PMID- 27856330 OWN - NLM STAT- MEDLINE DCOM- 20171113 LR - 20220317 IS - 1872-8057 (Electronic) IS - 0303-7207 (Print) IS - 0303-7207 (Linking) VI - 440 DP - 2017 Jan 15 TI - Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. PG - 57-68 LID - S0303-7207(16)30470-1 [pii] LID - 10.1016/j.mce.2016.11.011 [doi] AB - 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, PPARgamma, 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/EBPbeta, 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. CI - Copyright (c) 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved. FAU - Chen, Suet Ching AU - Chen SC AD - The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK; Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Brooks, Rebecca AU - Brooks R AD - The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK. FAU - Houskeeper, Jessica AU - Houskeeper J AD - Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Bremner, Shaun K AU - Bremner SK AD - Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Dunlop, Julia AU - Dunlop J AD - Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Viollet, Benoit AU - Viollet B AD - INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Universite Paris Descartes, Sorbonne Paris Cite, France. FAU - Logan, Pamela J AU - Logan PJ AD - Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Salt, Ian P AU - Salt IP AD - Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK. FAU - Ahmed, S Faisal AU - Ahmed SF AD - The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK. FAU - Yarwood, Stephen J AU - Yarwood SJ AD - Institute of Biological Chemistry, Biophysics and Bioengineering, Edinburgh Campus, Heriot-Watt University, Edinburgh EH14 4AS, UK. Electronic address: S.Yarwood@hw.ac.uk. LA - eng GR - PG/10/26/28303/BHF_/British Heart Foundation/United Kingdom GR - BB/D015324/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom GR - PG/15/15/31316/BHF_/British Heart Foundation/United Kingdom GR - MR/N003403/1/MRC_/Medical Research Council/United Kingdom GR - FS/17/12/32703/BHF_/British Heart Foundation/United Kingdom PT - Journal Article DEP - 20161114 PL - Ireland TA - Mol Cell Endocrinol JT - Molecular and cellular endocrinology JID - 7500844 RN - 0 (Biomarkers) RN - 0 (Biphenyl Compounds) RN - 0 (Pyrones) RN - 0 (Thiophenes) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - P68477CD2C (4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Mol Cell Endocrinol. 2017 Mar 5;443:176. PMID: 28183460 MH - AMP-Activated Protein Kinases/*metabolism MH - Adipogenesis/*drug effects MH - Animals MH - Biomarkers/metabolism MH - Biphenyl Compounds MH - Embryo, Mammalian/cytology MH - Enzyme Activation/drug effects MH - Fibroblasts/drug effects/metabolism MH - Mesenchymal Stem Cells/drug effects/metabolism MH - Metformin/*pharmacology MH - Mice, Knockout MH - Pyrones/pharmacology MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction/drug effects MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Thiophenes/pharmacology PMC - PMC5228588 OTO - NOTNLM OT - AMPK OT - Adipogenesis OT - Diabetes OT - Mesenchymal stem cells OT - Metformin OT - Osteogenesis EDAT- 2016/11/20 06:00 MHDA- 2017/11/14 06:00 PMCR- 2017/01/15 CRDT- 2016/11/19 06:00 PHST- 2016/04/12 00:00 [received] PHST- 2016/11/11 00:00 [revised] PHST- 2016/11/12 00:00 [accepted] PHST- 2016/11/20 06:00 [pubmed] PHST- 2017/11/14 06:00 [medline] PHST- 2016/11/19 06:00 [entrez] PHST- 2017/01/15 00:00 [pmc-release] AID - S0303-7207(16)30470-1 [pii] AID - 10.1016/j.mce.2016.11.011 [doi] PST - ppublish SO - Mol Cell Endocrinol. 2017 Jan 15;440:57-68. doi: 10.1016/j.mce.2016.11.011. Epub 2016 Nov 14.