Hypothalamic Leucine Metabolism Regulates Liver Glucose Production

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 th...

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Autores principales: Su, Ya, Lam, Tony K.T., He, Wu, Pocai, Alessandro, Bryan, Joseph, Aguilar-Bryan, Lydia, Gutiérrez-Juárez, Roger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237640/
https://www.ncbi.nlm.nih.gov/pubmed/22187376
http://dx.doi.org/10.2337/db11-0857
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author Su, Ya
Lam, Tony K.T.
He, Wu
Pocai, Alessandro
Bryan, Joseph
Aguilar-Bryan, Lydia
Gutiérrez-Juárez, Roger
author_facet Su, Ya
Lam, Tony K.T.
He, Wu
Pocai, Alessandro
Bryan, Joseph
Aguilar-Bryan, Lydia
Gutiérrez-Juárez, Roger
author_sort Su, Ya
collection PubMed
description 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 (K(ATP) 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 K(ATP) 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.
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spelling pubmed-32376402013-01-01 Hypothalamic Leucine Metabolism Regulates Liver Glucose Production Su, Ya Lam, Tony K.T. He, Wu Pocai, Alessandro Bryan, Joseph Aguilar-Bryan, Lydia Gutiérrez-Juárez, Roger Diabetes Metabolism 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 (K(ATP) 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 K(ATP) 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. American Diabetes Association 2012-01 2011-12-12 /pmc/articles/PMC3237640/ /pubmed/22187376 http://dx.doi.org/10.2337/db11-0857 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Metabolism
Su, Ya
Lam, Tony K.T.
He, Wu
Pocai, Alessandro
Bryan, Joseph
Aguilar-Bryan, Lydia
Gutiérrez-Juárez, Roger
Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title_full Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title_fullStr Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title_full_unstemmed Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title_short Hypothalamic Leucine Metabolism Regulates Liver Glucose Production
title_sort hypothalamic leucine metabolism regulates liver glucose production
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237640/
https://www.ncbi.nlm.nih.gov/pubmed/22187376
http://dx.doi.org/10.2337/db11-0857
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