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Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance

We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats...

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Autores principales: Kumashiro, Naoki, Beddow, Sara A., Vatner, Daniel F., Majumdar, Sachin K., Cantley, Jennifer L., Guebre-Egziabher, Fitsum, Fat, Ioana, Guigni, Blas, Jurczak, Michael J., Birkenfeld, Andreas L., Kahn, Mario, Perler, Bryce K., Puchowicz, Michelle A., Manchem, Vara Prasad, Bhanot, Sanjay, Still, Christopher D., Gerhard, Glenn S., Petersen, Kitt Falk, Cline, Gary W., Shulman, Gerald I., Samuel, Varman T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712050/
https://www.ncbi.nlm.nih.gov/pubmed/23423574
http://dx.doi.org/10.2337/db12-1311
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author Kumashiro, Naoki
Beddow, Sara A.
Vatner, Daniel F.
Majumdar, Sachin K.
Cantley, Jennifer L.
Guebre-Egziabher, Fitsum
Fat, Ioana
Guigni, Blas
Jurczak, Michael J.
Birkenfeld, Andreas L.
Kahn, Mario
Perler, Bryce K.
Puchowicz, Michelle A.
Manchem, Vara Prasad
Bhanot, Sanjay
Still, Christopher D.
Gerhard, Glenn S.
Petersen, Kitt Falk
Cline, Gary W.
Shulman, Gerald I.
Samuel, Varman T.
author_facet Kumashiro, Naoki
Beddow, Sara A.
Vatner, Daniel F.
Majumdar, Sachin K.
Cantley, Jennifer L.
Guebre-Egziabher, Fitsum
Fat, Ioana
Guigni, Blas
Jurczak, Michael J.
Birkenfeld, Andreas L.
Kahn, Mario
Perler, Bryce K.
Puchowicz, Michelle A.
Manchem, Vara Prasad
Bhanot, Sanjay
Still, Christopher D.
Gerhard, Glenn S.
Petersen, Kitt Falk
Cline, Gary W.
Shulman, Gerald I.
Samuel, Varman T.
author_sort Kumashiro, Naoki
collection PubMed
description We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat–fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes.
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spelling pubmed-37120502014-07-01 Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance Kumashiro, Naoki Beddow, Sara A. Vatner, Daniel F. Majumdar, Sachin K. Cantley, Jennifer L. Guebre-Egziabher, Fitsum Fat, Ioana Guigni, Blas Jurczak, Michael J. Birkenfeld, Andreas L. Kahn, Mario Perler, Bryce K. Puchowicz, Michelle A. Manchem, Vara Prasad Bhanot, Sanjay Still, Christopher D. Gerhard, Glenn S. Petersen, Kitt Falk Cline, Gary W. Shulman, Gerald I. Samuel, Varman T. Diabetes Original Research We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat–fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. American Diabetes Association 2013-07 2013-06-14 /pmc/articles/PMC3712050/ /pubmed/23423574 http://dx.doi.org/10.2337/db12-1311 Text en © 2013 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 Original Research
Kumashiro, Naoki
Beddow, Sara A.
Vatner, Daniel F.
Majumdar, Sachin K.
Cantley, Jennifer L.
Guebre-Egziabher, Fitsum
Fat, Ioana
Guigni, Blas
Jurczak, Michael J.
Birkenfeld, Andreas L.
Kahn, Mario
Perler, Bryce K.
Puchowicz, Michelle A.
Manchem, Vara Prasad
Bhanot, Sanjay
Still, Christopher D.
Gerhard, Glenn S.
Petersen, Kitt Falk
Cline, Gary W.
Shulman, Gerald I.
Samuel, Varman T.
Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title_full Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title_fullStr Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title_full_unstemmed Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title_short Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
title_sort targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712050/
https://www.ncbi.nlm.nih.gov/pubmed/23423574
http://dx.doi.org/10.2337/db12-1311
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