MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3

• DOI: 10.1016/j.celrep.2015.08.006
• Publication Date: 2015-08-29T04:53:00Z
• Authors: Michele Cioffi; Mireia Vallespino...; Sara M. Trabulo; Pablo Jose Fernan...; Ashley N. Firment; Berta N. Vazquez; Catarina R. Vieira; Francesca Mulero; Juan A. Camara; Ultan P. Cronin; Manuel Perez; Joaquim Soriano; Beatriz G. Galvez; Alvaro Castells-G...; Verena Haage; Deepak Raj; Diego Megias; Stephan Hahn; Lourdes Serrano; Anne Moon; Alexandra Aicher; Christopher Heeschen
• Keywords: Male; 0301 basic medicine; QH301-705.5; Adipose Tissue, White; Mice, Obese; General Biochemistry, Genetics and Molecular Biology; Mice; 03 medical and health sciences; 3T3-L1 Cells; Adipocytes; Animals; Sirtuins; Biology (General); Cell Self Renewal; IN-VIVO; Adiposity; RISK; Metabolic Syndrome; Mice, Knockout; 2. Zero hunger; INSULIN-RESISTANCE; ADIPOCYTE DIFFERENTIATION; Adipogenesis; IDENTIFICATION; 3. Good health; Mice, Inbred C57BL; MicroRNAs; Adipose Tissue; TISSUE; OBESITY; GROWTH; Female; RNA Interference; Insulin Resistance; REGULATOR; T-Box Domain Proteins; STEM-CELLS

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.