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Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice
AIMS/HYPOTHESIS: Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the path...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer-Verlag
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131508/ https://www.ncbi.nlm.nih.gov/pubmed/21562757 http://dx.doi.org/10.1007/s00125-011-2170-0 |
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author | Kiefer, F. W. Neschen, S. Pfau, B. Legerer, B. Neuhofer, A. Kahle, M. Hrabé de Angelis, M. Schlederer, M. Mair, M. Kenner, L. Plutzky, J. Zeyda, M. Stulnig, T. M. |
author_facet | Kiefer, F. W. Neschen, S. Pfau, B. Legerer, B. Neuhofer, A. Kahle, M. Hrabé de Angelis, M. Schlederer, M. Mair, M. Kenner, L. Plutzky, J. Zeyda, M. Stulnig, T. M. |
author_sort | Kiefer, F. W. |
collection | PubMed |
description | AIMS/HYPOTHESIS: Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the pathogenesis of NAFLD. Here we aimed to identify the role of OPN in obesity-associated hepatic steatosis and impaired hepatic glucose metabolism. METHODS: Wild-type (WT) and Opn (also known as Spp1) knockout (Opn (−/−)) mice were fed a high-fat or low-fat diet to study OPN effects in obesity-driven hepatic alterations. RESULTS: We show that genetic OPN deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis. Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver. Euglycaemic–hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (−/−) mice. OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes. In addition, obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency. CONCLUSIONS/INTERPRETATION: Our data strongly emphasise OPN as mediator of obesity-associated hepatic alterations including steatosis, inflammation, insulin resistance and excess gluconeogenesis. Targeting OPN action could therefore provide a novel therapeutic strategy to prevent obesity-related complications such as NAFLD and type 2 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-011-2170-0) contains supplementary material, which is available to authorised users. |
format | Online Article Text |
id | pubmed-3131508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-31315082011-08-10 Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice Kiefer, F. W. Neschen, S. Pfau, B. Legerer, B. Neuhofer, A. Kahle, M. Hrabé de Angelis, M. Schlederer, M. Mair, M. Kenner, L. Plutzky, J. Zeyda, M. Stulnig, T. M. Diabetologia Article AIMS/HYPOTHESIS: Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the pathogenesis of NAFLD. Here we aimed to identify the role of OPN in obesity-associated hepatic steatosis and impaired hepatic glucose metabolism. METHODS: Wild-type (WT) and Opn (also known as Spp1) knockout (Opn (−/−)) mice were fed a high-fat or low-fat diet to study OPN effects in obesity-driven hepatic alterations. RESULTS: We show that genetic OPN deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis. Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver. Euglycaemic–hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (−/−) mice. OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes. In addition, obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency. CONCLUSIONS/INTERPRETATION: Our data strongly emphasise OPN as mediator of obesity-associated hepatic alterations including steatosis, inflammation, insulin resistance and excess gluconeogenesis. Targeting OPN action could therefore provide a novel therapeutic strategy to prevent obesity-related complications such as NAFLD and type 2 diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-011-2170-0) contains supplementary material, which is available to authorised users. Springer-Verlag 2011-05-12 2011 /pmc/articles/PMC3131508/ /pubmed/21562757 http://dx.doi.org/10.1007/s00125-011-2170-0 Text en © The Author(s) 2011 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Kiefer, F. W. Neschen, S. Pfau, B. Legerer, B. Neuhofer, A. Kahle, M. Hrabé de Angelis, M. Schlederer, M. Mair, M. Kenner, L. Plutzky, J. Zeyda, M. Stulnig, T. M. Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title | Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title_full | Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title_fullStr | Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title_full_unstemmed | Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title_short | Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
title_sort | osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131508/ https://www.ncbi.nlm.nih.gov/pubmed/21562757 http://dx.doi.org/10.1007/s00125-011-2170-0 |
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