TY - JOUR
T1 - Activated Kupffer cells inhibit insulin sensitivity in obese mice
AU - Tencerova, Michaela
AU - Aouadi, Myriam
AU - Vangala, Pranitha
AU - Nicoloro, Sarah M.
AU - Yawe, Joseph C.
AU - Cohen, Jessica L.
AU - Shen, Yuefei
AU - Garcia-Menendez, Lorena
AU - Pedersen, David J.
AU - Gallagher-Dorval, Karen
AU - Perugini, Richard A.
AU - Gupta, Olga T.
AU - Czech, Michael P.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
KW - Hepatic steatosis
KW - Insulin resistance
KW - Liver macrophages
KW - Small interfering RNA
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U2 - 10.1096/fj.15-270496
DO - 10.1096/fj.15-270496
M3 - Article
C2 - 25805830
AN - SCOPUS:84940417328
SN - 0892-6638
VL - 29
SP - 2959
EP - 2969
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -