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This version published online on June 30, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0558
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Submitted on March 13, 2009
Accepted on June 23, 2009

JNK1/2 ACTIVATION BY TNF-{alpha} INDUCES INSULIN RESISTANCE IN HUMAN VISCERAL BUT NOT SUBCUTANEOUS ADIPOCYTES: REVERSAL BY LXR AGONISTS

Sonia Fernández-Veledo*, Rocio Vila-Bedmar, Iria Nieto-Vazquez, and Margarita Lorenzo

From Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, (Spain); and CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM)

* To whom correspondence should be addressed. 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-alpha 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-alpha-induced insulin resistance in human adipose tissue.

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

Results: TNF-alpha per se increased GLUT4 translocation to the plasma membrane and glucose uptake by activating the AMPK/AS160 pathway in both visceral and subcutaneous adipocytes. Nevertheless, this cytokine induced an insulin-resistant state in visceral adipocytes by impairing insulin-stimulated glucose uptake and insulin signaling at the IRS1/AKT level. Activation of JNK1/2 seems to be involved in TNF-alpha-induced insulin resistance, causing phosphorylation of IRS1 at the Ser312 residue. Accordingly, silencing JNK1/2 with either siRNA or chemical inhibitors impaired serine-phosphorylation of IRS1, restored downstream insulin-signaling and normalized insulin-induced glucose uptake in the presence of TNF-alpha. Furthermore, TNF-alpha increased the secretion of other pro-inflammatory cytokines such as IL-6. Pharmacological treatment of adipocytes with LXR-agonists re-established insulin sensitivity by impairing TNF-alpha induction of JNK1/2, phosphorylation of IRS1(Ser312) and stabilizing IL-6 secretion.

Conclusions. TNF-alpha induces insulin resistance on glucose uptake in human visceral but not in subcutaneous adipocytes, suggesting depot-specific effects of TNF-alpha 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 LXR agonists.
Key words: cytokines • glucose transporter • insulin signaling • insulin resistance • pro-inflammatory kinases • nuclear receptor agonists






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