TNF-α Upregulates IKKε 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 (IKKε) contributes to blunted catecholamine-induced lipolysis. Tumor necrosis factor α (TNF-α) upregulates adipose IKKε expression to inhibit stimulated lipolysis, which can be reversed by IKKε inhibitors. This study investigated adipose IKKε expression in children with and without obesity and potential involvement of the Lin28B/let-7a axis in posttranscriptional regulation of TNF-α-stimulated IKKε in adipocytes. METHODS: Adipose IKKε was detected in children both with and without obesity. The effects of TNF-α on IKKε 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-α-mediated IKKε upregulation. Reporter assays were performed to confirm that let-7a targets the IKKε gene. RESULTS: Adipose IKKε expression in children with obesity was upregulated to a greater extent than that in children without obesity and was positively correlated with BMI. TNF-α increased IKKε 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-α by inhibiting IKKε expression. Reporter assays confirmed that IKKε is a target of let-7a. CONCLUSIONS: Adipose IKKε expression in children with obesity is substantially elevated and positively correlated with BMI. TNF-α induces catecholamine resistance via activation of the Lin28B/let-7a/IKKε pathway.