Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex |
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| Authors: | Joan Francesc Mir Sebastián Zagmutt Mathieu P Lichtenstein Judit García-Villoria Minéia Weber Ana Gracia Gemma Fabriàs Josefina Casas Miguel López Núria Casals Antònia Ribes Cristina Suñol Laura Herrero Dolors Serra |
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| Institution: | 1.Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l’Alimentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB),Universitat de Barcelona,Barcelona,Spain;2.Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN),Instituto de Salud Carlos III,Madrid,Spain;3.Institut d’Investigacions Biomèdiques de Barcelona, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP),Barcelona,Spain;4.Sección de Errores Congénitos del Metabolismo – IBC, Servicio de Bioquímica y Genética Molecular, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER),Barcelona,Spain;5.Nutrition and Food Science Area, School of Pharmacy,Universidad del País Vasco/Euskal Herriko Unibersitatea,Leioa,Spain;6.Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry,Institute of Advanced Chemistry of Catalonia (IQAC)/CSIC,Barcelona,Spain;7.NeurObesity Group, Department of Physiology, CIMUS,University of Santiago de Compostela-Instituto de Investigación Sanitaria,Santiago de Compostela,Spain;8.Departament de Ciències Bàsiques, Facultat de Medicina i Ciències de la Salut,Universitat Internacional de Catalunya (UIC),Barcelona,Spain |
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| Abstract: | Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and α-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system. |
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