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.

Systemic administration of brain-derived neurotrophic factor (BDNF) decreases nonfasted blood glucose in obese, non-insulin-dependent diabetic C57BLKS-Lepr(db)/lepr(db) (db/db) mice, with a concomitant decrease in body weight. By measuring percent HbA1c in BDNF-treated and pair-fed animals, we show that the effects of BDNF on nonfasted blood glucose levels are not caused by decreased food intake but reflect a significant improvement in blood glucose control. Furthermore, once established, this effect can persist for weeks after cessation of BDNF treatment. Oral glucose tolerance tests were performed to examine the effects of BDNF on blood glucose control in the fasted state and after an oral glucose challenge. BDNF treatment normalized fasting blood glucose from initially hyperglycemic levels and also showed evidence for beneficial, although less marked, effects on the ability to remove exogenous glucose from blood. One means to lower fasting blood glucose is to reduce the glucose output of peripheral tissues that normally play a part in the maintenance of fasting hyperglycemia. Because the liver is the major endogenous source of glucose in blood during fasting, and because hepatic weight and glucose output are increased in type 2 diabetes, we evaluated the effects of BDNF on liver tissue. BDNF reduced the hepatomegaly present in db/db mice, in association with reduced liver glycogen and reduced liver enzyme activity in serum, supporting the possible involvement of liver tissue in the mechanism of action for BDNF.

No abstract

No abstract

The suprachiasmatic nucleus (SCN) acts as a pacemaker for mammalian circadian rhythms. Receptors for excitatory amino acids like N-methyl-D-aspartate (NMDA) and non-NMDA receptors have both been found to play an important role in the transmission of photic information from the retina to the SCN. Therefore, we investigated whether the application of glutamate receptor agonists could reset the phase of the circadian rhythm of SCN firing activity in vitro. Treatment with NMDA (0.1-10 microM) for 15 min or 1 h during the early part of the subjective night produced phase delay, whereas treatment during the late subjective night caused an advance in phase. The phase-response curve for NMDA was similar to that previously obtained in response to light pulses in vivo. Application of DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) (1 or 10 microM), a non-NMDA-receptor agonist, also produced a dose-dependent phase delay of SCN activity. The NMDA-induced phase delay was antagonized by an NMDA-receptor antagonist MK-801. These findings suggest that both NMDA and non-NMDA receptors may be involved in the transmission of information to the SCN via the retinohypothalamic tract. In addition, both the advances and delays in phase caused by NMDA were potentiated by cotreatment with neuropeptide Y, whereas AMPA-induced phase delay was not potentiated by neuropeptide Y. This points to a functional link between NMDA and neuropeptide Y receptor-mediated mechanisms in the SCN.