Lactate induces Fndc5 levels, a PGC1a-dependent Bdnf inducer. A, Voluntary exercise for 4 weeks significantly induces Fndc5 expression in the hippocampus as measured by real-time RT-PCR. The number of animals used for each group (control and exercise) is 3 and 4, respectively. *p < 0.05 (unpaired t test; p = 0.0183 and df = 5). B, Intraperitoneal injections of lactate (117 mg/kg) significantly induced hippocampal Fndc5 gene expression levels as measured by real-time RT-PCR. The number of animals used for each group is 5. *p < 0.05 (unpaired t test; p = 0.0152 and df = 8). C, Representative Western blot image depicting the increase in FNDC5 protein levels in the hippocampus of control animals compared with exercising mice. D, Quantification of the FNDC5 Western blot. *p < 0.05 (unpaired t test; p = 0.0347 and df = 4). E, Representative Western blot image depicting the increase in FNDC5 protein levels in the hippocampus of mice receiving 117 mg/kg of lactate compared with mice receiving saline. F, Quantification of the FNDC5 Western blot. *p < 0.05 (unpaired t test; p = 0.0112 and df = 4). G, SirtI knockdown abolishes the lactate-mediated increase in Fndc5 mRNA expression. *p < 0.05 (unpaired t test; p = 0.0318 and df = 2 for Ctrl shRNA vs Ctrl shRNA + lactate 20 mm).