title: Long-term increased carnitine palmitoyltransferase 1A expression in ventromedial hypotalamus causes hyperphagia and alters the hypothalamic lipidomic profile.
abstract: Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. Carnitine palmitoyltransferase (CPT) 1A is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation and it has been proposed as a crucial mediator of fasting and ghrelin orexigenic signalling. However, the relationship between changes in CPT1A activity and the intracellular downstream effectors in the VMH that contribute to appetite modulation is not fully understood. To this end, we examined the effect of long-term expression of a permanently activated CPT1A isoform by using an adeno-associated viral vector injected into the VMH of rats. Peripherally, this procedure provoked hyperghrelinemia and hyperphagia, which led to overweight, hyperglycemia and insulin resistance. In the mediobasal hypothalamus (MBH), long-term CPT1AM expression in the VMH did not modify acyl-CoA or malonyl-CoA levels. However, it altered the MBH lipidomic profile since ceramides and sphingolipids increased and phospholipids decreased. Furthermore, we detected increased vesicular γ-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions, both transporters involved in this orexigenic signal. Taken together, these observations indicate that CPT1A contributes to the regulation of feeding by modulating the expression of neurotransmitter transporters and lipid components that influence the orexigenic pathways in VMH.
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Mera
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Joan Francesc
authors.initials: JF
authors.lastname: Mir
authors.affiliation: Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC)/CSIC, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
authors.affiliation: Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC)/CSIC, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Ana S H
authors.initials: AS
authors.lastname: Costa
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Maria Ida
authors.initials: MI
authors.lastname: Malandrino
authors.affiliation: Department of Nutrition and Food Science, Facultat de Biologia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: José-Antonio
authors.initials: JA
authors.lastname: Fernández-López
authors.affiliation: Department of Nutrition and Food Science, Facultat de Biologia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Remesar
authors.affiliation: Scripps Research Institute, Jupiter, Florida, United States of America.
authors.forename: Su
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Bioresource Science, College of Agriculture, Ibaraki University, Ibaraki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chohnan
authors.affiliation: UniQure, Amsterdam, The Netherlands.
authors.forename: Maria Sol
authors.initials: MS
authors.lastname: Rodríguez-Peña
authors.affiliation: UniQure, Amsterdam, The Netherlands.
authors.forename: Harald
authors.initials: H
authors.lastname: Petry
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Asins
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Herrero
authors.affiliation: Department of Biochemistry and Molecular Biology, Facultat de Farmàcia, Universitat de Barcelona and Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000235:genetics; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004435:Eating / Q000235:genetics; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics; D006963:Hyperphagia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D002334:Carnitine O-Palmitoyltransferase