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.
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.