Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production

Grace W.C. Cheung,Brenda B. Su,Carol K.L. Lam,Madhu Chari,Teresa Y.Y. Lai,Clair S. Yang,Andrea Kokorovic,Tony K.T. Lam,Penny Y.T. Wang

doi:10.1074/jbc.m109.087338

Grace W.C. Cheung, Brenda B. Su + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m109.087338

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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.

Highlights

To date, the mechanisms underlying the regulation of hepatic glucose production and homeostasis in healthy and obese/diabetic conditions remain to be elucidated
Four days post- vation of the NMDA receptor in the dorsal vagal complex (DVC) targeting the NTS via intravenous catherization, animals whose daily food intake and DVC glycine administration regulates glucose homeostasis in body weight had recovered back to within 10% of baseline vivo (Fig. 1a)
We here demonstrate with pharmacological, molecular and surgical approaches that direct activation of DVC NMDA receptors triggers the hepatic vagus to lower glucose production in vivo

Summary

Introduction

The mechanisms underlying the regulation of hepatic glucose production and homeostasis in healthy and obese/diabetic conditions remain to be elucidated. Direct administration of NMDA receptor blocker into the DVC negates the ability of lipid/cholecystokinin-sensing mechanisms in the gut to regulate glucose production [17, 18]. It remains unknown whether direct activation of NMDA receptors in the DVC control glucose homeostasis.

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