Activated Kupffer cells inhibit insulin sensitivity in obese mice

Michaela Tencerova, Myriam Aouadi, Pranitha Vangala, Sarah M. Nicoloro, Joseph C. Yawe, Jessica L. Cohen, Yuefei Shen, Lorena Garcia-Menendez, David J. Pedersen, Karen Gallagher-Dorval, Richard A. Perugini, Olga T. Gupta, Michael P. Czech

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. 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-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB 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 formetabolic disease. -Tencerova, M., Aouadi,M., Vangala, P., Nicoloro, S. M., Yawe, J. C., Cohen, J. L., Shen, Y., Garcia-Menendez, L., Pedersen, D. J., Gallagher-Dorval, K., Perugini, R. A., Gupta, O. T., Czech, M. P. Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Original languageEnglish (US)
Pages (from-to)2959-2969
Number of pages11
JournalFASEB Journal
Volume29
Issue number7
DOIs
StatePublished - Jul 1 2015

Keywords

  • Hepatic steatosis
  • Insulin resistance
  • Liver macrophages
  • Small interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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