Overexpression of miR-10a-3p mediates TGF-β1/Smad Signaling Pathway to suppress adipogenesis and AT inflammation

Abstract Obesity, an epidemic of our time is a multifactorial disease characterized by an enhanced amount of fat and energy storage in adipose tissue (AT). Growing evidence suggests that obesity promotes activation in resident T cells and macrophages to maintain low-grade inflammation. MicroRNAs (miRs) are shown to maintain immune response in the AT and are associated with adipocyte differentiation, and function during obesity. Microarray analysis shows differential expression of miRs in the AT immune cells in mice fed with a high-fat diet (HFD) for 12 weeks. Pathways analysis demonstrated that miR-10a-3p (miR-10a) expression is downregulated in AT and its expression has been correlated with obesity progression. Thus, we aimed to evaluate miR-10a overexpression effects on AT inflammation, metabolic markers, and signaling pathways during obesity. Our ex vivoanalysis shows that mimicking miR-10a reduces the expression of inflammatory M1 macrophage, TGF-b1, KLF4, IL-17F, and inflammatory cytokine while inducing FoxP3 expression in immune cells derived from AT of HFD-fed mice as compared to ND. Correspondingly, we noticed that mimicking miR-10a in NIH3T3-L1 adipocytes reduces proinflammatory genes, adipocyte size, cytokines, and lipids accumulation as compared to the control. Further, overexpression of miR-10a also reduces TGF-b1, Smad3, CHOP10, and C/EBPa expression in NIH3T3-L1 as compared to the control. Thus, our findings suggest that miR-10a mimics mediate the TGF-β1/Smad3 signaling pathway, which suppresses cytokine, and metabolic markers, to reduce adipogenesis and AT inflammation. Our studies strongly suggest miR-10a as a new target to therapeutically cope with obesity and its associated metabolic disorders. Supported by NIH grant R01 AI140405).