Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice

J Physiol Biochem. 2016 Jun;72(2):345-52. doi: 10.1007/s13105-016-0484-6. Epub 2016 Apr 18.


The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance.

Keywords: C57/BL/6J mice; Glucose transporter 4; High-fat diet; Insulin receptor; Insulin signaling; Rosiglitazone; Skeletal muscle; Ursolic acid.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Obesity Agents / adverse effects
  • Anti-Obesity Agents / therapeutic use
  • Antioxidants / therapeutic use
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / adverse effects
  • Drug Therapy, Combination / adverse effects
  • Glucose Transporter Type 4 / metabolism
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Receptor Substrate Proteins / agonists*
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Male
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Obesity / chemically induced
  • Obesity / complications
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • Rosiglitazone
  • Second Messenger Systems / drug effects
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / therapeutic use*
  • Triterpenes / adverse effects
  • Triterpenes / therapeutic use*
  • Ursolic Acid
  • Weight Gain / drug effects


  • Anti-Obesity Agents
  • Antioxidants
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Slc2a4 protein, mouse
  • Thiazolidinediones
  • Triterpenes
  • Rosiglitazone
  • Phosphatidylinositol 3-Kinase