Mechanism of TNFα-induced downregulation of salt-inducible kinase 2 in adipocytes.

Salt-inducible kinase 2 (SIK2) is highly expressed in white adipocytes, but downregulated in individuals with obesity and insulin resistance. These conditions are often associated with a low-grade inflammation in adipose tissue. We and others have previously shown that SIK2 is downregulated by tumor necrosis factor α (TNFα), however, involvement of other pro-inflammatory cytokines, or the mechanisms underlying TNFα-induced SIK2 downregulation, remain to be elucidated. In this study we have shown that TNFα downregulates SIK2 protein expression not only in 3T3L1- but also in human in vitro differentiated adipocytes. Furthermore, monocyte chemoattractant protein-1 and interleukin (IL)-1β, but not IL-6, might also contribute to SIK2 downregulation during inflammation. We observed that TNFα-induced SIK2 downregulation occurred also in the presence of pharmacological inhibitors against several kinases involved in inflammation, namely c-Jun N-terminal kinase, mitogen activated protein kinase kinase 1, p38 mitogen activated protein kinase or inhibitor of nuclear factor kappa-B kinase (IKK). However, IKK may be involved in SIK2 regulation as we detected an increase of SIK2 when inhibiting IKK in the absence of TNFα. Increased knowledge about inflammation-induced downregulation of SIK2 could ultimately be used to develop strategies for the reinstalment of SIK2 expression in insulin resistance.