Adaptor protein SH2-B linking receptor-tyrosine kinase and Akt promotes adipocyte differentiation by regulating peroxisome proliferator-activated receptor gamma messenger ribonucleic acid levels.
Adaptor protein SH2-B linking receptor-tyrosine kinase and Akt promotes adipocyte differentiation by regulating peroxisome proliferator-activated receptor gamma messenger ribonucleic acid levels.
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DOI：
10.1210/me.2006-0413
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发表时间：
2007-05
影响因子：
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通讯作者：
D. Yoshiga;Naoichi Sato;T. Torisu;H. Mori;Ryoko Yoshida;Seiji Nakamura;G. Takaesu;Takashi Kobayashi;A. Yoshimura
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文献类型：
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作者：
D. Yoshiga;Naoichi Sato;T. Torisu;H. Mori;Ryoko Yoshida;Seiji Nakamura;G. Takaesu;Takashi Kobayashi;A. Yoshimura
脂肪细胞分化受胰岛素和IGF-I调节，胰岛素和IGF-I通过激活其受体酪氨酸激酶来传递信号。SH 2-B是含有普列克底物蛋白同源性和Src同源性2（SH 2）结构域的衔接蛋白，其已经涉及胰岛素和IGF-I受体信号传导。在这项研究中，我们发现SH 2-B水平和脂肪形成之间有很强的联系。在SH 2-B-/-小鼠的白色脂肪组织中，脂肪质量和脂肪形成基因（包括过氧化物酶体增殖物激活受体γ（PPARgamma））的表达减少。观察到SH 2-B缺陷小鼠胚胎成纤维细胞（MEF）的脂肪细胞分化在胰岛素和地塞米松的作用下减少，而逆转录病毒SH 2-B过表达增强了3 T3-L1前脂肪细胞向脂肪细胞的分化。SH 2-B过表达增加了3 T3-L1细胞中PPARgamma的mRNA水平，而在SH 2-B缺陷的MEFs中，PPARgamma水平响应于胰岛素而降低。SH 2-B介导的PPARgamma mRNA的上调被磷脂酰肌醇3-激酶抑制剂阻断，但不被MAPK激酶抑制剂阻断。胰岛素诱导的Akt活化和叉形头转录因子（FKHR/Foxo 1）磷酸化（一种PPARgamma转录的负调节因子）在SH 2-B过表达时上调，但在SH 2-B缺陷的MEFs中降低。这些数据表明，SH 2-B是体内和体外脂肪形成的关键调节剂，通过调节胰岛素/IGF-I受体-Akt-Foxo 1-PPARgamma途径。
Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor gamma (PPARgamma) were reduced in white adipose tissue of SH2-B-/- mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPARgamma in 3T3-L1 cells, whereas PPARgamma levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPARgamma mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPARgamma transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficient MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPARgamma pathway.