Activated Ask1-MKK4-p38MAPK/JNK Stress Signaling Pathway in Human Omental Fat Tissue May Link Macrophage Infiltration to Whole-Body Insulin Sensitivity
Activated Ask1-MKK4-p38MAPK/JNK Stress Signaling Pathway in Human Omental Fat Tissue May Link Macrophage Infiltration to Whole-Body Insulin Sensitivity
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DOI：
10.1210/jc.2009-0002
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发表时间：
2009-07-01
影响因子：
5.8
通讯作者：
Rudich, Assaf
中科院分区：
文献类型：
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作者：
Blueher, Matthias;Bashan, Nava;Rudich, Assaf
背景：肥胖的脂肪组织被认为暴露于各种压力下，主要是在腹内储存。我们最近报道了p38MAPK和Jun n -末端激酶（JNK），而不是ERK和抑制性κ B激酶β，在肥胖的人网膜（OM）脂肪组织中表达和激活更高。目的：目的是研究最终激活p38MAPK和JNK的途径的上游成分。环境和患者：通过Western和real-time PCR分析，研究了来自两个不同队列（n = 36和n = 196）的瘦肉和肥胖受试者的OM和sc脂肪组织成对样本中激酶的磷酸化和表达。通过相关分析评估其与脂肪分布、巨噬细胞浸润、胰岛素敏感性和葡萄糖代谢的关系。结果：激酶磷酸化形式的数量为激活的应激感应途径提供了证据，该途径由MAP3K Ask1（但不包括MLK3或Tak1）和map2k mkk4,3 /6（但不包括MKK7）组成，特别是在OM中。OM Ask1-mRNA在腹内肥胖人群中表达更高，与估计的内脏脂肪最密切相关。糖尿病仅在瘦组中与较高的OM Ask1-mRNA相关。在OM中，巨噬细胞浸润与Ask1-mRNA密切相关，但肥胖相关的Ask1-mRNA升高可能主要归因于脂肪细胞比例。最后，多变量回归分析显示OM-Ask1是正糖-高胰岛素钳中全身葡萄糖摄取的独立预测因子。结论：Ask1-MKK4-p38MAPK/JNK通路反映了与脂肪组织炎症相关的脂肪细胞应激，将内脏脂肪与肥胖的全身胰岛素抵抗联系起来。[J] .中华内分泌杂志，2009,31(2):357 - 357。
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-kappa B 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.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. (J Clin Endocrinol Metab 94: 2507-2515, 2009)