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Activated Kupffer cells inhibit insulin sensitivity in obese mice.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2015 Jul; Vol. 29 (7), pp. 2959-69. Date of Electronic Publication: 2015 Mar 24. - Publication Year :
- 2015
-
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.<br /> (© FASEB.)
- Subjects :
- Animals
Cytokines metabolism
Drug Delivery Systems
Fatty Liver genetics
Fatty Liver metabolism
Fatty Liver pathology
Gene Silencing
Glucose Tolerance Test
Humans
In Vitro Techniques
Injections, Intravenous
Kupffer Cells pathology
Lipid Metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Obesity genetics
Obesity pathology
RNA, Small Interfering administration & dosage
RNA, Small Interfering genetics
Transcription Factor RelA genetics
Insulin Resistance physiology
Kupffer Cells metabolism
Obesity metabolism
Transcription Factor RelA antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 29
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 25805830
- Full Text :
- https://doi.org/10.1096/fj.15-270496