Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body Insulin sensitivity.
BACKGROUND
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-kappaB kinase beta, 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.


METHODS
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.
Department of Medicine, University of Leipzig, 04107 Leipzig, Germany.
Matthias
M
Blüher
Nava
N
Bashan
Iris
I
Shai
Ilana
I
Harman-Boehm
Tanya
T
Tarnovscki
Eliezer
E
Avinaoch
Michael
M
Stumvoll
Arne
A
Dietrich
Nora
N
Klöting
Assaf
A
Rudich
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002633:Chemotaxis / Q000276:immunology; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism / Q000502:physiology*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009852:Omentum / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human