Tnf-Alpha Upregulates Ikk Epsilon Expression Via The Lin28b/Let-7a Pathway To Induce Catecholamine Resistance In Adipocytes

Objective Overexpression of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKK epsilon) contributes to blunted catecholamine-induced lipolysis. Tumor necrosis factor alpha (TNF-alpha) upregulates adipose IKK epsilon expression to inhibit stimulated lipolysis, which can be reversed by IKK epsilon inhibitors. This study investigated adipose IKK epsilon expression in children with and without obesity and potential involvement of the Lin28B/let-7a axis in posttranscriptional regulation of TNF-alpha-stimulated IKK epsilon in adipocytes. Methods Adipose IKK epsilon was detected in children both with and without obesity. The effects of TNF-alpha on IKK epsilon expression of adipocytes were investigated. Inhibitor and mimics of microRNA let-7a or short interfering RNA of protein lin-28 homolog B (Lin28B) were used to determine the effect of the Lin28B/let-7a axis on TNF-alpha-mediated IKK epsilon upregulation. Reporter assays were performed to confirm that let-7a targets the IKK epsilon gene. Results Adipose IKK epsilon expression in children with obesity was upregulated to a greater extent than that in children without obesity and was positively correlated with BMI. TNF-alpha increased IKK epsilon expression through activation of Lin28B/let-7a and then inhibited isoproterenol-stimulated lipolysis in adipocytes. Blocking the Lin28B /let-7a axis rescued inhibition of isoproterenol-stimulated lipolysis produced by TNF-alpha by inhibiting IKK epsilon expression. Reporter assays confirmed that IKK epsilon is a target of let-7a. Conclusions Adipose IKK epsilon expression in children with obesity is substantially elevated and positively correlated with BMI. TNF-alpha induces catecholamine resistance via activation of the Lin28B/let-7a/IKK epsilon pathway.