1. Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice.
- Author
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Ito Y, Fukui M, Kanda M, Morishita K, Shoji Y, Kitao T, Hinoi E, and Shirahase H
- Subjects
- 3T3 Cells, Adipocytes cytology, Animals, Benzamides therapeutic use, Biphenyl Compounds therapeutic use, Cell Differentiation drug effects, Diabetes Mellitus, Experimental genetics, Dose-Response Relationship, Drug, Enzyme Inhibitors therapeutic use, Hep G2 Cells, Humans, Insulin physiology, Leptin physiology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Molecular Targeted Therapy, Obesity genetics, Phosphorylation, STAT3 Transcription Factor metabolism, Benzamides pharmacology, Biphenyl Compounds pharmacology, Diabetes Mellitus, Experimental drug therapy, Enzyme Inhibitors pharmacology, Insulin metabolism, Leptin metabolism, Obesity drug therapy, Protein Tyrosine Phosphatase, Non-Receptor Type 1 antagonists & inhibitors, Signal Transduction drug effects
- Abstract
The anti-diabetic and anti-obesity effects of the allosteric protein tyrosine phosphatase 1B (PTP1B) inhibitor 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzoylamide (KY-226) were pharmacologically evaluated. KY-226 inhibited human PTP1B activity (IC
50 = 0.28 μM), but did not exhibit peroxisome proliferator-activated receptor γ (PPARγ) agonist activity. In rodent preadipocytes (3T3-L1), KY-226 up to 10 μM had no effects on adipocyte differentiation, whereas pioglitazone, a PPARγ agonist, markedly promoted it. In human hepatoma-derived cells (HepG2), KY-226 (0.3-10 μM) increased the phosphorylated insulin receptor (pIR) produced by insulin. In db/db mice, the oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks) significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c values without increasing body weight gain, while pioglitazone exerted similar effects with increases in body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test. KY-226 also increased pIR and phosphorylated Akt in the liver and femoral muscle. In high-fat diet-induced obese mice, the oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks) decreased body weight gain, food consumption, and fat volume gain with increases in phosphorylated STAT3 in the hypothalamus. In conclusion, KY-226 exerted anti-diabetic and anti-obesity effects by enhancing insulin and leptin signaling, respectively., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)- Published
- 2018
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