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Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms

People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of...

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Autores principales: Chen, Suet Ching, Brooks, Rebecca, Houskeeper, Jessica, Bremner, Shaun K., Dunlop, Julia, Viollet, Benoit, Logan, Pamela J., Salt, Ian P., Ahmed, S. Faisal, Yarwood, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: North Holland Publishing 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228588/
https://www.ncbi.nlm.nih.gov/pubmed/27856330
http://dx.doi.org/10.1016/j.mce.2016.11.011
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author Chen, Suet Ching
Brooks, Rebecca
Houskeeper, Jessica
Bremner, Shaun K.
Dunlop, Julia
Viollet, Benoit
Logan, Pamela J.
Salt, Ian P.
Ahmed, S. Faisal
Yarwood, Stephen J.
author_facet Chen, Suet Ching
Brooks, Rebecca
Houskeeper, Jessica
Bremner, Shaun K.
Dunlop, Julia
Viollet, Benoit
Logan, Pamela J.
Salt, Ian P.
Ahmed, S. Faisal
Yarwood, Stephen J.
author_sort Chen, Suet Ching
collection PubMed
description People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70(S6K) signalling pathway. Basal AMPK and mTOR/p70(S6K) activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context.
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spelling pubmed-52285882017-01-23 Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms Chen, Suet Ching Brooks, Rebecca Houskeeper, Jessica Bremner, Shaun K. Dunlop, Julia Viollet, Benoit Logan, Pamela J. Salt, Ian P. Ahmed, S. Faisal Yarwood, Stephen J. Mol Cell Endocrinol Article People with Type 2 diabetes mellitus (T2DM) have reduced bone mineral density and an increased risk of fractures due to altered mesenchymal stem cell (MSC) differentiation in the bone marrow. This leads to a shift in the balance of differentiation away from bone formation (osteogenesis) in favour of fat cell development (adipogenesis). The commonly used anti-diabetic drug, metformin, activates the osteogenic transcription factor Runt-related transcription factor 2 (Runx2), which may suppress adipogenesis, leading to improved bone health. Here we investigate the involvement of the metabolic enzyme, AMP-activated protein kinase (AMPK), in these protective actions of metformin. The anti-adipogenic actions of metformin were observed in multipotent C3H10T1/2 MSCs, in which metformin exerted reciprocal control over the activities of Runx2 and the adipogenic transcription factor, PPARγ, leading to suppression of adipogenesis. These effects appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70(S6K) signalling pathway. Basal AMPK and mTOR/p70(S6K) activity did appear to be required for adipogenesis, as demonstrated by the use of the AMPK inhibitor, compound C. This observation was further supported by using AMPK knockout mouse embryo fibroblasts (MEFs) where adipogenesis, as assessed by reduced lipid accumulation and expression of the adipogeneic transcription factor, C/EBPβ, was found to display an absolute requirement for AMPK. Further activation of AMPK in wild type MEFS, with either metformin or the AMPK-specific activator, A769662, was also associated with suppression of adipogenesis. It appears, therefore, that basal AMPK activity is required for adipogenesis and that metformin can inhibit adipogenesis through AMPK-dependent or -independent mechanisms, depending on the cellular context. North Holland Publishing 2017-01-15 /pmc/articles/PMC5228588/ /pubmed/27856330 http://dx.doi.org/10.1016/j.mce.2016.11.011 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Suet Ching
Brooks, Rebecca
Houskeeper, Jessica
Bremner, Shaun K.
Dunlop, Julia
Viollet, Benoit
Logan, Pamela J.
Salt, Ian P.
Ahmed, S. Faisal
Yarwood, Stephen J.
Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title_full Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title_fullStr Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title_full_unstemmed Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title_short Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms
title_sort metformin suppresses adipogenesis through both amp-activated protein kinase (ampk)-dependent and ampk-independent mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5228588/
https://www.ncbi.nlm.nih.gov/pubmed/27856330
http://dx.doi.org/10.1016/j.mce.2016.11.011
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