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c-Jun N-Terminal Kinase 1/2 Activation by Tumor Necrosis Factor- Induces Insulin Resistance In Human Visceral But Not Subcutaneous Adipocytes: Reversal by Liver X Receptor Agonists

From the Department of Biochemistry and Molecular Biology II (S.F.-V., R.V.-B., I.N.-V., M.L.), Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (S.F.-V., R.V.-B., I.N.-V., M.L.), 08036 Barcelona, Spain

Address all correspondence and requests for reprints to: Sonia Fernández-Veledo, Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040, Madrid, Spain. E-mail: soferve{at}farm.ucm.es.

Aims: Obesity is associated with a chronic systemic low-grade inflammatory state. Markers of inflammation such as TNF- are linked with increased risk for insulin resistance and type 2 diabetes. The objective of the present study was to dissect the molecular mechanisms that may regulate TNF--induced insulin resistance in human adipose tissue.

Methods: We analyzed the impact of TNF- on glucose uptake and insulin action in human visceral and sc adipocytes. The contribution of different intracellular signaling pathways on metabolic effects of TNF- and the reversal of some of these effects with nuclear receptor agonists were also studied.

Results: TNF- per se increased glucose transporter-4 translocation to the plasma membrane and glucose uptake by activating the AMP-activated protein kinase/AS160 pathway in both visceral and sc adipocytes. Nevertheless, this cytokine induced an insulin-resistant state in visceral adipocytes by impairing insulin-stimulated glucose uptake and insulin signaling at the insulin receptor substrate (IRS)-1/AKT level. Activation of c-Jun N-terminal kinase (JNK) 1/2 seems to be involved in TNF--induced insulin resistance, causing phosphorylation of IRS1 at the Ser312 residue. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired serine phosphorylation of IRS1, restored downstream insulin signaling, and normalized insulin-induced glucose uptake in the presence of TNF-. Furthermore, TNF- increased the secretion of other proinflammatory cytokines such as IL-6. Pharmacological treatment of adipocytes with liver X receptor agonists reestablished insulin sensitivity by impairing TNF- induction of JNK1/2, phosphorylation of IRS1 (Ser312), and stabilizing IL-6 secretion.

Conclusions: TNF- induces insulin resistance on glucose uptake in human visceral but not sc adipocytes, suggesting depot-specific effects of TNF- on glucose uptake. Activation of JNK1/2 appears to be involved in serine phosphorylation of IRS1 and subsequently insulin resistance on glucose uptake, a state that can be reversed by liver X receptor agonists.