IKK-β links inflammation to obesity-induced insulin resistance

MC Arkan, AL Hevener, FR Greten, S Maeda, ZW Li… - Nature medicine, 2005 - nature.com
MC Arkan, AL Hevener, FR Greten, S Maeda, ZW Li, JM Long, A Wynshaw-Boris, G Poli
Nature medicine, 2005nature.com
Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes.
IκB kinase β (IKK-β, encoded by Ikbkb) is a central coordinator of inflammatory responses
through activation of NF-κB. To understand the role of IKK-β in insulin resistance, we used
mice lacking this enzyme in hepatocytes (Ikbkb Δhep) or myeloid cells (Ikbkb Δmye). Ikbkb
Δhep 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 Δmye mice retain global …
Abstract
Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IκB kinase β (IKK-β, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-κB. To understand the role of IKK-β in insulin resistance, we used mice lacking this enzyme in hepatocytes (IkbkbΔhep) or myeloid cells (IkbkbΔmye). IkbkbΔhep mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, IkbkbΔmye mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-β acts locally in liver and systemically in myeloid cells, where NF-κB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-β in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-β, especially in myeloid cells, may be used to treat insulin resistance.
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