IKK-beta links inflammation to obesity-induced insulin resistance.
Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) 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(Deltamye) 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-kappaB 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.
Arkan
Melek C
MC
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.
Hevener
Andrea L
AL
Greten
Florian R
FR
Maeda
Shin
S
Li
Zhi-Wei
ZW
Long
Jeffrey M
JM
Wynshaw-Boris
Anthony
A
Poli
Giuseppe
G
Olefsky
Jerrold
J
Karin
Michael
M
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004041:Dietary Fats; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D051550:I-kappa B Kinase; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse