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.
Lantz
Kristen A
KA
Department of Preclinical Research, Genaera Corporation, Plymouth Meeting, Pennsylvania, USA.
Hart
Susan G Emeigh
SG
Planey
Sonia L
SL
Roitman
Mitchell F
MF
Ruiz-White
Inez A
IA
Wolfe
Henry R
HR
McLane
Michael P
MP
D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001823:Body Composition / Q000187:drug effects*; D002776:Cholestanes / Q000494:pharmacology*; D004032:Diet; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects*
C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; D002776:Cholestanes; D000960:Hypolipidemic Agents; D007328:Insulin; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013096:Spermine; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1