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Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance

OBJECTIVE: Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improv...

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Autores principales: Perfield, James W., Lee, Yunkyoung, Shulman, Gerald I., Samuel, Varman T., Jurczak, Michael J., Chang, Eugene, Xie, Chen, Tsichlis, Phillip N., Obin, Martin S., Greenberg, Andrew S.
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064090/
https://www.ncbi.nlm.nih.gov/pubmed/21346175
http://dx.doi.org/10.2337/db10-0715
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author Perfield, James W.
Lee, Yunkyoung
Shulman, Gerald I.
Samuel, Varman T.
Jurczak, Michael J.
Chang, Eugene
Xie, Chen
Tsichlis, Phillip N.
Obin, Martin S.
Greenberg, Andrew S.
author_facet Perfield, James W.
Lee, Yunkyoung
Shulman, Gerald I.
Samuel, Varman T.
Jurczak, Michael J.
Chang, Eugene
Xie, Chen
Tsichlis, Phillip N.
Obin, Martin S.
Greenberg, Andrew S.
author_sort Perfield, James W.
collection PubMed
description OBJECTIVE: Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS: We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS: Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.
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spelling pubmed-30640902012-04-01 Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance Perfield, James W. Lee, Yunkyoung Shulman, Gerald I. Samuel, Varman T. Jurczak, Michael J. Chang, Eugene Xie, Chen Tsichlis, Phillip N. Obin, Martin S. Greenberg, Andrew S. Diabetes Obesity Studies OBJECTIVE: Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS: We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS: Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity. American Diabetes Association 2011-04 2011-03-22 /pmc/articles/PMC3064090/ /pubmed/21346175 http://dx.doi.org/10.2337/db10-0715 Text en © 2011 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 Obesity Studies
Perfield, James W.
Lee, Yunkyoung
Shulman, Gerald I.
Samuel, Varman T.
Jurczak, Michael J.
Chang, Eugene
Xie, Chen
Tsichlis, Phillip N.
Obin, Martin S.
Greenberg, Andrew S.
Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title_full Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title_fullStr Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title_full_unstemmed Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title_short Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance
title_sort tumor progression locus 2 (tpl2) regulates obesity-associated inflammation and insulin resistance
topic Obesity Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064090/
https://www.ncbi.nlm.nih.gov/pubmed/21346175
http://dx.doi.org/10.2337/db10-0715
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