Inhibition of PTP1B by Trodusquemine (MSI-1436) Causes Fat-specific Weight Loss in Diet-induced Obese Mice

被引：209

作者：

Lantz, Kristen A. ^{[1
]}

Hart, Susan G. Emeigh ^{[1
]}

Planey, Sonia L. ^{[1
]}

Roitman, Mitchell F. ^{[2
]}

Ruiz-White, Inez A. ^{[1
]}

Wolfe, Henry R. ^{[1
]}

McLane, Michael P. ^{[1
]}

机构：

[1] Genaera Corp, Dept Preclin Res, Plymouth Meeting, PA USA

[2] Univ Illinois, Dept Psychol, Chicago, IL 60680 USA

来源：

OBESITY | 2010年 / 18卷 / 08期

关键词：

TYROSINE-PHOSPHATASE; 1B; INSULIN-RECEPTOR; LEPTIN RESISTANCE; BODY-WEIGHT; EXPRESSION; REDUCTION; DEPHOSPHORYLATION; HOMEOSTASIS; DELETION; DISEASE;

D O I：

10.1038/oby.2009.444

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Trodusquemine (MSI-1436) causes rapid and reversible weight loss in genetic models of obesity. To better predict the potential effects of trodusquemine in the clinic, we investigated the effects of trodusquemine treatment in a murine model of diet-induced obesity (DIO). Trodusquemine suppressed appetite, reduced body weight (BW) in a fat-specific manner, and improved plasma insulin and leptin levels in mice. Screening assays revealed that trodusquemine selectively inhibited protein-tyrosine phosphatase 1B (PTP1B), a key enzyme regulating insulin and leptin signaling. Trodusquemine significantly enhanced insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) beta and STAT3, direct targets of PTP1B, in HepG2 cells in vitro and/or hypothalamic tissue in vivo. These data establish trodusquemine as an effective central and peripheral PTP1B inhibitor with the potential to elicit noncachectic fat-specific weight loss and improve insulin and leptin levels.

引用

页码：1516 / 1523

页数：8

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