title: Activated Kupffer cells inhibit insulin sensitivity in obese mice.
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 for metabolic disease.
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Michaela
authors: M
authors: Tencerova
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA myriam.aouadi@ki.se michael.czech@umassmed.edu.
authors: Myriam
authors: M
authors: Aouadi
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Pranitha
authors: P
authors: Vangala
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Sarah M
authors: SM
authors: Nicoloro
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Joseph C
authors: JC
authors: Yawe
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Jessica L
authors: JL
authors: Cohen
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Yuefei
authors: Y
authors: Shen
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Lorena
authors: L
authors: Garcia-Menendez
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: David J
authors: DJ
authors: Pedersen
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Karen
authors: K
authors: Gallagher-Dorval
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Richard A
authors: RA
authors: Perugini
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors: Olga T
authors: OT
authors: Gupta
authors: *Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA myriam.aouadi@ki.se michael.czech@umassmed.edu.
authors: Michael P
authors: MP
authors: Czech
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D005951:Glucose Tolerance Test; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA
keywords: hepatic steatosis; insulin resistance; liver macrophages; small interfering RNA