Metab. 2007 Aug;6(2):99-104
references.pmid: 17681145
references.citation: Crit Rev Neurobiol. 2004;16(3):187-224
references.pmid: 15701057
references.citation: Science. 1988 Aug 12;241(4867):835-7
references.pmid: 2841759
references.citation: Brain Res. 2001 Aug 10;910(1-2):192-4
references.pmid: 11489271
references.citation: Neuron. 1994 Aug;13(2):325-38
references.pmid: 8060614
references.citation: Nature. 2008 Apr 24;452(7190):1012-6
references.pmid: 18401341
references.citation: Diabetes. 2008 Apr;57(4):836-40
references.pmid: 18184925
references.citation: J Pharmacol Exp Ther. 2005 Feb;312(2):834-40
references.pmid: 15388787
references.citation: Neuron. 2008 May 22;58(4):472-97
references.pmid: 18498731
references.citation: Cell Metab. 2006 Apr;3(4):267-75
references.pmid: 16581004
references.citation: Nature. 2005 Apr 21;434(7036):1026-31
references.pmid: 15846348
references.citation: J Clin Invest. 2005 Mar;115(3):703-10
references.pmid: 15711637
references.citation: J Neurochem. 1977 Aug;29(2):291-7
references.pmid: 886334
references.citation: Nat Rev Neurosci. 2008 Jul;9(7):519-31
references.pmid: 18509340
references.citation: Nat Med. 2002 Dec;8(12):1376-82
references.pmid: 12426561
references.citation: Cell. 1999 Apr 2;97(1):9-12
references.pmid: 10199397
references.citation: Cell Metab. 2007 Jun;5(6):438-49
references.pmid: 17550779
references.citation: J Pharmacol Exp Ther. 2007 Sep;322(3):982-8
references.pmid: 17551091
references.citation: Cell Metab. 2006 Jan;3(1):67-73
references.pmid: 16399506
references.citation: Obesity (Silver Spring). 2006 Aug;14 Suppl 5:216S-221S
references.pmid: 17021370
references.citation: Physiology (Bethesda). 2009 Jun;24:159-70
references.pmid: 19509126
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15730-4
references.pmid: 9861038
references.citation: Cell Metab. 2009 Aug;10(2):99-109
references.pmid: 19656488
references.citation: J Neurophysiol. 2005 Jul;94(1):147-52
references.pmid: 15744010
references.citation: Nat Med. 2010 Apr;16(4):392-5
references.pmid: 20376051
references.citation: Science. 2005 Aug 5;309(5736):943-7
references.pmid: 16081739
references.citation: J Clin Invest. 2007 Jan;117(1):13-23
references.pmid: 17200702
references.citation: Mol Pharmacol. 2007 Oct;72(4):907-20
references.pmid: 17622578
references.citation: Cell Metab. 2006 Aug;4(2):123-32
references.pmid: 16890540
references.citation: Nature. 2006 Sep 21;443(7109):289-95
references.pmid: 16988703
references.citation: Nat Med. 2003 Jun;9(6):756-61
references.pmid: 12754501
references.citation: Diabetes. 2008 Aug;57(8):2061-5
references.pmid: 18511848