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Cell Rep. 2015 Sep 8;12(10):1594-605. doi: 10.1016/j.celrep.2015.08.006. Epub 2015 Aug 28.

MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3.

Author information

1
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
2
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.
3
Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
4
Weis Center for Research, Danville, PA 17822, USA.
5
Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
6
Bioimaging, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
7
Flow Cytometry Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
8
Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28028, Spain.
9
Spanish National Cardiovascular Research Center (CNIC), Madrid 28028, Spain.
10
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
11
Department of Molecular Gastrointestinal Oncology, Ruhr-University, Bochum 44801, Germany.
12
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.
13
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.

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.

PMID:
26321631
DOI:
10.1016/j.celrep.2015.08.006
[Indexed for MEDLINE]
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