Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus

[eng] Previous studies have reported the importance of carnitine palmitoyltransferase (CPT) 1A as an essential part of downstream ghrelin signaling in the central nervous system (CNS) for the control of food intake. Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pat...

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Autor: Mir Bonnín, Joan Francesc
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2016
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/105184
Acesso em linha:https://hdl.handle.net/2445/105184
http://hdl.handle.net/10803/398850
Access Level:acceso abierto
Palavra-chave:Neuroendocrinologia
Metabolisme dels lípids
Hipotàlem
Escorça cerebral
Obesitat
Neuroendocrinology
Lipid metabolism
Hypothalamus
Cerebral cortex
Obesity
id ES_558b9f4ae5d220795a0bfda9d581a77d
oai_identifier_str oai:diposit.ub.edu:2445/105184
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
title Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
spellingShingle Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
Mir Bonnín, Joan Francesc
Neuroendocrinologia
Metabolisme dels lípids
Hipotàlem
Escorça cerebral
Obesitat
Neuroendocrinology
Lipid metabolism
Hypothalamus
Cerebral cortex
Obesity
title_short Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
title_full Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
title_fullStr Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
title_full_unstemmed Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
title_sort Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
dc.creator.none.fl_str_mv Mir Bonnín, Joan Francesc
author Mir Bonnín, Joan Francesc
author_facet Mir Bonnín, Joan Francesc
author_role author
dc.contributor.none.fl_str_mv Serra i Cucurull, Dolors
García Hegardt, Fausto
Universitat de Barcelona. Departament de Bioquímica i Fisiologia
dc.subject.none.fl_str_mv Neuroendocrinologia
Metabolisme dels lípids
Hipotàlem
Escorça cerebral
Obesitat
Neuroendocrinology
Lipid metabolism
Hypothalamus
Cerebral cortex
Obesity
topic Neuroendocrinologia
Metabolisme dels lípids
Hipotàlem
Escorça cerebral
Obesitat
Neuroendocrinology
Lipid metabolism
Hypothalamus
Cerebral cortex
Obesity
description [eng] Previous studies have reported the importance of carnitine palmitoyltransferase (CPT) 1A as an essential part of downstream ghrelin signaling in the central nervous system (CNS) for the control of food intake. Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. 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, nor its possible involvement in central extra-hypothalamic functions of ghrelin. In this work, we examine the effect of long-term expression of a permanently activated CPT1A isoform (CPT1AM) by using an adeno-associated viral vector, injected into the VMH of rats. CPT1AM overexpression produces a sustained increase in food intake which leads to overweight. Mechanistically, CPT1AM alters the lipidomic profile of mediobasal hypothalamus, provoking an increase in ceramides and sphingolipids and a decrease in phospholipids. Furthermore, we detect increased vesicular y-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions. These changes are noteworthy, since both GABA and glutamate have been proposed to be mediators in food intake control. This signature led us to assess the effect of ghrelin in GABAergic neurons. Ghrelin reduces fatty acid oxidation, mitochondrial respiration and mitochondrial reactive oxygen species formation in GT1-7 cells. Moreover, ghrelin produces a reduction in GABA release from primary cortical neurons which is blocked by both pharmacological and genetic inhibition of CPT1A. In addition, ghrelin produces a reduction in: (1) mitochondrial oxygen consumption, (2) citrate and a-ketoglutarate cellular content and (3) GABA shunt connecting TCA cycle and releasable GABA pool. 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. Moreover, it seems that ghrelin and changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism, which affect eventually to GABAergic neurotransmission.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/105184
http://hdl.handle.net/10803/398850
url https://hdl.handle.net/2445/105184
http://hdl.handle.net/10803/398850
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Mir, 2016
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Mir, 2016
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Departament - Bioquímica i Fisiologia
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamusMir Bonnín, Joan FrancescNeuroendocrinologiaMetabolisme dels lípidsHipotàlemEscorça cerebralObesitatNeuroendocrinologyLipid metabolismHypothalamusCerebral cortexObesity[eng] Previous studies have reported the importance of carnitine palmitoyltransferase (CPT) 1A as an essential part of downstream ghrelin signaling in the central nervous system (CNS) for the control of food intake. Lipid metabolism in the ventromedial hypothalamus (VMH) has emerged as a crucial pathway in the regulation of feeding and energy homeostasis. 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, nor its possible involvement in central extra-hypothalamic functions of ghrelin. In this work, we examine the effect of long-term expression of a permanently activated CPT1A isoform (CPT1AM) by using an adeno-associated viral vector, injected into the VMH of rats. CPT1AM overexpression produces a sustained increase in food intake which leads to overweight. Mechanistically, CPT1AM alters the lipidomic profile of mediobasal hypothalamus, provoking an increase in ceramides and sphingolipids and a decrease in phospholipids. Furthermore, we detect increased vesicular y-aminobutyric acid transporter (VGAT) and reduced vesicular glutamate transporter 2 (VGLUT2) expressions. These changes are noteworthy, since both GABA and glutamate have been proposed to be mediators in food intake control. This signature led us to assess the effect of ghrelin in GABAergic neurons. Ghrelin reduces fatty acid oxidation, mitochondrial respiration and mitochondrial reactive oxygen species formation in GT1-7 cells. Moreover, ghrelin produces a reduction in GABA release from primary cortical neurons which is blocked by both pharmacological and genetic inhibition of CPT1A. In addition, ghrelin produces a reduction in: (1) mitochondrial oxygen consumption, (2) citrate and a-ketoglutarate cellular content and (3) GABA shunt connecting TCA cycle and releasable GABA pool. 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. Moreover, it seems that ghrelin and changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism, which affect eventually to GABAergic neurotransmission.[cat] Estudis previs havien destacat la importància de la carnitina palmitoïltransferasa (CPT) 1A com a part essencial de la senyalització de la grelina al sistema nerviós central (SNC) per al control de la ingesta alimentària. El metabolisme lipídic en el nucli ventromedial de l'hipotàlem (VMH) ha emergit com una via crucial per a la regulació de la ingesta i l'homeòstasi energètica. Això no obstant, la relació entre els canvis en l'activitat de la CPT1A i els efectors intrace•ulars subjacents en el VMH que contribueixen a la modulació de la gana no són totalment compresos, com tampoc la seva involucració en les funcions centrals extrahipotalàmiques de la grelina. En aquest treball, hem examinat l'efecte a llarg termini de l'expressió d'una isoforma mutada permanentment activa de la CPT1A (CPT1AM), fent ús d'un vector víric adeno-associat, injectat en el VMH de rates. La sobreexpressió de la CPT1AM produeix un augment sostingut de la ingesta alimentària que hi promou sobrepès. En la descripció mecanística, la CPT1AM altera el perfil lipidòmic del hipotàlem mediobasal, induint-hi un augment de ceramides i esfingolípids i alhora una reducció en fosfolípids. A més a més, hem detectat un augment en les expressions del transportador vesicular de l'àcid y-aminobutíric (GABA) (VGAT, en les seves sigles en anglès) i una reducció del transportador vesicular de glutamat 2 (VGLUT2, en les seves sigles en anglès). Aquests canvis són destacables, ja que tant GABA como glutamat han sigut proposats com a mediadors en el control de la ingesta alimentària. Aquestes observacions ens dugueren a estudiar l'efecte de la grelina en neurones GABAèrgiques. La grelina redueix l'oxidació d'àcids grassos, la respiració mitocondrial i la formació d'espècies reactives d'oxigen en cèl•lules GT1-7. D'afegitó, la grelina produeix una reducció en l'alliberament de GABA de neurones corticals primàries, la qual cosa és blocada tant per inhibició genètica i farmacològica de la CPT1A. A més a més, la grelina hi produeix una reducció: (1) del consum mitocondrial d'oxigen, (2) del contingut cel•lular de citrat i d'a-cetoglutarat i (3) de la via de desviació de GABA que connecta el cicle dels àcids tricarboxílics i el contingut alliberable de GABA. En conjunt, aquestes observacions indiquen que la CPT1A contribueix a la regulació de la ingesta amb la modulació de l'expressió de transportadors involucrats en la neurotransmissió i la modulació de components lipídics que influencien les vies orexigèniques del VMH. A més a més, sembla que la grelina i els canvis en l'activitat CPT1A modulen la funció mitocondrial, obtenint-ne canvis al metabolisme del GABA, que afecten en darrera instància a la neurotransmissió GABAèrgica.Universitat de BarcelonaSerra i Cucurull, DolorsGarcía Hegardt, FaustoUniversitat de Barcelona. Departament de Bioquímica i Fisiologia2016info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/105184http://hdl.handle.net/10803/398850Tesis Doctorals - Departament - Bioquímica i Fisiologiareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Mir, 2016info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1051842026-05-27T06:46:51Z
score 15,301603

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