Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation.
Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN), the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ) of the dentate gyrus (DG) and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v.) microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.
Department of Biology, Metabolomics Research Center, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America ; Department of Biology, Functional Genomics Research Core, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico, United States of America.
Nataliya E
NE
Chorna
Iván J
IJ
Santos-Soto
Nestor M
NM
Carballeira
Joan L
JL
Morales
Janneliz
J
de la Nuez
Alma
A
Cátala-Valentin
Anatoliy P
AP
Chornyy
Adrinel
A
Vázquez-Montes
Sandra Peña
SP
De Ortiz
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation; D002531:Cerebellum / Q000201:enzymology; D003071:Cognition; D018891:Dentate Gyrus / Q000166:cytology / Q000201:enzymology*; D004790:Enzyme Induction; D004924:Escape Reaction; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis; D012420:Running / Q000523:psychology*; D015854:Up-Regulation
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D005227:Fatty Acids; D054890:Fatty Acid Synthase, Type I; D015107:4-Butyrolactone