Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice

Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 20; pp. 8278 - 8283
Main Authors:	Aouadi, Myriam, Tencerova, Michaela, Vangala, Pranitha, Yawe, Joseph C., Nicoloro, Sarah M., Amano, Shinya U., Cohen, Jessica L., Czech, Michael P.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 14-05-2013 National Acad Sciences
Subjects:	Adipocytes Adipose Tissue - cytology Adipose tissues Animals Biological Sciences Cytokines Cytokines - metabolism Diabetes Epididymis - cytology Epididymis - metabolism Gene expression Gene Silencing Glucose Intolerance - genetics Glucose Intolerance - metabolism Inflammation Insulin resistance Liver Macrophages Macrophages - cytology Macrophages - metabolism Male Mice Mice, Inbred C57BL Mice, Obese Microscopy, Fluorescence Obesity Obesity - physiopathology Osteopontin - metabolism Phagocytes Phagocytosis RNA Interference RNA, Small Interfering Rodents Small interfering RNA T lymphocytes Tumor Necrosis Factor-alpha - metabolism Type 2 diabetes mellitus immune cells RNAi obesity
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Summary:	Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack of methods to ablate inflammatory genes expressed in macrophages specifically localized within AT depots, leaving macrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-α or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistent with the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance.
Bibliography:	http://dx.doi.org/10.1073/pnas.1300492110 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: M.A. and M.P.C. conceptualized the study; M.A., M.T., P.V., J.C.Y., S.M.N., and M.P.C. designed research; M.A., M.T., P.V., J.C.Y., S.M.N., S.U.A., and J.L.C. performed research; S.U.A. and J.L.C. contributed new reagents/analytic tools; M.A., M.T., P.V., J.C.Y., S.M.N., and M.P.C. analyzed data; and M.A. and M.P.C. wrote the paper. Edited* by Bruce M. Spiegelman, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, and approved April 5, 2013 (received for review January 9, 2013)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1300492110