3 research outputs found
Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging
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)-1a wereobserved only in adipose tissue
from 16-month-old wild-type mice. Similarly, islet hyperplasia
and hyperinsulinemia were observed in wild-type mice with agingassociated
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 upregulated
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-dependentT2DMThis work was supported by grants from Ministerio de Ciencia e
Innovación (Spain) SAF2009-08114 and (to A.M.V.), BFU2008-
04901-C03-02 and 03 (to M.R and J.M.C., respectively),
BFU2008-01283 (to M.V), Comunidad de Madrid S2010/BMD-
2423 and Centro de Investigación Biomédica en Red de Diabetes
y Enfermedades Metabólicas Asociadas (CIBERDEM) (Instituto Salud
Carlos III). CBMSO is recipient of institutional aid from Ramón
Areces Foundation. We also acknowledge grants NIH-R01
DK080756, ADA 7-07-RA-80, and NIH U24-DK093000 (to J.K.K.)
and UMass Mouse Phenotyping Center supported by UMass Diabetes
and Endocrinology Research Center Grant (DK32520) and
EFSD/Amylin Programme 2011 grant (to A.M.V.)
Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging
El pdf del artículo es el manuscrito de autor.-- et al.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 16months 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 16months, 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. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.This work was supported by grants from Ministerio de Ciencia e Innovación (Spain) SAF2009-08114 and (to A.M.V.), BFU2008-04901-C03-02 and 03 (to M.R and J.M.C., respectively), BFU2008-01283 (to M.V), Comunidad de Madrid S2010/BMD-2423 and Centro de Investigación Biomedica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (Instituto Salud Carlos III). CBMSO is recipient of institutional aid from Ramón Areces Foundation. We also acknowledge grants NIH-R01DK080756, ADA 7-07-RA-80, and NIH U24-DK093000 (to J.K.K.) and UMass Mouse Phenotyping Center supported by UMass Diabetes and Endocrinology Research Center Grant (DK32520) and EFSD/Amylin Programme 2011 grant (to A.M.V.).Peer Reviewe