miR-467 regulates inflammation and blood insulin and glucose
inflammation; insulin resistance; macrophages; microRNA/miR-467a-5p
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
Gajeton J; Krukovets I; Yendamuri R; Verbovetskiy D; Vasanji A; Sul L; Stenina-Adognravi O
Journal Of Cellular And Molecular Medicine
journalArticle
<a href="http://doi.org/10.1111/jcmm.16224" target="_blank" rel="noreferrer noopener">10.1111/jcmm.16224</a>
Thrombospondin-4 mediates TGF-beta-induced angiogenesis.
Angiogenesis Inducing Agents/*metabolism; Animals; Cell Movement/drug effects; Cell Proliferation/drug effects; Cells; Chick Embryo; Cultured; Endothelium; Female; Gene Expression Regulation/drug effects; Humans; Inbred C57BL; Male; Mice; Muscle; Neovascularization; Pathologic/drug therapy/metabolism/*pathology; Signal Transduction/drug effects; Smooth; Thrombospondins/*physiology; Transforming Growth Factor beta/*pharmacology; Vascular/drug effects/metabolism/*pathology
TGF-beta is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-beta signaling are process-and stage-dependent, and it is not uncommon that TGF-beta exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-beta are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-beta1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-beta1 and mediates the effects of TGF-beta1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of
Muppala S; Xiao R; Krukovets I; Verbovetsky D; Yendamuri R; Habib N; Raman P; Plow E; Stenina-Adognravi O
Oncogene
2017
2017-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/onc.2017.140" target="_blank" rel="noreferrer noopener">10.1038/onc.2017.140</a>