Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1

Abstract Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce i...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Benoit Denhez, Marina Rousseau, Crysta Spino, David-Alexandre Dancosst, Marie-Ève Dumas, Andréanne Guay, Farah Lizotte, Pedro Geraldes
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/001826e303744528bfd12ad76bcac7f8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:001826e303744528bfd12ad76bcac7f8
record_format	dspace
spelling	oai:doaj.org-article:001826e303744528bfd12ad76bcac7f82021-12-02T11:43:58ZSaturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC110.1038/s41598-020-78376-12045-2322https://doaj.org/article/001826e303744528bfd12ad76bcac7f82020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78376-1https://doaj.org/toc/2045-2322Abstract Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse podocytes exposed to palmitic acid for 24 h followed by an insulin stimulation. Renal function and pathology were evaluated at 25 weeks of age to confirm the DN development. Our results demonstrate that saturated FFA activated the serine/threonine kinases IκB kinase (IKK)β/IκBα and mTORC1/S6K1, but not protein kinase C and c-jun N-terminal kinase, in podocytes and glomeruli of db/db mice. Activation of both kinases promoted serine 307 phosphorylation of IRS1, a residue known to provoke IRS1 inhibition. Using IKK, mTORC1 and ceramide production inhibitors, we were able to blunt IRS1 serine 307 phosphorylation and restore insulin stimulation of Akt. In conclusion, our results indicate that FFA and diabetes contribute to insulin resistance through the activation of IKKβ and S6K1 leading to podocyte dysfunction and DN.Benoit DenhezMarina RousseauCrysta SpinoDavid-Alexandre DancosstMarie-Ève DumasAndréanne GuayFarah LizottePedro GeraldesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Benoit Denhez Marina Rousseau Crysta Spino David-Alexandre Dancosst Marie-Ève Dumas Andréanne Guay Farah Lizotte Pedro Geraldes Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
description	Abstract Diabetic nephropathy (DN), a microvascular complication of diabetes, is the leading cause of end-stage renal disease worldwide. Multiple studies have shown that podocyte dysfunction is a central event in the progression of the disease. Beside chronic hyperglycemia, dyslipidemia can induce insulin resistance and dysfunction in podocytes. However, the exact mechanisms of free fatty acid (FFA)-induced podocyte insulin unresponsiveness are poorly understood. We used a type 2 diabetic mouse model (db/db) and mouse podocytes exposed to palmitic acid for 24 h followed by an insulin stimulation. Renal function and pathology were evaluated at 25 weeks of age to confirm the DN development. Our results demonstrate that saturated FFA activated the serine/threonine kinases IκB kinase (IKK)β/IκBα and mTORC1/S6K1, but not protein kinase C and c-jun N-terminal kinase, in podocytes and glomeruli of db/db mice. Activation of both kinases promoted serine 307 phosphorylation of IRS1, a residue known to provoke IRS1 inhibition. Using IKK, mTORC1 and ceramide production inhibitors, we were able to blunt IRS1 serine 307 phosphorylation and restore insulin stimulation of Akt. In conclusion, our results indicate that FFA and diabetes contribute to insulin resistance through the activation of IKKβ and S6K1 leading to podocyte dysfunction and DN.
format	article
author	Benoit Denhez Marina Rousseau Crysta Spino David-Alexandre Dancosst Marie-Ève Dumas Andréanne Guay Farah Lizotte Pedro Geraldes
author_facet	Benoit Denhez Marina Rousseau Crysta Spino David-Alexandre Dancosst Marie-Ève Dumas Andréanne Guay Farah Lizotte Pedro Geraldes
author_sort	Benoit Denhez
title	Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
title_short	Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
title_full	Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
title_fullStr	Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
title_full_unstemmed	Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1
title_sort	saturated fatty acids induce insulin resistance in podocytes through inhibition of irs1 via activation of both ikkβ and mtorc1
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/001826e303744528bfd12ad76bcac7f8
work_keys_str_mv	AT benoitdenhez saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT marinarousseau saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT crystaspino saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT davidalexandredancosst saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT marieevedumas saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT andreanneguay saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT farahlizotte saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1 AT pedrogeraldes saturatedfattyacidsinduceinsulinresistanceinpodocytesthroughinhibitionofirs1viaactivationofbothikkbandmtorc1
_version_	1718395321760874496

Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1

Ejemplares similares