Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice

We previously reported that brain-derived neurotrophic factor (BDNF) regula tes both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice. To elucidate the e ffect of BDNF on glucose metabolism, we designed a novel pellet pair-feedin g apparatus to eliminate the effect of appetite alteration on glucose metab olism. The apparatus was used to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. It was shown using this pellet pair-feeding apparatus that BDNF administered daily (20 mg . kg(-1) . day( -1)) to db/db mice significantly lowered blood glucose compared with pellet pair-fed db/db mice. To evaluate the effect of BDNF on insulin action, we used streptozotocin-induced type 1 diabetic mice. In this case, BDNF did no t lower blood glucose concentration but rather enhanced the hypoglycemic ac tion of insulin. In hyperglycemic db/db mice, pancreatic insulin content wa s reduced and glucagon content was increased compared with normoglycemic db /m mice. BDNF administered to db/db mice significantly restored both pancre atic insulin and glucagon content. Histological observations of aldehyde-fu chsin staining and immunostaining with anti-insulin indicated that insulin- positive pancreatic beta-cells were extensively regranulated by BDNF admini stration. We also studied the effect of BDNF on KK mice, normoglycemic anim als with impaired glucose tolerance. In these mice, BDNF administration imp roved insulin resistance in the oral glucose tolerance test. To elucidate h ow blood glucose was metabolized in BDNF-treated animals, we investigated t he effect of BDNF on the energy metabolism of db/db mice. Body temperature and oxygen consumption of the pellet pair-fed vehicle-treated mice were rem arkably lower than the ad libitum-fed vehicle-treated mice. Daily BDNF admi nistration for 3 weeks completely ameliorated both of the reductions. Final ly, to clarify its action mechanism, the effect of intracerebroventricular administration of BDNF on db/db mice was examined. Here, a small dose of BD NF was found to be effective in lowering blood glucose concentration. This indicates that BDNF regulates glucose metabolism by acting directly on the brain.