Activated Kupffer cells inhibit insulin sensitivity in obese mice
Program in Molecular Medicine; Department of Surgery; Department of Pediatrics, Division of Endocrinology/Diabetes
Endocrinology | Endocrinology, Diabetes, and Metabolism | Pediatrics
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-kappaB, 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-kappaB complex caused loss of NF-kappaB p65 expression in KCs without disrupting NF-kappaB in hepatocytes or macrophages in other tissues. Silencing of NF-kappaB 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.
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Citation: FASEB J. 2015 Jul;29(7):2959-69. doi: 10.1096/fj.15-270496. Epub 2015 Mar 24. Link to article on publisher's site
Tencerova, Michaela; Cohen, Jessica L.; Shen, Yuefei; Garcia-Menendez, Lorena; Gupta, Olga T.; Czech, Michael P.; Aouadi, Myriam; Vangala, Pranitha; Nicoloro, Sarah M.; Yawe, Joseph; Pedersen, David J.; Gallagher-Dorval, Karen A.; and Perugini, Richard A., "Activated Kupffer cells inhibit insulin sensitivity in obese mice" (2015). Pediatric Publications and Presentations. 52.