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

Aim/hypothesis. We previously reported that repeated subcutaneous or intrac erebroventricular injection of brain-derived neurotrophic factor (BDNF) red uces blood glucose concentrations in obese diabetic C57BL/KsJ-db/db mice. I n this study, we assessed the effects of BDNF on insulin action in peripher al tissues of diabetic mice. Methods. First, brain-derived neurotrophic factor (20 mg/kg) was subcutaneo usly given to male db/db mice for lit days and then the insulin-stimulated tyrosine phosphorylation of insulin receptors and insulin-stimulated phosph atidylinositol (PI) 3-kinase activity in peripheral tissues was assessed. S econd, we examined the effects of a single subcutaneous or intracerebrovent ricular brain-derived neurotrophic factor injection on insulin responsivene ss in liver and skeletal muscle of streptozotocin (STZ)-induced diabetic mi ce. Third, the effects of brain-derived neurothrophic factor on insulin act ion were also examined in cultured cells. Results. Repeated injection of BDNF to db/db mice for 14 days enhanced insu lin-stimulated tyrosine phosphorylation of insulin receptors in liver and i nsulin-stimulated PI 3-kinase activity in liver, skeletal muscle and inters capular brown adipose tissue. We then examined the rapid effect of BDNF on insulin signalling in vivo. A single subcutaneous or intracerebroventricula r injection of BDNF rapidly increased insulin-stimulated tyrosine phosphory lation of insulin receptors and PI 3-kinase activity in liver of STZ-mice. No direct effect of brain-derived neurothrophic factor was observed on insu lin signalling in primary cultured hepatocytes, L6 muscle cells or 3T3-L1 a dipocytes. Brain-derived neurothrophic factor did not affect either glucose uptake or gluconeogenesis in these cells. Conclusion/interpretation. These data indicate that brain-derived neurothro phic factor rapidly enhances insulin signal transduction in liver and shows hypoglycaemic action in diabetic mice.