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

Chorna NE, Santos-Soto IJ, Carballeira NM, Morales JL, de la Nuez J, Cátala-Valentin A, Chornyy AP, Vázquez-Montes A, De Ortiz SP - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

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Related in: MedlinePlus

Experimental design.Experiment 1. Mice were allowed to run for 28 days and were then sacrificed followed by the analysis of FA content in the brain and of the expression of genes encoding metabolic enzymes. Experiment 2. Mice were allowed to run for 33 days and given chronic i.c.v. injections of C75 (▾) at the indicated times. On day 29th of running, Barnes maze behavioral testing was initiated, which consisted of five days. The complete running period spanned the entire experimental design for 33 days.
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pone-0077845-g001: Experimental design.Experiment 1. Mice were allowed to run for 28 days and were then sacrificed followed by the analysis of FA content in the brain and of the expression of genes encoding metabolic enzymes. Experiment 2. Mice were allowed to run for 33 days and given chronic i.c.v. injections of C75 (▾) at the indicated times. On day 29th of running, Barnes maze behavioral testing was initiated, which consisted of five days. The complete running period spanned the entire experimental design for 33 days.

Mentions: Sedentary controls were housed individually for one month in a standard cage without any equipment to exercise. The experimental physically active groups were housed under the same conditions as their sedentary counterparts with the only exception that they had continued access to an unlocked wireless low profile running wheel (Med Associates), located within their home cages. The experimental design (Fig. 1) included two independent experiments and groups of mice. In Experiment 1, mice exercised for 28 days, after which they were immediately sacrificed and their brains used for the analysis of FA and the expression of genes encoding metabolic enzymes (see description below). In Experiment 2, mice exercised for an entire period of 33 days and received chronic intracerebroventrically (i.c.v.) injections of C75 at the indicated times (Fig. 1). On the 29th day of running, we began to administer the Barnes maze behavioral test (see description below), which was given daily for 5 d. After completion of the Barnes maze behavioral testing, mice were sacrificed immediately followed by the carrying out of histological procedures (see description below).


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

Chorna NE, Santos-Soto IJ, Carballeira NM, Morales JL, de la Nuez J, Cátala-Valentin A, Chornyy AP, Vázquez-Montes A, De Ortiz SP - PLoS ONE (2013)

Experimental design.Experiment 1. Mice were allowed to run for 28 days and were then sacrificed followed by the analysis of FA content in the brain and of the expression of genes encoding metabolic enzymes. Experiment 2. Mice were allowed to run for 33 days and given chronic i.c.v. injections of C75 (▾) at the indicated times. On day 29th of running, Barnes maze behavioral testing was initiated, which consisted of five days. The complete running period spanned the entire experimental design for 33 days.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818398&req=5

pone-0077845-g001: Experimental design.Experiment 1. Mice were allowed to run for 28 days and were then sacrificed followed by the analysis of FA content in the brain and of the expression of genes encoding metabolic enzymes. Experiment 2. Mice were allowed to run for 33 days and given chronic i.c.v. injections of C75 (▾) at the indicated times. On day 29th of running, Barnes maze behavioral testing was initiated, which consisted of five days. The complete running period spanned the entire experimental design for 33 days.
Mentions: Sedentary controls were housed individually for one month in a standard cage without any equipment to exercise. The experimental physically active groups were housed under the same conditions as their sedentary counterparts with the only exception that they had continued access to an unlocked wireless low profile running wheel (Med Associates), located within their home cages. The experimental design (Fig. 1) included two independent experiments and groups of mice. In Experiment 1, mice exercised for 28 days, after which they were immediately sacrificed and their brains used for the analysis of FA and the expression of genes encoding metabolic enzymes (see description below). In Experiment 2, mice exercised for an entire period of 33 days and received chronic intracerebroventrically (i.c.v.) injections of C75 at the indicated times (Fig. 1). On the 29th day of running, we began to administer the Barnes maze behavioral test (see description below), which was given daily for 5 d. After completion of the Barnes maze behavioral testing, mice were sacrificed immediately followed by the carrying out of histological procedures (see description below).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Show MeSH
Related in: MedlinePlus