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

Chen, S. C., Brooks, R., Houskeeper, J., Bremner, S. K., Dunlop, J. , Viollet, B., Logan, P. J., Salt, I. P. , Ahmed, S. F. and Yarwood, S. J. (2017) Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Molecular and Cellular Endocrinology, 440, pp. 57-68. (doi: 10.1016/j.mce.2016.11.011) (PMID:27856330) (PMCID:PMC5228588)

[img]
Preview
Text
131821.pdf - Published Version
Available under License Creative Commons Attribution.

3MB

Abstract

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/p70S6K signalling pathway. Basal AMPK and mTOR/p70S6K 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.

Item Type:Articles
Additional Information:A correction to this article is available at http://dx.doi.org/10.1016/j.mce.2017.01.049.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salt, Dr Ian and Logan, Dr Pamela Jane and Dunlop, Mrs Julia and Ahmed, Professor Syed Faisal and Yarwood, Dr Stephen and Chen, Dr Ching
Authors: Chen, S. C., Brooks, R., Houskeeper, J., Bremner, S. K., Dunlop, J., Viollet, B., Logan, P. J., Salt, I. P., Ahmed, S. F., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Molecular and Cellular Endocrinology
Publisher:Elsevier
ISSN:0303-7207
ISSN (Online):1872-8057
Published Online:14 November 2016
Copyright Holders:Copyright © 2016 Elsevier Ireland Ltd
First Published:First published in Molecular and Cellular Endocrinology 440:57-68
Publisher Policy:Reproduced under a creative commons license
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
580311The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetesIan SaltDiabetes UK (DIABETESUK)11/0004309RI CARDIOVASCULAR & MEDICAL SCIENCES
683671Regulation of Anti-inflammatory Gene Expression in Vascular Endothelial Cells by EPAC1Stephen YarwoodBritish Heart Foundation (BHF)PG/15/15/31316RI MOLECULAR CELL & SYSTEMS BIOLOGY