Essential role of protein tyrosine phosphatase 1B in obesity‐induced inflammation and peripheral insulin resistance during aging

Aging Cell

Águeda González-Rodríguez¹  Jose A. Más-Gutierrez⁶  Mercedes Mirasierra¹  Antonio Fernandez-Pérez¹  Yong J. Lee²  Hwi J. Ko²  Jason K. Kim²  Eduardo Romanos³  Jose M. Carrascosa⁴  Manuel Ros⁶  Mario Vallejo¹  Cristina M. Rondinone⁵ 

[1] Institute of Biomedicine Alberto Sols (CSIC/UAM), 28029 Madrid, Spain;Program in Molecular Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USA;Phenotyping Unit, IIS Aragon, Zaragoza, Spain;Center of Molecular Biology Severo Ochoa (CSIC/UAM), 28049 Madrid, Spain;Metabolic Diseases Research, Global Pharmaceutical Research Division, Abbott Laboratories, Department 47R, Building AP1, Abbott Park, IL 60064-6099, USA;Faculty of Health Sciences, University Rey Juan Carlos, 28922 Madrid, Spain

关键词: insulin resistance;    type 2 diabetes;    obesity;    inflammation;    PTP1B;   

DOI  :  10.1111/j.1474-9726.2011.00786.x

来源: Wiley

【 摘 要 】

Summary

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes (T2DM). In this study, we have evaluated the role of PTP1B in the development of aging-associated obesity, inflammation, and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B^−/− mice maintained on mixed genetic background (C57Bl/6J × 129Sv/J). Whereas fat mass and adipocyte size were increased in wild-type control mice at 16 months, these parameters did not change with aging in PTP1B^−/− mice. Increased levels of pro-inflammatory cytokines, crown-like structures, and hypoxia-inducible factor (HIF)-1α were observed only in adipose tissue from 16-month-old wild-type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild-type mice with aging-associated obesity, but not in PTP1B^−/− animals. Leanness in 16-month-old PTP1B^−/− mice was associated with increased energy expenditure. Whole-body insulin sensitivity decreased in 16-month-old control mice; however, studies with the hyperinsulinemic–euglycemic clamp revealed that PTP1B deficiency prevented this obesity-related decreased peripheral insulin sensitivity. At a molecular level, PTP1B expression and enzymatic activity were up-regulated in liver and muscle of 16-month-old wild-type mice as were the activation of stress kinases and the expression of p53. Conversely, insulin receptor-mediated Akt/Foxo1 signaling was attenuated in these aged control mice. Collectively, these data implicate PTP1B in the development of inflammation and insulin resistance associated with obesity during aging and suggest that inhibition of this phosphatase by therapeutic strategies might protect against age-dependent T2DM.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland