title: MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3.
abstract: Conquering obesity has become a major socioeconomic challenge. Here, we show that reduced expression of the miR-25-93-106b cluster, or miR-93 alone, increases fat mass and, subsequently, insulin resistance. Mechanistically, we discovered an intricate interplay between enhanced adipocyte precursor turnover and increased adipogenesis. First, miR-93 controls Tbx3, thereby limiting self-renewal in early adipocyte precursors. Second, miR-93 inhibits the metabolic target Sirt7, which we identified as a major driver of in vivo adipogenesis via induction of differentiation and maturation of early adipocyte precursors. Using mouse parabiosis, obesity in mir-25-93-106b(-/-) mice could be rescued by restoring levels of circulating miRNA and subsequent inhibition of Tbx3 and Sirt7. Downregulation of miR-93 also occurred in obese ob/ob mice, and this phenocopy of mir-25-93-106b(-/-) was partially reversible with injection of miR-93 mimics. Our data establish miR-93 as a negative regulator of adipogenesis and a potential therapeutic option for obesity and the metabolic syndrome.
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Michele
authors: M
authors: Cioffi
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Mireia
authors: M
authors: Vallespinos-Serrano
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors: Sara M
authors: SM
authors: Trabulo
authors: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Pablo Jose
authors: PJ
authors: Fernandez-Marcos
authors: Weis Center for Research, Danville, PA 17822, USA.
authors: Ashley N
authors: AN
authors: Firment
authors: Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
authors: Berta N
authors: BN
authors: Vazquez
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Catarina R
authors: CR
authors: Vieira
authors: Bioimaging, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Francesca
authors: F
authors: Mulero
authors: Bioimaging, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Juan A
authors: JA
authors: Camara
authors: Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Ultan P
authors: UP
authors: Cronin
authors: Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Manuel
authors: M
authors: Perez
authors: Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Joaquim
authors: J
authors: Soriano
authors: Spanish National Cardiovascular Research Center (CNIC), Madrid 28028, Spain.
authors: Beatriz
authors: B
authors: G Galvez
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Alvaro
authors: A
authors: Castells-Garcia
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Verena
authors: V
authors: Haage
authors: Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors: Deepak
authors: D
authors: Raj
authors: Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
authors: Diego
authors: D
authors: Megias
authors: Department of Molecular Gastrointestinal Oncology, Ruhr-University, Bochum 44801, Germany.
authors: Stephan
authors: S
authors: Hahn
authors: Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
authors: Lourdes
authors: L
authors: Serrano
authors: Weis Center for Research, Danville, PA 17822, USA.
authors: Anne
authors: A
authors: Moon
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: aicher_a@yahoo.com.
authors: Alexandra
authors: A
authors: Aicher
authors: Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: c.heeschen@qmul.ac.uk.
authors: Christopher
authors: C
authors: Heeschen
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000502:physiology; D050156:Adipogenesis; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000818:Animals; D000066673:Cell Self Renewal; D005260:Female; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D035683:MicroRNAs / Q000502:physiology*; D034622:RNA Interference; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C551470:Mirn93 microRNA, mouse; C539736:Sirt7 protein, mouse; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D037761:Sirtuins