State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing, China.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China.
J Biol Chem. 2020 Jul 31;295(31):10842-10856. doi: 10.1074/jbc.RA119.011840. Epub 2020 Jun 16.
Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both and Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.
慢性低度炎症在 2 型糖尿病的发病机制中起着重要作用。Src 同源 2 结构域酪氨酸磷酸酶-2（SHP2）已被报道在代谢紊乱的发展过程中在不同组织中发挥多种作用。我们之前报道过，巨噬细胞中 SHP2 的抑制会导致细胞因子的产生增加。在这里，我们研究了巨噬细胞中 SHP2 抑制与代谢疾病发展之间的关系。出乎意料的是，我们发现巨噬细胞中条件性 SHP2 敲除（cSHP2-KO）的小鼠改善了代谢紊乱。与高脂肪饮食（HFD）喂养的 WT 同窝仔相比，cSHP2-KO 小鼠体重增加较少，肝脂肪变性减轻，葡萄糖耐量和胰岛素敏感性改善。进一步的实验表明，SHP2 缺乏导致半胱氨酸天冬氨酸蛋白酶-1（caspase-1）的过度激活，随后白细胞介素 18（IL-18）水平升高，这两者都与胰岛素抵抗有关。值得注意的是，IL-18 中和和 caspase-1 敲除逆转了 cSHP2-KO 小鼠肝脂肪变性和胰岛素抵抗的改善。两种特定的 SHP2 抑制剂 SHP099 和 Phps1 的给药改善了 HFD 诱导的肝脂肪变性和胰岛素抵抗。我们的研究结果提供了关于巨噬细胞 SHP2 在代谢紊乱中的作用的详细见解。我们得出结论，SHP2 的药理学抑制可能代表管理 2 型糖尿病的一种治疗策略。
