Hypothalamic Nutrient Sensing Activates a Forebrain-Hindbrain Neuronal Circuit to Regulate Glucose Production In Vivo
Open Access
- 24 September 2010
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 60 (1), 107-113
- https://doi.org/10.2337/db10-0994
Abstract
OBJECTIVE: Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production. RESEARCH DESIGN AND METHODS: We implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK α2 [D157A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo. RESULTS: MBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production. CONCLUSIONS: Molecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.Keywords
This publication has 25 references indexed in Scilit:
- Hypothalamic AMP-Activated Protein Kinase Regulates Glucose ProductionDiabetes, 2010
- Activation of N-Methyl-d-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose ProductionPublished by Elsevier BV ,2010
- A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy ExpenditureCell, 2009
- Hypothalamic Leptin Signaling Regulates Hepatic Insulin Sensitivity via a Neurocircuit Involving the Vagus NerveEndocrinology, 2009
- Mediobasal Hypothalamic Leucine Sensing Regulates Food Intake through Activation of a Hypothalamus-Brainstem CircuitJournal of Neuroscience, 2009
- Hypothalamic Protein Kinase C Regulates Glucose ProductionDiabetes, 2008
- Central insulin action regulates peripheral glucose and fat metabolism in miceJCI Insight, 2008
- Activation of Central Lactate Metabolism Lowers Glucose Production in Uncontrolled Diabetes and Diet-Induced Insulin ResistanceDiabetes, 2008
- The Hormonal Control of Food IntakeCell, 2007
- Gastrointestinal regulation of food intakeJCI Insight, 2007