Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism

Abstract Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine pal...

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Autores principales:	Anne Skøttrup Mørkholt, Ove Wiborg, Jette G. K. Nieland, Søren Nielsen, John Dirk Nieland
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/609d40b02d7a4b0797ff5bf08332f693
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spelling	oai:doaj.org-article:609d40b02d7a4b0797ff5bf08332f6932021-12-02T11:52:57ZBlocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism10.1038/s41598-017-02343-62045-2322https://doaj.org/article/609d40b02d7a4b0797ff5bf08332f6932017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02343-6https://doaj.org/toc/2045-2322Abstract Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression. Therefore, we hypothesized that inhibition of CPT1a activity can be developed as an innovative treatment strategy for depression. Stress exposure combined with different pharmacological treatment regimens; Etomoxir, CPT1 blocker, and Escitalopram, a favoured antidepressant drug, was applied in state-of-the-art chronic mild stress model. Etomoxir treatment induced statistical significant reduction of anhedonic behavior compared to vehicle treatment (p < 0.0001) and reversed depression-like phenotype in 90% of the rats (p = 0.0007), whereas Escitalopram only proved 57% efficacy. Moreover, Etomoxir revealed downregulation of interferon-γ, interleukin-17α and tumor necrosis factor-α. This indicate that alteration in metabolism is pivotal in the pathogenesis of depression, since CPT1 blockage is highly efficient in treating anhedonia and inflammation, thereby opening up for a novel class of antidepressant medication.Anne Skøttrup MørkholtOve WiborgJette G. K. NielandSøren NielsenJohn Dirk NielandNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anne Skøttrup Mørkholt Ove Wiborg Jette G. K. Nieland Søren Nielsen John Dirk Nieland Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
description	Abstract Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression. Therefore, we hypothesized that inhibition of CPT1a activity can be developed as an innovative treatment strategy for depression. Stress exposure combined with different pharmacological treatment regimens; Etomoxir, CPT1 blocker, and Escitalopram, a favoured antidepressant drug, was applied in state-of-the-art chronic mild stress model. Etomoxir treatment induced statistical significant reduction of anhedonic behavior compared to vehicle treatment (p < 0.0001) and reversed depression-like phenotype in 90% of the rats (p = 0.0007), whereas Escitalopram only proved 57% efficacy. Moreover, Etomoxir revealed downregulation of interferon-γ, interleukin-17α and tumor necrosis factor-α. This indicate that alteration in metabolism is pivotal in the pathogenesis of depression, since CPT1 blockage is highly efficient in treating anhedonia and inflammation, thereby opening up for a novel class of antidepressant medication.
format	article
author	Anne Skøttrup Mørkholt Ove Wiborg Jette G. K. Nieland Søren Nielsen John Dirk Nieland
author_facet	Anne Skøttrup Mørkholt Ove Wiborg Jette G. K. Nieland Søren Nielsen John Dirk Nieland
author_sort	Anne Skøttrup Mørkholt
title	Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
title_short	Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
title_full	Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
title_fullStr	Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
title_full_unstemmed	Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
title_sort	blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/609d40b02d7a4b0797ff5bf08332f693
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Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism

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