The Role Of ALKBH1 In Macrophage Polarization And Insulin Resistance In Obesity

Objectives: Proinflammatory activation of adipose tissue macrophages(ATMs)contributes to insulin resistance and promoted obesity.However,the molecular mechanisms that regulate the plasticity of macrophage polarization are poorly understood.The present study aims to further explore the effect of ALKBH1 on the plasticity of macrophage polarization in obesity,clarify the molecular mechanism of DNA m6 A demethylase ALKBH1 affects insulin resistance by regulating macrophage polarization,and further provides a new therapeutic target for insulin resistance and obesity.Materials and Methods: The q RT-PCR and western blot assays were used to determine the ALKBH1’s expression in mouse macrophages.ATMs specific ALKBH1-deficient mice were used to examine the role of ALKBH1 on whole body metabolism.H&E staining was used to assess phenotypes of mice in adipose tissue and liver.Flow cytometry and q RTPCR were used to examine the polarization state of ATMs.Dot blotting assay was used to determine the level of 6m A in genomic DNA.Results: ALKBH1 was suppressed in stromal vascular fraction(SVF)cells of diet-induced obesity mice and was closely associated with adipose tissue inflammation.Myeloid-specific deletion of ALKBH1 in obese mice contributed to white adipose tissue expansion and inflammation,and promoted insulin resistance and obesity by enhancing M1 macrophages.Mechanistically,Loss of ALKBH1 activated M1 macrophage polarization through MAPK/Akt signaling pathway.Conclusions: Our study demonstrates that ALKBH1 regulates ATMs polarization state and metabolic homeostasis in obesity,and provides a potential therapeutic target for insulin resistance and obesity.