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Mitogen-Activated Protein Kinases, Inhibitory-B Kinase, and Insulin Signaling in Human Omental Versus Subcutaneous Adipose Tissue in Obesity

Department of Clinical Biochemistry (N.B., K.D., T.T., S.O., R.P., A.R.), The National Institute of Biotechnology in the Negev (S.O.), and The S. Daniel Abraham Center of Health and Nutrition (A.R.), Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel; Soroka Medical Center (I.H.-B., I.F.L., T.M.-Z., E.A.), Beer-Sheva 84101, Israel; and Medical Department III and Interdisciplinary Centre for Clinical Research (M.B., M.S.), University of Leipzig, Leipzig D-04103, Germany

Address all correspondence and requests for reprints to: Assaf Rudich, M.D., Ph.D., Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel. E-mail: rudich{at}bgu.ac.il.

MAPKs and inhibitory-B kinase (IKK) were suggested to link various conditions thought to develop in adipose tissue in obesity (oxidative, endoplasmic reticulum stress, inflammation) with insulin resistance. Yet whether in obesity these kinases are affected in a fat-depot-differential manner is unknown. We assessed the expression and phosphorylation of these kinases in paired omental and abdominal-sc fat biopsies from 48 severely obese women (body mass index > 32 kg/m²). Protein and mRNAs of p38MAPK, ERK, c-Jun kinase-1, and IKKß were increased 1.5–2.5-fold in omental vs. sc fat. The phosphorylated (activated) forms of these kinases were also increased to similar magnitudes as the total expression. However, phosphorylation of insulin receptor substrate-1 on Ser312 (equivalent of murine Ser307) was not increased in omental, compared with sc, fat. Consistently, fat tissue fragments stimulated with insulin demonstrated that tyrosine phosphorylation and signal transduction to Akt/protein kinase B in omental fat was not inferior to that observable in sc fat. Comparison with lean women (body mass index 23.2 ± 2.9 kg/m²) revealed similar ERK2 and IKKß expression and phosphorylation in both fat depots. However, as compared with lean controls, obese women exhibited 480 and 270% higher amount of the phosphorylated forms of p38MAPK and c-Jun kinase, respectively, in omental, but not sc, fat, and this expression level correlated with clinical parameters of glycemia and insulin sensitivity. Increased expression of stress-activated kinases and IKK and their phosphorylated forms in omental fat occurs in obesity, potentially contributing to differential roles of omental and sc fat in the pathophysiology of obesity.

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