Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body insulin sensitivity

Matthias Blüher, Nava Bashan, Iris Shai, Ilana Harman-Boehm, Tanya Tarnovscki, Eliezer Avinaoch, Michael Stumvoll, Arne Dietrich, Nora Klöting, Assaf Rudich

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

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-κB 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.

Original languageEnglish
Pages (from-to)2507-2515
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number7
DOIs
StatePublished - 1 Jan 2009

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