title: Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms.
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/p70S6Ksignalling pathway. Basal AMPK and mTOR/p70S6Kactivity 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.
authors.affiliation: 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.
authors.forename: Suet Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brooks
authors.affiliation: Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Houskeeper
authors.affiliation: Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Bremner
authors.affiliation: Institute of Molecular, Cell and Systems Biology, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France, CNRS, UMR8104, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Logan
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University Avenue, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Salt
authors.affiliation: The Developmental Endocrinology Research Group, School of Medicine, University of Glasgow, Glasgow G51 4TF, UK.
authors.forename: S Faisal
authors.initials: SF
authors.lastname: Ahmed
authors.affiliation: Institute of Biological Chemistry, Biophysics and Bioengineering, Edinburgh Campus, Heriot-Watt University, Edinburgh EH14 4AS, UK. Electronic address: S.Yarwood@hw.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yarwood
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001713:Biphenyl Compounds; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D018345:Mice, Knockout; D011753:Pyrones / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; D011753:Pyrones; D013876:Thiophenes; D008687:Metformin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; D020123:Sirolimus
keywords: AMPK; Adipogenesis; Diabetes; Mesenchymal stem cells; Metformin; Osteogenesis