Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism

Abstract Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment ha...

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Autores principales:	Thomas S. Postler, Vincent Peng, Dev M. Bhatt, Sankar Ghosh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6c9dde354c9449a39ec178a57d0a2807
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spelling	oai:doaj.org-article:6c9dde354c9449a39ec178a57d0a28072021-12-02T18:14:30ZMetformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism10.1038/s41598-021-97441-x2045-2322https://doaj.org/article/6c9dde354c9449a39ec178a57d0a28072021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97441-xhttps://doaj.org/toc/2045-2322Abstract Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.Thomas S. PostlerVincent PengDev M. BhattSankar GhoshNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas S. Postler Vincent Peng Dev M. Bhatt Sankar Ghosh Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
description	Abstract Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.
format	article
author	Thomas S. Postler Vincent Peng Dev M. Bhatt Sankar Ghosh
author_facet	Thomas S. Postler Vincent Peng Dev M. Bhatt Sankar Ghosh
author_sort	Thomas S. Postler
title	Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
title_short	Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
title_full	Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
title_fullStr	Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
title_full_unstemmed	Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism
title_sort	metformin selectively dampens the acute inflammatory response through an ampk-dependent mechanism
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6c9dde354c9449a39ec178a57d0a2807
work_keys_str_mv	AT thomasspostler metforminselectivelydampenstheacuteinflammatoryresponsethroughanampkdependentmechanism AT vincentpeng metforminselectivelydampenstheacuteinflammatoryresponsethroughanampkdependentmechanism AT devmbhatt metforminselectivelydampenstheacuteinflammatoryresponsethroughanampkdependentmechanism AT sankarghosh metforminselectivelydampenstheacuteinflammatoryresponsethroughanampkdependentmechanism
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Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism

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