We previously reported that brain-derived neurotrophic factor (BDNF) regulates both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr N eurotrophins are important regulators in the embryogenesis, development, and functioning of nervous systems (1,2). At present, four neurotrophins are known: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4 / N T-5 (3-6) in mammals. BDNF, discovered long after NGF, enhances the survival and differentiation of several classes of neurons in the central and peripheral nervous systems, including motoneurons and sensory neurons. BDNF and its receptor, TrkB, are widely expressed in a variety of neurons through the embryonic, postnatal, and adult stages (7-10). These results and the many activities of BDNF described in in vitro cell cultures and lesioned animal studies (11,12) indicate that BDNF is likely to have multiple functions.In addition to the efficacy of BDNF in neurological disorders, we previously found that BDNF reduces food intake and blood glucose concentration in rodent obese diabetic models, such as C57BL/KsJ-d b/d b mice (13,14). To eliminate the effect of reduced food intake on the regulation of glucose metabolism, we evaluated the hypoglycemic effect of BDNF in d b/d b mice using the conventional pair-feeding protocol in which the amount of food provided to each pair-fed mouse was the same as the average amount of food eaten by the BDNF-treated mice during the preceding 24-h period (13,14). H o w e v e r, because such hyperphagic diabetic mice given a vehicle ate all of the food over a period of several hours, leaving them in a fasting condition until the next feeding, this protocol was inappropriate to study the effect of antidiabetic agents on glucose metabolism by mechanisms other than appetite alteration.In this study, to overcome these drawbacks, we designed a novel pellet pair-feeding apparatus and evaluated the effect of Received for publication 28 April 1999 and accepted in revised form 1 8 November 1999. B D N F, brain-derived neurotrophic factor; ELISA, enzyme-linked immunosorbent assay; NGF, nerve growth factor; NT, neurotrophin; PBS, phosphate-buffered saline; PPA R-, peroxisome proliferator-a c t i v a t e d r e c e p t o r-; STZ, streptozotocin.

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Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin-family which includes nerve growth factor, neurotrophin-3 and neurotrophin-4/5 [1±4]. BDNF promotes neurite outgrowth and trophic support to certain neurons in the central and peripheral nervous systems. The efficacy of BDNF in the treatment of neurological disorders has been demostrated elsewhere [1, 5±7]. We have previously found that BDNF reduces food intake and lowers blood glucose in obese diabetic models such as C57BL/KsJ-db/db mice [8±10]. This was the first evi- Diabetologia (2001) Abstract 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 STZmice. 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. [Diabetologia (2001) 44: 555±566]

Taken together with the accelerating effect of BDNF on energy metabolism, these findings indicate that BDNF improves glucose and lipid metabolism in obese diabetic animals without enlarging liver or adipose tissues.

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