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Activated Kupffer cells inhibit insulin sensitivity in obese mice
Author(s) -
Tencerova Michaela,
Aouadi Myriam,
Vangala Pranitha,
Nicoloro Sarah M.,
Yawe Joseph C.,
Cohen Jessica L.,
Shen Yuefei,
GarciaMenendez Lorena,
Pedersen David J.,
GallagherDorval Karen,
Perugini Richard A.,
Gupta Olga T.,
Czech Michael P.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-270496
Subject(s) - insulin resistance , inflammation , endocrinology , medicine , gene silencing , kupffer cell , insulin , small interfering rna , biology , chemistry , transfection , gene , biochemistry
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, G‐eRPs 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 for metabolic 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. FASEB J . 29, 2959‐2969 (2015). www.fasebj.org