- 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 , 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 (n36 and n196) 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:Theamountofphosphorylatedformsofthekinasesprovidedevidenceforanactivatedstress-sensingpathwayconsisting 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 morehighlyexpressedinpredominantlyintraabdominallyobesepersonsandmoststronglycorrelatedwithestimatedvisceralfat. 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 may reflect adipocyte stress in response to adipose tissue inflammation, linking visceral adiposity to whole-body insulin resistance in obesity.