title: Inhibition of IKK-beta: a new development in the mechanism of the anti-obesity effects of PTP1B inhibitors SA18 and SA32.
abstract: In a previous study, protein tyrosine phosphatase 1B (PTP1B) inhibitors, SA18 and SA32, exhibited anti-obesity effects in a mouse model by suppressing weight gain and improving blood parameters, including free fatty acid (FFA) levels. In a separate study, depletion of the PTP1B gene in mice suppressed weight gain without significant change in FFA levels. The discrepancy in FFA concentrations between the two studies suggested that the in vivo target of the SA compounds might not be limited to PTP1B. In this study, SA18 and SA32 were found to be potent inhibitors of IkappaB Kinase-beta (IKK-beta). In vivo relevance of the inhibitory activity was evaluated in differentiated adipocytes. Inhibition of IKK-beta, in addition to inhibition of PTP1B, in mice treated with the SA compounds, could be a possible mechanism of the compound's biological response including the resistance to diet-induced weight gain and improvement in blood parameters. As potent and cell-permeable IKK-beta inhibitors, SA18 and SA32 could also be valuable in biological experiments.
authors.affiliation: Department of Chemistry, College of Natural Science, Inha University, Incheon 402-751, Republic of Korea.
authors.forename: Bharat Raj
authors.initials: BR
authors.lastname: Bhattarai
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Ko
authors.forename: Suja
authors.initials: S
authors.lastname: Shrestha
authors.forename: Bhooshan
authors.initials: B
authors.lastname: Kafle
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Hyeongjin
authors.initials: H
authors.lastname: Cho
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse