2024-03-28T08:53:59Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/3988502017-08-30T02:19:32Zcom_10803_1col_10803_398696
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Neuroendocrinologia
Neuroendocrinología
Neuroendocrinology
Metabolisme dels lípids
Metabolismo de los lípidos
Lipid metabolism
Hipotàlem
Hipotálamo
Hypothalamus
Escorça cerebral
Corteza cerebral
Cerebral cortex
Obesitat
Obesidad
Obesity
Role of carnitine palmitoyltransferase 1A as a downstream effector of ghrelin in cortical neurons and hypothalamus
[Barcelona] :
Universitat de Barcelona,
2016
Accés lliure
http://hdl.handle.net/10803/398850
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Mir Bonnín, Joan Francesc,
autor
1 recurs en línia (290 pàgines)
Tesi
Doctorat
Universitat de Barcelona. Departament de Bioquímica i Fisiologia
2016
Universitat de Barcelona. Departament de Bioquímica i Fisiologia
Tesis i dissertacions electròniques
Serra i Cucurull, Dolors,
supervisor acadèmic
García Hegardt, Fausto,
supervisor acadèmic
TDX
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.
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