Nature Medicine11, 191 - 198 (2005)
Published online: 30 January 2005; | doi:10.1038/nm1185
IKK- links inflammation to obesity-induced insulin resistance
Melek C Arkan1, Andrea L Hevener2, Florian R Greten1, Shin Maeda1, Zhi-Wei Li1, 3, Jeffrey M Long4, Anthony Wynshaw-Boris4, Giuseppe Poli5, Jerrold Olefsky2
& Michael Karin1
1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
2
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
3
Moffit Cancer Center and Research Institute, 3011 West Holly Drive, SRB-22344, Tampa, Florida 33612, USA.
4
Departments of Pediatrics and Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
5
Department of Clinical and Biological Sciences, S. Luigi Hospital, University of Turin, Orbassano, Turin, 10043, Italy.
Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IB kinase (IKK-, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-B. To understand the role of IKK- in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkbhep) or myeloid cells (Ikbkbmye). Ikbkbhep mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkbmye mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK- acts locally in liver and systemically in myeloid cells, where NF-B activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK- in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-, especially in myeloid cells, may be used to treat insulin resistance.
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links inflammation to obesity-induced insulin resistance
B kinase 
(IKK-
hep) or myeloid cells (Ikbkb
