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首页> 外文期刊>Molecular and Cellular Biology >Differential Roles of Insulin Receptor Substrates in Brown Adipocyte Differentiation
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Differential Roles of Insulin Receptor Substrates in Brown Adipocyte Differentiation

机译：胰岛素受体底物在褐色脂肪细胞分化中的差异作用

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Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. To determine more precisely the roles of various IRS proteins in adipogenesis, we established and characterized brown preadipocyte cell lines from wild-type and IRS knockout (KO) animals. While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. Cells lacking both IRS-1 and IRS-3 completely failed to differentiate. Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARγ coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. These data indicate that both IRS-1 and -3 play important roles in the differentiation of brown adipocytes and that the N terminus of IRS-1 is more important for this function of the molecule. Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells.
机译：胰岛素通过涉及多个胰岛素受体底物（IRS）的复杂信号网络促进脂肪细胞分化。在培养的褐色前脂肪细胞中，IRS-1和IRS-2 mRNA和蛋白的表达在分化为成熟脂肪细胞之前和之后都处于较高水平，而在脂肪前细胞中未检测到IRS-3转录，但在分化过程中IRS-3转录升高。在两种状态下都几乎未检测到IRS-4 mRNA。为了更准确地确定各种IRS蛋白在脂肪形成中的作用，我们建立了野生型和IRS基因敲除（KO）动物的棕色前脂肪细胞细胞系并对其进行了表征。虽然野生型，IRS-2 KO和IRS-4 KO细胞完全分化为成熟的脂肪细胞，但IRS-3 KO细胞在分化过程中表现出中度缺陷，而IRS-1 KO细胞在此过程中表现出严重缺陷。同时缺乏IRS-1和IRS-3的细胞无法分化。脂肪形成标记过氧化物酶体增殖物激活受体γ（PPARγ），CCAAT /增强子结合蛋白α，脂肪酸合酶，葡萄糖转运蛋白4，转录因子信号转导子和转录激活子5以及棕发的表达特异性标记PPARγ共激活因子1α和解偶联蛋白1反映了分化模式。用IRS-1和IRS-4而非IRS-2或IRS-3重建IRS-1 KO细胞可以弥补IRS-1 KO细胞缺乏分化的缺点。包含IRS-1的N端和IRS-2的C端的嵌合分子，但不包含具有IRS-2的N端和IRS-1的C端的嵌合分子，也可以挽救分化。在IRS-1 KO细胞中，Wnt 10a（一种已知可抑制脂肪生成的分子）的表达急剧增加，而IRS-1或IRS-4的过表达可降低这种表达，这与分化的恢复相关。这些数据表明，IRS-1和-3在棕色脂肪细胞的分化中都起着重要作用，而IRS-1的N端对该分子的这一功能更为重要。尽管IRS-4对于该过程不是必需的，但IRS-4的过度表达可以弥补IRS-1 KO细胞分化的不足。

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