IKK-[beta] links inflammation to obesity-induced insulin resistance

Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. I[kappa]B kinase [beta] (IKK-[beta], encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-[kappa]B. To understand the role of IKK-[beta] in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb[sup.[DELTA]hep]) or myeloid cells (Ikbkb[sup.[DELTA]mye]). Ikbkb[sup.[DELTA]hep] mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb[sup.[DELTA]mye] mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-[beta] acts locally in liver and systemically in myeloid cells, where NF-[kappa]B activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-[beta] in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-[beta], especially in myeloid cells, may be used to treat insulin resistance.
Author(s): Melek C Arkan [1]; Andrea L Hevener [2]; Florian R Greten [1]; Shin Maeda [1]; Zhi-Wei Li [1, 3]; Jeffrey M Long [4]; Anthony Wynshaw-Boris [4]; Giuseppe Poli [5]; [...]