Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors

Abstract Maintenance of the adipose tissue requires a proper balance between self-renewal and differentiation of adipose progenitors (AP). Any deregulation leads either to fat overexpansion and obesity or fat loss and consequent lipodystrophies. Depending on the fat pad location, APs and adipocytes...

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Autores principales:	Christophe Ravaud, Martin Paré, Stéphane Azoulay, Christian Dani, Annie Ladoux
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0e2ec10c8aec4b0c99693f6c740bebc0
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spelling	oai:doaj.org-article:0e2ec10c8aec4b0c99693f6c740bebc02021-12-02T15:05:01ZImpairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors10.1038/s41598-017-02807-92045-2322https://doaj.org/article/0e2ec10c8aec4b0c99693f6c740bebc02017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02807-9https://doaj.org/toc/2045-2322Abstract Maintenance of the adipose tissue requires a proper balance between self-renewal and differentiation of adipose progenitors (AP). Any deregulation leads either to fat overexpansion and obesity or fat loss and consequent lipodystrophies. Depending on the fat pad location, APs and adipocytes are heterogeneous. However, information on the pharmacological sensitivity of distinct APs to drugs known to alter the function of adipose tissue, especially HIV protease inhibitors (PIs) is scant. Here we show that PIs decreased proliferation and clonal expansion of APs, modifying their self-renewal potential. Lopinavir was the most potent PI tested. Decrease in self-renewal was accompanied by a reduced expression of the immediate early response gene IER3, a gene associated with tissue expansion. It was more pronounced in chin-derived APs than in knee-derived APs. Furthermore, lopinavir lowered the activin A–induced ERK1/2 phosphorylation. Expressions of the transcription factor EGR1 and its targets, including INHBA were subsequently altered. Therefore, activin A secretion was reduced leading to a dramatic impairment of APs self-renewal sustained by the activin A autocrine loop. All together, these observations highlight the activin A autocrine loop as a crucial effector to maintain APs self-renewal. Targeting this pathway by HIV-PIs may participate in the induction of unwanted side effects.Christophe RavaudMartin ParéStéphane AzoulayChristian DaniAnnie LadouxNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christophe Ravaud Martin Paré Stéphane Azoulay Christian Dani Annie Ladoux Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
description	Abstract Maintenance of the adipose tissue requires a proper balance between self-renewal and differentiation of adipose progenitors (AP). Any deregulation leads either to fat overexpansion and obesity or fat loss and consequent lipodystrophies. Depending on the fat pad location, APs and adipocytes are heterogeneous. However, information on the pharmacological sensitivity of distinct APs to drugs known to alter the function of adipose tissue, especially HIV protease inhibitors (PIs) is scant. Here we show that PIs decreased proliferation and clonal expansion of APs, modifying their self-renewal potential. Lopinavir was the most potent PI tested. Decrease in self-renewal was accompanied by a reduced expression of the immediate early response gene IER3, a gene associated with tissue expansion. It was more pronounced in chin-derived APs than in knee-derived APs. Furthermore, lopinavir lowered the activin A–induced ERK1/2 phosphorylation. Expressions of the transcription factor EGR1 and its targets, including INHBA were subsequently altered. Therefore, activin A secretion was reduced leading to a dramatic impairment of APs self-renewal sustained by the activin A autocrine loop. All together, these observations highlight the activin A autocrine loop as a crucial effector to maintain APs self-renewal. Targeting this pathway by HIV-PIs may participate in the induction of unwanted side effects.
format	article
author	Christophe Ravaud Martin Paré Stéphane Azoulay Christian Dani Annie Ladoux
author_facet	Christophe Ravaud Martin Paré Stéphane Azoulay Christian Dani Annie Ladoux
author_sort	Christophe Ravaud
title	Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
title_short	Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
title_full	Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
title_fullStr	Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
title_full_unstemmed	Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
title_sort	impairment of the activin a autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0e2ec10c8aec4b0c99693f6c740bebc0
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Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors

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