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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It has been previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates glucose metabolism and energy expenditure in rodent diabetic models such as C57BL/KsJ-leprdb/leprdb (db/db) mice. Central administration of BDNF has been found to reduce blood glucose in db/db mice, suggesting that BDNF acts through the central nervous system. In the present study we have expanded these investigations to explore the effect of central administration of BDNF on energy metabolism. Intracerebroventricular administration of BDNF lowered blood glucose and increased pancreatic insulin content of db/db mice compared with vehicle-treated pellet pair-fed db/db mice. While body temperatures of the pellet pair-fed db/db mice given vehicle were reduced because of restricted food supply in this pair-feeding condition, BDNF treatment remarkably alleviated the reduction of body temperature suggesting the enhancement of thermogenesis. BDNF enhanced norepinephrine turnover and increased uncoupling protein-1 mRNA expression in the interscapular brown adipose tissue. Our evidence indicates that BDNF activates the sympathetic nervous system via the central nervous system and regulates energy expenditure in obese diabetic animals.