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Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF\u2010\u03baB, in KCs in obese mice. We used glucan\u2010encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Following intravenous injections, G\u2010eRPs containing siRNA against p65 of the NF\u2010\u03baB complex caused loss of NF\u2010\u03baB p65 expression in KCs without disrupting NF\u2010\u03baB in hepatocytes or macrophages in other tissues. Silencing of NF\u2010\u03baB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.\u2014Tencerova, M., Aouadi, M., Vangala, P., Nicoloro, S. M., Yawe, J. C., Cohen, J. L., Shen, Y., Garcia\u2010Menendez, L., Pedersen, D. J., Gallagher\u2010Dorval, K., Perugini, R. A., Gupta, O. T., Czech, M. P. Activated Kupffer cells inhibit insulin sensitivity in obese mice.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 29, 2959\u20102969 (2015).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.15-270496","type":"journal-article","created":{"date-parts":[[2015,3,25]],"date-time":"2015-03-25T01:48:50Z","timestamp":1427248130000},"page":"2959-2969","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Activated Kupffer cells inhibit insulin sensitivity in obese mice"],"prefix":"10.1096","volume":"29","author":[{"given":"Michaela","family":"Tencerova","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine University of Massachusetts Medical School Worcester Massachusetts 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