Format

Send to

Choose Destination
FASEB J. 2015 Jul;29(7):2959-69. doi: 10.1096/fj.15-270496. Epub 2015 Mar 24.

Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Author information

1
*Program in Molecular Medicine, Department of Surgery, and Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
2
*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.

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.

KEYWORDS:

hepatic steatosis; insulin resistance; liver macrophages; small interfering RNA

PMID:
25805830
PMCID:
PMC4478794
DOI:
10.1096/fj.15-270496
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center