Centre for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life sciences, University of Hyderabad Campus, Hyderabad 500046, Telangana, India; Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India; Registered as a PhD student with MAHE, Manipal, India.
Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.
Biochim Biophys Acta Mol Basis Dis. 2024 Jan;1870(1):166878. doi: 10.1016/j.bbadis.2023.166878. Epub 2023 Sep 4.
Macrophage-driven chronic low-grade inflammatory response is intimately associated with pathogenesis of insulin resistance and type 2 diabetes (T2D). However, the molecular basis for skewing of pro-inflammatory macrophage is still elusive. Here, we describe the mechanism and significance of TGS1/PIMT (PRIP-Interacting protein with Methyl Transferase domain) in regulating macrophage activation and polarization and its impact on the development of insulin resistance in skeletal muscle cells. We show altered expression of TGS1 in M1 polarized cultured macrophages, bone marrow-derived (BMDM) and adipose tissue macrophages. Moreover, in High Fat Diet (HFD)-fed mice enhanced TGS1 expression is predominantly localized to the nucleus of adipose tissue macrophages suggesting its potential functional role. Gain and loss of TGS1 expression in macrophage further established its role in the secretion of pro-inflammatory mediators. Mechanistically, TGS1 controls the transcription of numerous genes linked to inflammation by forming a complex with Histone Acetyl Transferase (HAT)-containing transcriptional co-activators CBP and p300. Functionally, TGS1 mediated macrophage inflammatory response induces the development of insulin resistance in skeletal muscle cells and adipocytes. Our findings thus demonstrate an unexpected contribution of TGS1 in the regulation of macrophage mediated inflammation and insulin resistance highlighting that TGS1 antagonism could be a promising therapeutic target for the management of inflammation and insulin resistance in T2D.
巨噬细胞驱动的慢性低度炎症反应与胰岛素抵抗和 2 型糖尿病（T2D）的发病机制密切相关。然而，导致促炎巨噬细胞发生倾斜的分子基础仍然难以捉摸。在这里，我们描述了 TGS1/PIMT（PRIP 相互作用蛋白与甲基转移酶结构域）在调节巨噬细胞激活和极化及其对骨骼肌细胞胰岛素抵抗发展的影响中的机制和意义。我们显示了 TGS1 在 M1 极化培养的巨噬细胞、骨髓来源的（BMDM）和脂肪组织巨噬细胞中的表达改变。此外，在高脂肪饮食（HFD）喂养的小鼠中，增强的 TGS1 表达主要定位于脂肪组织巨噬细胞的核内，表明其潜在的功能作用。巨噬细胞中 TGS1 的表达增加和减少进一步证实了其在促炎介质分泌中的作用。从机制上讲，TGS1 通过与包含组蛋白乙酰转移酶（HAT）的转录共激活因子 CBP 和 p300 形成复合物，控制与炎症相关的众多基因的转录。功能上，TGS1 介导的巨噬细胞炎症反应诱导骨骼肌细胞和脂肪细胞发生胰岛素抵抗。因此，我们的发现表明 TGS1 在调节巨噬细胞介导的炎症和胰岛素抵抗方面的作用令人惊讶，这表明 TGS1 拮抗剂可能是 T2D 中炎症和胰岛素抵抗管理的有前途的治疗靶点。
