Hyperglycemia enhances adipogenic induction of lipid accumulation:: Involvement of extracellular signal-regulated protein kinase 1/2, phosphoinositide 3-kinase/Akt, and peroxisome proliferator-activated receptor γ signaling
Hyperglycemia enhances adipogenic induction of lipid accumulation:: Involvement of extracellular signal-regulated protein kinase 1/2, phosphoinositide 3-kinase/Akt, and peroxisome proliferator-activated receptor γ signaling
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DOI：
10.1210/en.2007-0179
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发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Shing Hwa
中科院分区：
文献类型：
--
作者：
Chuang, Chia Chi;Yang, Rong Sen;Liu, Shing Hwa
高血糖引发的脂肪形成诱导脂质蓄积增加的分子事件仍不清楚。我们研究了高血糖对脂肪形成诱导脂质积聚及其相关信号分子的影响，如磷酸肌醇3-激酶（PI 3 K），ERK和过氧化物酶体增殖物激活受体γ（PPAR γ）。FVB/N小鼠骨髓间充质干细胞（MSCs）在成脂培养基中可分化为脂肪细胞。通过RT-PCR、ELISA、流式细胞术、免疫染色和免疫印迹在体外评估高糖（HG）（25.5 mM）的影响。在链脲佐菌素（STZ）诱导的糖尿病FVB/N小鼠中进一步研究了高血糖症的体内影响。与5.5 mM葡萄糖相比，暴露于HG的MSC增强脂肪形成诱导的脂质积累。在脂肪形成过程中，HG增加了PPARgamma表达和PI 3 K活性及其下游效应物Akt磷酸化。用PI 3 K抑制剂LY 294002或通过表达显性负性p85或Akt抑制PI 3 K/Akt活性可阻止HG增强的PPAR γ依赖性脂肪形成诱导脂质积聚。此外，HG增加了脂肪形成过程中ERK 1/2的磷酸化。MAPK/ERK抑制剂PD 98059可抑制高糖诱导的PI 3 K活性、Akt磷酸化和脂质蓄积。PI 3 K抑制剂LY 294002不影响脂肪形成过程中HG增加的ERK 1/2磷酸化。我们接下来观察到从STZ诱导的糖尿病小鼠分离的MSC的脂质积累的脂肪形成诱导增强。此外，STZ-糖尿病小鼠骨骼中的甘油三酯、PPAR γ表达、磷酸化Akt和ERK 1/2以及骨髓脂肪也增加。这些结果表明，高血糖通过ERK 1/2激活的PI 3 K/Akt调节的PPAR γ途径增强脂肪形成诱导脂质积聚。
The molecular events of hyperglycemia-triggered increase in adipogenic induction of lipid accumulation remain unclear. We examined the effects of hyperglycemia on adipogenic induction of lipid accumulation and its involved signaling molecules, such as phosphoinositide 3-kinase ( PI3K), ERKs, and peroxisome proliferator-activated receptor gamma ( PPAR gamma). Bone marrow-derived mesenchymal stem cells ( MSCs) isolated from FVB/N mice were capable of differentiating into adipocytes in adipogenic medium. The effects of high glucose ( HG) ( 25.5 mM) were assessed in vitro by RT-PCR, ELISA, flow cytometry, immunostaining, and immunoblotting. The in vivo effect of hyperglycemia was further studied in streptozotocin ( STZ)-induced diabetic FVB/N mice. Exposure of MSCs to HG enhanced adipogenic induction of lipid accumulation as compared with 5.5 mM glucose. HG increased PPAR gamma expression and PI3K activity and its downstream effector Akt phosphorylation during adipogenesis. Inhibition of PI3K/Akt activity with PI3K inhibitor LY294002 or by expressing the dominant negative p85 or Akt prevented the HG-enhanced PPAR gamma-dependent adipogenic induction of lipid accumulation. Moreover, HG increased the phosphorylation of ERK1/2 during adipogenesis. MAPK/ERK inhibitor PD98059 inhibited the PI3K activity, Akt phosphorylation, and lipid accumulation triggered by HG. PI3K inhibitor LY294002 did not affect the HG-increased ERK1/2 phosphorylation during adipogenesis. We next observed that adipogenic induction of lipid accumulation of MSCs isolated from STZ-induced diabetic mice is enhanced. Moreover, triglyceride, PPAR gamma expression, phosphorylated Akt and ERK1/2, and marrow fat in bones of STZ-diabetic mice were also increased. These results suggest that hyperglycemia enhances the adipogenic induction of lipid accumulation through an ERK1/2-activated PI3K/Akt-regulated PPAR gamma pathway.