Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation.

Nataliya E Chorna,Adrinel Vázquez-Montes,Janneliz De La Nuez,Iván J Santos-Soto,Alma Cátala-Valentin,Nestor M Carballeira,Sandra Peña De Ortiz,Anatoliy P Chornyy,Joan L Morales,Cristoforo Scavone

doi:10.1371/journal.pone.0077845

Nataliya E Chorna, Adrinel Vázquez-Montes + Show 8 more

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https://doi.org/10.1371/journal.pone.0077845

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Abstract

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.

Highlights

Numerous human and animal studies have clearly demonstrated that voluntary exercise enhances and protects diverse aspects of brain function
Of interest to us was the idea that relevant metabolic perturbations, as well as specific factors related to lipid metabolism could be associated with the beneficial effects of exercise on hippocampal-dependent learning and memory and neurogenesis
Bonferroni post-testing indicated that such induction of fasn mRNA by running was specific to the hippocampus (***P,0.001), not being observed in the cortex or the cerebellum (P.0.05, each)

Summary

Introduction

Numerous human and animal studies have clearly demonstrated that voluntary exercise enhances and protects diverse aspects of brain function. Human studies report that running improves learning and memory, as well as executive function, while counteracting mental decline [1,2,3,4,5]. Research on rodents demonstrates that running improves hippocampal-dependent learning and memory [7,11,12,13,14,15,16,17]. Of interest to us was the idea that relevant metabolic perturbations, as well as specific factors related to lipid metabolism could be associated with the beneficial effects of exercise on hippocampal-dependent learning and memory and neurogenesis. FA may function as intracrine messengers or as paracrine neuromodulators, possibly contributing to the maintenance of neuronal networks associated with learning and memory. Various mental illnesses characterized by improper cognition, including manic depression and schizophrenia, as well as neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Niemann-Pick diseases, are associated with impaired lipid metabolism [20,21]

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