Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice

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.