Optogenetic decoding of Akt2-regulated metabolic signaling pathways in skeletal muscle cells using transomics analysis
Optogenetic decoding of Akt2-regulated metabolic signaling pathways in skeletal muscle cells using transomics analysis
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DOI：
10.1126/scisignal.abn0782
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发表时间：
2023-02-21
影响因子：
7.3
通讯作者：
Ozawa，Takeaki
中科院分区：
文献类型：
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作者：
Kawamura，Genki;Kokaji，Toshiya;Ozawa，Takeaki
胰岛素通过激活Akt激酶家族的特异性亚型来调节各种细胞代谢过程。在这里，我们阐明了以Akt2依赖性方式调节的代谢途径。我们构建了一个transomics网络，通过定量磷酸化Akt底物，代谢产物，并在C2C12骨骼肌细胞与急性，光遗传学诱导的激活Akt2的转录。我们发现，Akt2特异性激活主要影响Akt底物磷酸化和代谢物调节，而不是转录调控。transomics网络显示，Akt2调节较低的糖酵解途径和核苷酸代谢，并与Akt2非依赖性信号传导合作，促进这些过程中的限速步骤，如糖酵解的第一步，葡萄糖摄取和嘧啶代谢酶CAD的激活。总之，我们的研究结果揭示了Akt2依赖性代谢途径调节的机制，为糖尿病和代谢紊乱的Akt2靶向治疗铺平了道路。
Insulin regulates various cellular metabolic processes by activating specific isoforms of the Akt family of kinases. Here, we elucidated metabolic pathways that are regulated in an Akt2-dependent manner. We constructed a transomics network by quantifying phosphorylated Akt substrates, metabolites, and transcripts in C2C12 skeletal muscle cells with acute, optogenetically induced activation of Akt2. We found that Akt2-specific activation predominantly affected Akt substrate phosphorylation and metabolite regulation rather than transcript regulation. The transomics network revealed that Akt2 regulated the lower glycolysis pathway and nucleotide metabolism and cooperated with Akt2-independent signaling to promote the rate-limiting steps in these processes, such as the first step of glycolysis, glucose uptake, and the activation of the pyrimidine metabolic enzyme CAD. Together, our findings reveal the mechanism of Akt2-dependent metabolic pathway regulation, paving the way for Akt2-targeting therapeutics in diabetes and metabolic disorders.