The effects of brain-derived neurotrophic factor on insulin signal transduction in the liver of diabetic mice

Diabetologia. 2001 May;44(5):555-66. doi: 10.1007/s001250051661.


Aim/hypothesis: We previously reported that repeated subcutaneous or intracerebroventricular injection of brain-derived neurotrophic factor (BDNF) reduces blood glucose concentrations in obese diabetic C57BL/KsJ-db/db mice. In this study, we assessed the effects of BDNF on insulin action in peripheral tissues of diabetic mice.

Methods: First, brain-derived neurotrophic factor (20 mg/kg) was subcutaneously given to male db/db mice for 14 days and then the insulin-stimulated tyrosine phosphorylation of insulin receptors and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in peripheral tissues was assessed. Second, we examined the effects of a single subcutaneous or intracerebroventricular brain-derived neurotrophic factor injection on insulin responsiveness in liver and skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Third, the effects of brain-derived neurothrophic factor on insulin action were also examined in cultured cells.

Results: Repeated injection of BDNF to db/db mice for 14 days enhanced insulin-stimulated tyrosine phosphorylation of insulin receptors in liver and insulin-stimulated PI 3-kinase activity in liver, skeletal muscle and interscapular brown adipose tissue. We then examined the rapid effect of BDNF on insulin signalling in vivo. A single subcutaneous or intracerebroventricular injection of BDNF rapidly increased insulin-stimulated tyrosine phosphorylation of insulin receptors and PI 3-kinase activity in liver of STZ-mice. No direct effect of brain-derived neurothrophic factor was observed on insulin signalling in primary cultured hepatocytes, L6 muscle cells or 3T3-L1 adipocytes. Brain-derived neurothrophic factor did not affect either glucose uptake or gluconeogenesis in these cells.

Conclusion/interpretation: These data indicate that brain-derived neurothrophic factor rapidly enhances insulin signal transduction in liver and shows hypoglycaemic action in diabetic mice.

MeSH terms

  • 3T3 Cells
  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Brain-Derived Neurotrophic Factor / administration & dosage
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Cell Line
  • Cerebral Ventricles / drug effects
  • Diabetes Mellitus, Experimental / physiopathology*
  • Gluconeogenesis / drug effects
  • Glucose / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / physiology
  • Humans
  • Injections, Intraventricular
  • Insulin / pharmacology*
  • Insulin / physiology
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / drug effects
  • Receptor, Insulin / metabolism*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Blood Glucose
  • Brain-Derived Neurotrophic Factor
  • Insulin
  • Recombinant Proteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Glucose