title: Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B.
abstract: OBJECTIVE
  Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B.
  
  
  METHODS
  The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests.
  
  
  RESULTS
  Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity.
  
  
  CONCLUSIONS
  Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Hanying
authors.initials: H
authors.lastname: Ding
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.forename: Dongxia
authors.initials: D
authors.lastname: Hou
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yujing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects*; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D014966:Xanthenes / Q000627:therapeutic use*
chemical_list: D014966:Xanthenes; C069053:norathyriol; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1