Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression

Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression Derek Y.C. Yuen 1 , Renee M. Dwyer 2 , Vance B. Matthews 1 , Lei Zhang 2 , Brian G. Drew 3 , Bronwyn Neill 1 , Bronwyn A. Kingwell 3 , Michael G. Clark 2 , Stephen Rattigan 2 and Mark A. Febbraio 1 1 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 2 Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia; 3 Clinical Physiology Laboratory, Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Corresponding author: Mark A. Febbraio, mark.febbraio{at}bakeridi.edu.au , or Stephen Rattigan, s.rattigan{at}utas.edu.au . Abstract OBJECTIVE The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake. RESEARCH DESIGN AND METHODS The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion. RESULTS IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser 1177 ), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser 473 ) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)-α protein expression in HAECs without any effect on TNF-α in skeletal muscle. When HAECs were incubated with a TNF-α–neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished. CONCLUSIONS In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling b