Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
Open Access
- 12 December 2011
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 61 (1), 85-93
- https://doi.org/10.2337/db11-0857
Abstract
Amino acids profoundly affect insulin action and glucose metabolism in mammals. Here, we investigated the role of the mediobasal hypothalamus (MBH), a key center involved in nutrient-dependent metabolic regulation. Specifically, we tested the novel hypothesis that the metabolism of leucine within the MBH couples the central sensing of leucine with the control of glucose production by the liver. We performed either central (MBH) or systemic infusions of leucine in Sprague-Dawley male rats during basal pancreatic insulin clamps in combination with various pharmacological and molecular interventions designed to modulate leucine metabolism in the MBH. We also examined the role of hypothalamic ATP-sensitive K+ channels (KATP channels) in the effects of leucine. Enhancing the metabolism of leucine acutely in the MBH lowered blood glucose through a biochemical network that was insensitive to rapamycin but strictly dependent on the hypothalamic metabolism of leucine to α-ketoisocaproic acid and, further, insensitive to acetyl- and malonyl-CoA. Functional KATP channels were also required. Importantly, molecular attenuation of this central sensing mechanism in rats conferred susceptibility to developing hyperglycemia. We postulate that the metabolic sensing of leucine in the MBH is a previously unrecognized mechanism for the regulation of hepatic glucose production required to maintain glucose homeostasis.Keywords
This publication has 51 references indexed in Scilit:
- Metabolite profiles and the risk of developing diabetesNature Medicine, 2011
- Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitusNutrition & Metabolism, 2010
- Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC NeuronsDiabetes, 2009
- Mediobasal Hypothalamic Leucine Sensing Regulates Food Intake through Activation of a Hypothalamus-Brainstem CircuitJournal of Neuroscience, 2009
- A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin ResistanceCell Metabolism, 2009
- Disruption of BCATm in Mice Leads to Increased Energy Expenditure Associated with the Activation of a Futile Protein Turnover CycleCell Metabolism, 2007
- Long-term effects of popular dietary approaches on weight loss and features of insulin resistanceInternational Journal of Obesity, 2005
- Hypothalamic KATP channels control hepatic glucose productionNature, 2005
- A Nutrient Sensor Mechanism Controls Drosophila GrowthCell, 2003
- Effect of Starvation on the Turnover and Metabolic Response to LeucineJCI Insight, 1978