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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2013
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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. |
format | Online Article Text |
id | pubmed-3712050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
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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