Molecular mechanism of BDNF as a agent that circumvents leptin resistance

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In this study, we investigated whether or not brain-derived neurotrophic factor (BDNF) acts as an antiobesity and antidiabetic agent that can circumvent leptin resistance. We demonstrated that BDNF is effective in two different models of leptin resistance; an acquired model or C57BL/6J mice rendered obese by consumption of high-fat diet for 4 months (diet-induced obesity (DIO) mice) and a genetic model or lethal yellow agouti mice (KKA^y mice). Intraperitoneal (IP) administration of BDNF (10 mg/kg × 2) reduced significantly cumulative food intake of DIO mice over 24 h, whereas they were unresponsive to IP administration of leptin (10 mg/kg × 2). The antiobesity effect of BDNF was marginal in mice fed standard diet. IP injection of recombinant leptin caused a marked reduction of cumulative food intake in mice fed standard diet over 24. We next examined the effect of repetitive administration of BDNF (10 mg/kg/day for 6 days) in DIO mice and oral glucose tolerance test (OGTT) was conducted after the last administration. The area under curve (AUC) of blood glucose of BDNF-treated DIO mice was significantly lower than vehicle-treated DIO mice during OGTT (P < 0.01). We also observed that BDNF is effective in improving obesity and diabetes of KKA^y mice. Very recently, we have produced transgenic mice overexpressing BDNF under the control of the liver-specific serum amyloid P component P promoter and found that they exhibit reduced food intake and body weight relative to nontransgenic littermates, when fed either standard or high-fat diet. Collectively, these observations suggest that BDNF may be therapeutically used in the treatment of leptin-resistant obesity and diabetes.