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Context Toll-like receptor 4 (TLR4) activation contributes to obesity-associated insulin resistance in skeletal muscles (SM). TLR4 signaling involves two pathways: the myeloid differentiation primary response gene 88 (MyD88) leading to inflammatory cytokines production and the toll/interleukin-1 receptor domain-containing adapter-inducing interferon (IFN) I (TRIF)-dependent pathways leading to type 1 interferon (IFNI) and interferon stimulated genes (ISG) expression. The E3 ubiquitin ligase RNF41 allows the preferential activation of the TRIF-IFNI pathway; however, its role in insulin response has not been reported. Methods We measured RNF41 level and IFNI pathway activation (ISG expression) in SM biopsies of obese insulin sensitive (OIS) and obese insulin resistant (OIR) women. Then we isolated and differentiated in myotubes, primary human SM cell progenitors from OIS and OIR SM biopsies. We modulated RNF41 and ISG expression in these myotubes and investigated their effects on insulin response. Results RNF41 expression is down-regulated in vivo in OIR SM and myotubes compared to OIS SM and myotubes. TLR4 activation with palmitate induces TRIF-IFNI pathway and ISG in OIS myotubes but not in OIR myotubes. Inhibition of RNF41 expression with siRNF41 in OIS myotubes treated with palmitate attenuates insulin response, IFNI pathway activation and ISG induction, mimicking OIR phenotype. Further, overexpression of RNF41 in OIR myotubes increases insulin response and ISG expression. Exposure to IFNI or to its inducer polyinosinic-polycytidylic acid, restores ISG expression and insulin sensitivity in OIR myotubes and OIS myotubes transfected with siRNF41. Conclusion Our results identify RNF41 as essential to IFNI pathway activation in order to maintain muscle insulin sensitivity during human obesity. [ABSTRACT FROM AUTHOR]

Abstract: Portal vein glucose sensors detect variations in glycemia to induce a nervous signal that influences food intake and glucose homeostasis. Previous experiments using high infusions of glucose suggested a metabolic sensing involving glucose transporter 2 (GLUT2). Here we evaluated the afferent route for the signal and candidate molecules for detecting low glucose fluxes. Common hepatic branch vagotomy did not abolish the anorectic effect of portal glucose, indicating dorsal transmission. GLUT2-null mice reduced their food intake in response to portal glucose signal initiated by protein-enriched diet. A similar response of Trpm5-null mice and portal infusions of sweeteners also excluded sugar taste receptors. Conversely, infusions of alpha-methylglucose, but not 3-O-methylglucose, decreased food intake, while phlorizin prevented the effect of glucose. This suggested sensing through SGLT3, which was expressed in the portal area. From these results we propose a finely tuned dual mechanism for portal glucose sensing that responds to different physiological conditions. [Copyright &y& Elsevier]