Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance.
Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance.
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作者：
Kawano Y;Nakae J;Watanabe N;Fujisaka S;Iskandar K;Sekioka R;Hayashi Y;Tobe K;Kasuga M;Noda T;Yoshimura A;Onodera M;Itoh H
脂肪组织中的慢性炎症导致肥胖相关的胰岛素抵抗。3-磷酸肌醇依赖性蛋白激酶1（Pdk 1）/叉头转录因子（Foxo 1）通路在调节葡萄糖和能量稳态中是重要的，但对脂肪组织巨噬细胞（ATM）中的该通路知之甚少。为了研究这一点，我们产生了携带巨噬细胞/粒细胞特异性突变的转基因小鼠，包括Pdk 1敲除（LysMPDk 1 −/−），Pdk 1敲除与反式激活缺陷Foxo 1（Δ 256 LysMPDk 1 −/−），组成型活性核（CN）Foxo 1（CNFoxo 1 LysM）或反式激活缺陷Foxo 1（Δ 256 Foxo 1 LysM）。我们分析了葡萄糖代谢和基因表达的ATM人口分离荧光激活细胞分选。LysMPdk 1 −/−小鼠表现出脂肪组织中M1巨噬细胞的升高和胰岛素抵抗。过表达的反式激活缺陷Foxo 1拯救这些表型。CNFoxo 1 LysM促进ATM中C-C基序趋化因子受体2（Ccr 2）的转录，并增加脂肪组织中M1巨噬细胞的数量。在高脂肪饮食中，CNFoxo 1 LysM小鼠表现出胰岛素抵抗。骨髓源性巨噬细胞中的Pdk 1缺失或Foxo 1激活可消除参与替代性巨噬细胞激活的基因的胰岛素和白细胞介素-4诱导。因此，Pdk 1通过抑制Foxo 1诱导的Ccr 2表达来调节巨噬细胞浸润。这表明巨噬细胞Pdk 1/Foxo 1通路在体内调节胰岛素敏感性中是重要的。
Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1−/−), a Pdk1 knockout with transactivation-defective Foxo1 (Δ256LysMPdk1−/−), a constitutively active nuclear (CN) Foxo1 (CNFoxo1LysM), or a transactivation-defective Foxo1 (Δ256Foxo1LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1−/− mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1LysM mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow–derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.
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影响因子：
7.7
作者：
Nakae, Jun;Cao, Yongheng;Hayashi, Yoshitake
通讯作者：
Hayashi, Yoshitake
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
11.4
作者：
Nakae, J;Barr, V;Accili, D
通讯作者：
Accili, D
影响因子：
11.4
作者：
Fan, WuQiang;Morinaga, Hidetaka;Olefsky, Jerrold M.
通讯作者：
Olefsky, Jerrold M.
影响因子：
64.5
作者：
Lehtinen, Maria K.;Yuan, Zengqiang;Bonni, Azad
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Bonni, Azad