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Activated Ask1-MKK4-p38MAPK/JNK Stress Signaling Pathway in Human Omental Fat Tissue May Link Macrophage Infiltration to Whole-Body Insulin Sensitivity

Department of Medicine (M.B., M.S., N.K.), Department of Surgery II (A.D.), University of Leipzig, 04107 Leipzig, Germany; Department of Clinical Biochemistry (N.B., T.T., A.R.), and The S. Daniel Abraham Center of Health and Nutrition (I.S., A.R.), Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel; and Soroka Medical Center (I.H.-B., E.A.), Beer-Sheva 84101, Israel

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

Context: Adipose tissue in obesity is thought to be exposed to various stresses, predominantly in intraabdominal depots. We recently reported that p38MAPK and Jun N-terminal kinase (JNK), but not ERK and inhibitory-B kinase β, are more highly expressed and activated in human omental (OM) adipose tissue in obesity.

Objective: The aim was to investigate upstream components of the pathways that culminate in activation of p38MAPK and JNK.

Setting and Patients: Phosphorylation and expression of kinases were studied in paired samples of OM and sc adipose tissue from lean and obese subjects of two different cohorts (n = 36 and n = 196) by Western and real-time PCR analyses. The association with fat distribution, macrophage infiltration, insulin sensitivity, and glucose metabolism was assessed by correlation analyses.

Results: The amount of phosphorylated forms of the kinases provided evidence for an activated stress-sensing pathway consisting of the MAP3K Ask1 (but not MLK3 or Tak1), and the MAP2Ks MKK4, 3/6, (but not MKK7), specifically in OM. OM Ask1-mRNA was more highly expressed in predominantly intraabdominally obese persons and most strongly correlated with estimated visceral fat. Diabetes was associated with higher OM Ask1-mRNA only in the lean group. In OM, macrophage infiltration strongly correlated with Ask1-mRNA, but the obesity-associated increase in Ask1-mRNA could largely be attributed to the adipocyte cell fraction. Finally, multivariate regression analyses revealed OM-Ask1 as an independent predictor of whole-body glucose uptake in euglycemic-hyperinsulinemic clamps.

Conclusions: An Ask1-MKK4-p38MAPK/JNK pathway reflects adipocyte stress associated with adipose tissue inflammation, linking visceral adiposity to whole-body insulin resistance in obesity.