Acute effects of brain-derived neurotrophic factor on energy expenditure in obese diabetic mice

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Abstract
OBJECTIVE: We recently demonstrated that chronic treatment with brain-derived neurotrophic factor (BDNF) regulates energy expenditure in obese diabetic C57BL/KsJ-db/db mice. In this study, we investigated the acute effects of BDNF on energy expenditure. DESIGN: After BDNF was singly administered to male db/db mice (aged 10–12 weeks), their body temperature and whole body glucose oxidation were measured. Their norepinephrine (NE) turnover and uncoupling protein (UCP) 1 expression in interscapular brown adipose tissue (BAT) were also analyzed. RESULTS: Even though the body temperatures of hyperphagic db/db mice dropped remarkably in a 24 h period after food deprivation, only a single subcutaneous administration of BDNF significantly prevented the reduction of body temperature. BDNF was also observed to have similar efficacy in cold exposure experiments at 15°C. Respiratory excretion of 14CO2 after intravenous injection of D-[14C(U)]-glucose was significantly increased by BDNF administration, indicating that BDNF increases whole-body glucose oxidation. BDNF administered intracerebroventricularly was also able to prevent the reduction of body temperature of db/db mice. To clarify the BDNF action mechanism we examined NE turnover in BAT. Four hours after a single administration, BDNF reduced NE content in the presence of the tyrosine hydroxylase inhibitor, α-methyl-P-tyrosine methyl ester, indicating enhanced NE turnover in BAT. BDNF also increased the expression of the UCP1 mRNA and protein in BAT. CONCLUSION: These data indicate that BDNF rapidly regulates energy metabolism in obese diabetic animals, partly through activating the sympathetic nervous system and inducing UCP1 gene expression in BAT.