(121) miR-10a induces IL-33/ST2 signaling and Tregs to promote adipose browning and attenuate adipose tissue inflammation

Introduction/Rationale: Obesity is a pandemic, characterized by infiltrating macrophages and T cells in adipose tissue (AT) which triggers chronic inflammation. microRNA (miR) specifically downregulation of miR-10a in AT contributes to inflammation and alters adipocyte biology in obesity. In this study, we explored whether administering miR-10a mimic in the high-fat diet (HFD) mice alters AT inflammation, adipogenesis, and browning during obesity.

Methods: C57BL/6J mice were fed HFD for eight weeks and administered eight doses of miR-10a or scrambled RNA control (Sc-Control) via intravenous injection for next four weeks under HFD. Body weight, metabolic parameters were measured, and AT was collected to evaluate the metabolic and immune signatures by histology, flow cytometry, and RT-PCR analysis at the experimental endpoint. We also evaluated browning gene induction by IL-33 in 3T3-L1 adipocytes using in vitro analysis.

Results: Body weight change, fat depots, blood glucose, adipocyte size, and crown-like structures were reduced prominently in the miR-10a group as compared to Sc-Control. miR-10a administration in mice exhibited better glucose tolerance by IPGTT. Activated T cells, macrophages, and dendritic cells in AT were decreased in the miR-10a group as compared to control mice. Furthermore, regulatory T cells (Tregs) and IL-33-expressing macrophages and immune cells in AT were elevated, whereas inflammatory genes (TNF-α, NF-kB, STAT3) expression was suppressed in the miR-10a-treated group. We also noticed elevated expression of IL-25 in CD4 T cells and ST2 receptor on immune cells in AT of miR-10a group. Intriguingly, AT browning genes (PGC1-α, CIDEA, FNDC5) were notably increased in the miR-10a group. We also found that IL-33 stimulated similar thermogenic gene expression and reduced lipid deposition in 3T3-L1 adipocytes.

Conclusion: The results suggest that miR-10a stimulates the AT browning program and attenuates adipocyte hypertrophy and inflammation by inducing IL-33/ST2 signaling and Tregs in AT.