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J. Biol. Chem., Vol. 283, Issue 21, 14230-14241, May 23, 2008

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Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo^*

Janice M. Zabolotny¹, Young-Bum Kim, Laura A. Welsh, Erin E. Kershaw, Benjamin G. Neel, and Barbara B. Kahn

From the Division of Endocrinology, Diabetes, and Metabolism and Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin and leptin sensitivity. PTP1B overexpression in adipose tissue and skeletal muscle of humans and rodents may contribute to insulin resistance and obesity. The mechanisms mediating PTP1B overexpression in obese and diabetic states have been unclear. We find that adipose tissue inflammation and the pro-inflammatory cytokine tumor necrosis factor (TNF) regulate PTP1B expression in vivo. High fat feeding of mice increased PTP1B expression 1.5- to 7-fold in adipose tissue, liver, skeletal muscle, and arcuate nucleus of hypothalamus. PTP1B overexpression in high fat-fed mice coincided with increased adipose tissue expression of the macrophage marker CD68 and TNF, which is implicated in causing obesity-induced insulin resistance. TNF increased PTP1B mRNA and protein levels by 2- to 5-fold in a dose- and time-dependent manner in adipocyte and hepatocyte cell lines. TNF administration in mice increased PTP1B mRNA 1.4- to 4-fold in adipose tissue, liver, skeletal muscle, and hypothalamic arcuate nucleus and PTP1B protein 2-fold in liver. Actinomycin D treatment blocked, and high dose salicylate treatment inhibited by 80%, TNF-induced PTP1B expression in adipocyte cell lines, suggesting TNF may induce PTP1B transcription via nuclear factor B (NFB) activation. Chromatin immunoprecipitation from adipocyte cell lines and liver of mice demonstrated TNF-induced recruitment of NFB subunit p65 to the PTP1B promoter in vitro and in vivo. In mice with diet-induced obesity, TNF deficiency also partly blocked PTP1B overexpression in adipose tissue. Our data suggest that PTP1B overexpression in multiple tissues in obesity is regulated by inflammation and that PTP1B may be a target of anti-inflammatory therapies.

Received for publication, January 3, 2008 , and in revised form, February 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants K01 DK062212, R21 DK073530, P30 DK057521, and P30 DK046200 (to J. M. Z.), K08 DK065833 (to E. E. K.), R01 DK060839 (to B. B. K.), R01 DK060838 to (B. G. N. and B. B. K.), and R01 CA049152 (to B. G. N.). This work was also supported by the American Diabetes Association (to B. B. K. and B. G. N., and Grant 7-02-JF-26 to Y.-B. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Research North 325A, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-0258; Fax: 617-667-2927; E-mail: jzabolot{at}bidmc.harvard.edu.

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