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Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp...

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Autores principales: Xu, Elaine, Charbonneau, Alexandre, Rolland, Yannève, Bellmann, Kerstin, Pao, Lily, Siminovitch, Katherine A., Neel, Benjamin G., Beauchemin, Nicole, Marette, André
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402325/
https://www.ncbi.nlm.nih.gov/pubmed/22698917
http://dx.doi.org/10.2337/db11-1502
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author Xu, Elaine
Charbonneau, Alexandre
Rolland, Yannève
Bellmann, Kerstin
Pao, Lily
Siminovitch, Katherine A.
Neel, Benjamin G.
Beauchemin, Nicole
Marette, André
author_facet Xu, Elaine
Charbonneau, Alexandre
Rolland, Yannève
Bellmann, Kerstin
Pao, Lily
Siminovitch, Katherine A.
Neel, Benjamin G.
Beauchemin, Nicole
Marette, André
author_sort Xu, Elaine
collection PubMed
description The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6(f/f) littermates, Ptpn6(H-KO) mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6(H-KO) mice developed comparable levels of obesity as Ptpn6(f/f) mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6(H-KO) mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6(H-KO) mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.
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spelling pubmed-34023252013-08-01 Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance Xu, Elaine Charbonneau, Alexandre Rolland, Yannève Bellmann, Kerstin Pao, Lily Siminovitch, Katherine A. Neel, Benjamin G. Beauchemin, Nicole Marette, André Diabetes Metabolism The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6(f/f) littermates, Ptpn6(H-KO) mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6(H-KO) mice developed comparable levels of obesity as Ptpn6(f/f) mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6(H-KO) mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6(H-KO) mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes. American Diabetes Association 2012-08 2012-07-17 /pmc/articles/PMC3402325/ /pubmed/22698917 http://dx.doi.org/10.2337/db11-1502 Text en © 2012 by the American Diabetes Association. https://creativecommons.org/licenses/by-nc-nd/3.0/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/ (https://creativecommons.org/licenses/by-nc-nd/3.0/) for details.
spellingShingle Metabolism
Xu, Elaine
Charbonneau, Alexandre
Rolland, Yannève
Bellmann, Kerstin
Pao, Lily
Siminovitch, Katherine A.
Neel, Benjamin G.
Beauchemin, Nicole
Marette, André
Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title_full Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title_fullStr Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title_full_unstemmed Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title_short Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance
title_sort hepatocyte-specific ptpn6 deletion protects from obesity-linked hepatic insulin resistance
topic Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402325/
https://www.ncbi.nlm.nih.gov/pubmed/22698917
http://dx.doi.org/10.2337/db11-1502
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