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Science 309 (5736): 943-947

Copyright © 2005 by the American Association for the Advancement of Science

Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

Tony K. T. Lam, Roger Gutierrez-Juarez, Alessandro Pocai, Luciano Rossetti*

Abstract: The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)–sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

* To whom correspondence should be addressed. E-mail: rossetti{at}

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Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes.
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Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action.
K. Kimura, Y. Nakamura, Y. Inaba, M. Matsumoto, Y. Kido, S.-i. Asahara, T. Matsuda, H. Watanabe, A. Maeda, F. Inagaki, et al. (2013)
Diabetes 62, 2266-2277
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Evidence for a Role of Proline and Hypothalamic Astrocytes in the Regulation of Glucose Metabolism in Rats.
I. Arrieta-Cruz, Y. Su, C. M. Knight, T. K. T. Lam, and R. Gutierrez-Juarez (2013)
Diabetes 62, 1152-1158
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Gliotransmission and Brain Glucose Sensing: Critical Role of Endozepines.
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Diabetes 62, 801-810
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Hypothalamic Leucine Metabolism Regulates Liver Glucose Production.
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Diabetes 61, 85-93
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Study of GPR81, the Lactate Receptor, from Distant Species Identifies Residues and Motifs Critical for GPR81 Functions.
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Mol. Pharmacol. 80, 848-858
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NBCe1 Mediates the Acute Stimulation of Astrocytic Glycolysis by Extracellular K+.
I. Ruminot, R. Gutierrez, G. Pena-Munzenmayer, C. Anazco, T. Sotelo-Hitschfeld, R. Lerchundi, M. I. Niemeyer, G. E. Shull, and L. F. Barros (2011)
J. Neurosci. 31, 14264-14271
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Glucose Transporter-1 in the Hypothalamic Glial Cells Mediates Glucose Sensing to Regulate Glucose Production In Vivo.
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M. T. Wyss, R. Jolivet, A. Buck, P. J. Magistretti, and B. Weber (2011)
J. Neurosci. 31, 7477-7485
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Hypothalamic Nutrient Sensing Activates a Forebrain-Hindbrain Neuronal Circuit to Regulate Glucose Production In Vivo.
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Diabetes 60, 107-113
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Differential effects of hypothalamic long-chain fatty acid infusions on suppression of hepatic glucose production.
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Am J Physiol Endocrinol Metab 299, E633-E639
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Hypothalamic AMP-Activated Protein Kinase Regulates Glucose Production.
C. S. Yang, C. K. L. Lam, M. Chari, G. W. C. Cheung, A. Kokorovic, S. Gao, I. Leclerc, G. A. Rutter, and T. K. T. Lam (2010)
Diabetes 59, 2435-2443
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Activation of N-Methyl-D-aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production.
C. K. L. Lam, M. Chari, B. B. Su, G. W. C. Cheung, A. Kokorovic, C. S. Yang, P. Y. T. Wang, T. Y. Y. Lai, and T. K. T. Lam (2010)
J. Biol. Chem. 285, 21913-21921
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Fibroblast Growth Factor 21 Action in the Brain Increases Energy Expenditure and Insulin Sensitivity in Obese Rats.
D. A. Sarruf, J. P. Thaler, G. J. Morton, J. German, J. D. Fischer, K. Ogimoto, and M. W. Schwartz (2010)
Diabetes 59, 1817-1824
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Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite.
G. D. Lopaschuk, J. R. Ussher, and J. S. Jaswal (2010)
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High Fat and Highly Thermolyzed Fat Diets Promote Insulin Resistance and Increase DNA Damage in Rats.
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CNS Regulation of Glucose Homeostasis.
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Physiology 24, 159-170
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Biological Approaches to Mechanistically Understand the Healthy Life Span Extension Achieved by Calorie Restriction and Modulation of Hormones.
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J Gerontol A Biol Sci Med Sci
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Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81.
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Hypothalamic Protein Kinase C Regulates Glucose Production.
R. Ross, P. Y.T. Wang, M. Chari, C. K.L. Lam, L. Caspi, H. Ono, E. D. Muse, X. Li, R. Gutierrez-Juarez, P. E. Light, et al. (2008)
Diabetes 57, 2061-2065
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Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake.
D. A. Sandoval, D. Bagnol, S. C. Woods, D. A. D'Alessio, and R. J. Seeley (2008)
Diabetes 57, 2046-2054
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Central lactate metabolism regulates food intake.
C. K. L. Lam, M. Chari, P. Y. T. Wang, and T. K. T. Lam (2008)
Am J Physiol Endocrinol Metab 295, E491-E496
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Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte-Neuron Lactate-Shuttle Hypothesis.
J. S. Erlichman, A. Hewitt, T. L. Damon, M. Hart, J. Kurascz, A. Li, and J. C. Leiter (2008)
J. Neurosci. 28, 4888-4896
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Involvement of lactate in glucose metabolism and glucosensing function in selected tissues of rainbow trout.
S. Polakof and J. L. Soengas (2008)
J. Exp. Biol. 211, 1075-1086
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Activation of Central Lactate Metabolism Lowers Glucose Production in Uncontrolled Diabetes and Diet-Induced Insulin Resistance.
M. Chari, C. K.L. Lam, P. Y.T. Wang, and T. K.T. Lam (2008)
Diabetes 57, 836-840
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In vitro evidences for glucosensing capacity and mechanisms in hypothalamus, hindbrain, and Brockmann bodies of rainbow trout.
S. Polakof, J. M. Miguez, and J. L. Soengas (2007)
Am J Physiol Regulatory Integrative Comp Physiol 293, R1410-R1420
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Brain Glucose Sensing, Counterregulation, and Energy Homeostasis.
N. Marty, M. Dallaporta, and B. Thorens (2007)
Physiology 22, 241-251
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Orchestration of Glucose Homeostasis: From a Small Acorn to the California Oak.
R. N. Bergman (2007)
Diabetes 56, 1489-1501
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Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?.
P. D. Mountjoy and G. A. Rutter (2007)
Exp Physiol 92, 311-319
   Abstract »    Full Text »    PDF »
Role of malonyl-CoA in heart disease and the hypothalamic control of obesity.
C. D.L. Folmes and G. D. Lopaschuk (2007)
Cardiovasc Res 73, 278-287
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Transforming growth factor-beta in the brain regulates fat metabolism during endurance exercise.
T. Ishikawa, W. Mizunoya, T. Shibakusa, K. Inoue, and T. Fushiki (2006)
Am J Physiol Endocrinol Metab 291, E1151-E1159
   Abstract »    Full Text »    PDF »
Long-range negative correlation of glucose dynamics in humans and its breakdown in diabetes mellitus.
H. Ogata, K. Tokuyama, S. Nagasaka, A. Ando, I. Kusaka, N. Sato, A. Goto, S. Ishibashi, K. Kiyono, Z. R. Struzik, et al. (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R1638-R1643
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The Brain-Gut-Islet Connection.
S. C. Woods, S. C. Benoit, and D. J. Clegg (2006)
Diabetes 55, S114-S121
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Pancreatic signals controlling food intake; insulin, glucagon and amylin.
S. C Woods, T. A Lutz, N. Geary, and W. Langhans (2006)
Phil Trans R Soc B 361, 1219-1235
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Papers of Note.
Sci. Aging Knowl. Environ. 2005, nw30
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