title: Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism.
abstract: Silent information regulators (SIRTs) have been shown to deacetylate a range of metabolic enzymes, including those in glycolysis and the Krebs cycle, and thus alter their activity. SIRTs require NAD(+) for their activity, linking cellular energy status to enzyme activity. To examine the impact of SIRT1 modulation on oxidative metabolism, this study tests the effect of ligands that are either SIRT-activating compounds (resveratrol and SRT1720) or SIRT inhibitors (EX527) on the metabolism of (13)C-enriched substrates by guinea pig brain cortical tissue slices with (13)C and (1)H nuclear magnetic resonance spectroscopy. Resveratrol increased lactate labeling but decreased incorporation of (13)C into Krebs cycle intermediates, consistent with effects on AMPK and inhibition of the F0/F1-ATPase. By testing with resveratrol that was directly applied to astrocytes with a Seahorse analyzer, increased glycolytic shift and increased mitochondrial proton leak resulting from interactions of resveratrol with the mitochondrial electron transport chain were revealed. SRT1720, by contrast, stimulated incorporation of (13)C into Krebs cycle intermediates and reduced incorporation into lactate, although the inhibitor EX527 paradoxically also increased Krebs cycle (13)C incorporation. In summary, the various SIRT1 modulators show distinct acute effects on oxidative metabolism. The strong effects of resveratrol on the mitochondrial respiratory chain and on glycolysis suggest that caution should be used in attempts to increase bioavailability of this compound in the CNS.
authors: Neuroscience Research Australia, Randwick, New South Wales, Australia.|Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, The University of New South Wales, Randwick, New South Wales, Australia.
authors: Benjamin D
authors: BD
authors: Rowlands
authors: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Chew Ling
authors: CL
authors: Lau
authors: Stem Cell Metabolism and Regenerative Medicine Group, Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia.
authors: James G
authors: JG
authors: Ryall
authors: Mark Wainwright Analytical Centre, The University of New South Wales, Randwick, New South Wales, Australia.
authors: Donald S
authors: DS
authors: Thomas
authors: Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, The University of New South Wales, Randwick, New South Wales, Australia.
authors: Matthias
authors: M
authors: Klugmann
authors: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Philip M
authors: PM
authors: Beart
authors: Neuroscience Research Australia, Randwick, New South Wales, Australia.|Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, The University of New South Wales, Randwick, New South Wales, Australia.
authors: Caroline D
authors: CD
authors: Rae
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002227:Carbazoles / Q000494:pharmacology; D002247:Carbon Isotopes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000975:Antioxidants; D002227:Carbazoles; D002247:Carbon Isotopes; D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D013267:Stilbenes; D019344:Lactic Acid; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: EX-527; acetylation; sirtuin