MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3

• Published in: Cell reports (Cambridge) Vol. 12; no. 10; pp. 1594 - 1605
• Main Authors: Cioffi, Michele, Vallespinos-Serrano, Mireia, Trabulo, Sara M., Fernandez-Marcos, Pablo Jose, Firment, Ashley N., Vazquez, Berta N., Vieira, Catarina R., Mulero, Francesca, Camara, Juan A., Cronin, Ultan P., Perez, Manuel, Soriano, Joaquim, G. Galvez, Beatriz, Castells-Garcia, Alvaro, Haage, Verena, Raj, Deepak, Megias, Diego, Hahn, Stephan, Serrano, Lourdes, Moon, Anne, Aicher, Alexandra, Heeschen, Christopher
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-09-2015; Elsevier
• Subjects: 3T3-L1 Cells; Adipocytes - physiology; Adipogenesis; Adipose Tissue - metabolism; Adipose Tissue - pathology; Adipose Tissue, White - metabolism; Adipose Tissue, White - pathology; Adiposity; Animals; Cell Self Renewal; Female; Insulin Resistance; Male; Metabolic Syndrome - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; MicroRNAs - physiology; RNA Interference; Sirtuins - genetics; Sirtuins - metabolism; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.08.006

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.
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•Knockout of the miR-25-93-106b cluster increased fat mass and insulin resistance•MiR-93 controls Tbx3 and thereby limits self-renewal of early adipocyte precursors•MiR-93 further inhibits the metabolic target Sirt7 and thus in vivo adipogenesis•(Circulating) miR-93 reduced obesity in miR-25-93-106b KO and ob/ob mice
Cioffi et al. provide evidence that miRNA-93 suppresses Tbx3 and Sirt7, thereby controlling expansion of adipocyte precursors and inhibiting adipogenesis, respectively.