Essential role of protein tyrosine phosphatase 1B in obesity‐induced inflammation and peripheral insulin resistance during aging
Open Access
- 29 December 2011
- journal article
- Published by Wiley in Aging Cell
- Vol. 11 (2), 284-296
- https://doi.org/10.1111/j.1474-9726.2011.00786.x
Abstract
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.Keywords
This publication has 47 references indexed in Scilit:
- Fat tissue, aging, and cellular senescenceAging Cell, 2010
- Macrophages, Inflammation, and Insulin ResistanceAnnual Review of Physiology, 2010
- PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in miceJCI Insight, 2010
- Insulin Induces REDD1 Expression through Hypoxia-inducible Factor 1 Activation in AdipocytesJournal of Biological Chemistry, 2010
- Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosisJournal of Hepatology, 2010
- Prevention of Steatosis by Hepatic JNK1Cell Metabolism, 2009
- Serum and muscle interleukin-15 levels decrease in aging mice: Correlation with declines in soluble interleukin-15 receptor alpha expressionExperimental Gerontology, 2009
- S6K1 deficiency protects against apoptosis in hepatocytesHepatology, 2009
- Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in VivoPublished by Elsevier BV ,2008
- Critical nodes in signalling pathways: insights into insulin actionNature Reviews Molecular Cell Biology, 2006