title: Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis.
abstract: Breakdown of the major sleep-promoting neurotransmitter, γ-aminobutyric acid (GABA), in the GABA shunt generates catabolites that may enter the tricarboxylic acid cycle, but it is unknown whether catabolic by-products of the GABA shunt actually support metabolic homeostasis. In Drosophila, the loss of the specific enzyme that degrades GABA, GABA transaminase (GABAT), increases sleep, and we show here that it also affects metabolism such that flies lacking GABAT fail to survive on carbohydrate media. Expression of GABAT in neurons or glia rescues this phenotype, indicating a general metabolic function for this enzyme in the brain. As GABA degradation produces two catabolic products, glutamate and succinic semialdehyde, we sought to determine which was responsible for the metabolic phenotype. Through genetic and pharmacological experiments, we determined that glutamate, rather than succinic semialdehyde, accounts for the metabolic phenotype of gabat mutants. This is supported by biochemical measurements of catabolites in wild-type and mutant animals. Using in vitro labeling assays, we found that inhibition of GABAT affects energetic pathways. Interestingly, we also observed that gaba mutants display a general disruption in bioenergetics as measured by altered levels of tricarboxylic acid cycle intermediates, NAD(+)/NADH, and ATP levels. Finally, we report that the effects of GABAT on sleep do not depend upon glutamate, indicating that GABAT regulates metabolic and sleep homeostasis through independent mechanisms. These data indicate a role of the GABA shunt in the development of metabolic risk and suggest that neurological disorders caused by altered glutamate or GABA may be associated with metabolic disruption.
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Maguire
authors.affiliation: the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
authors.forename: Seth
authors.initials: S
authors.lastname: Rhoades
authors.affiliation: the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Chen
authors.affiliation: the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
authors.forename: Arjun
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lim
authors.affiliation: Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Physiology, Perelman School of Medicine, and.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Mitchell
authors.affiliation: the Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5158.
authors.forename: Aalim M
authors.initials: AM
authors.lastname: Weljie
authors.affiliation: From the Departments of Neuroscience and the Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, and the Department of Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6064 amita@mail.med.upenn.edu.
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D004331:Drosophila melanogaster; D004734:Energy Metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006706:Homeostasis; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D012890:Sleep
chemical_list: D007656:Ketoglutaric Acids; D018698:Glutamic Acid; D000612:4-Aminobutyrate Transaminase
keywords: Drosophila metabolism; amino acid; glutamate; mitochondria; tricarboxylic acid cycle (TCA cycle) (Krebs cycle)