Attenuation of macrophage accumulation and polarisation in obese diabetic mice by a small molecule significantly improved insulin sensitivity

作者：Mukherjee Sandip; Das Snehasis; Chattopadhyay Dipanjan; Sarkar Shuvasree; Chatterjee Subhendu Kumar; Talukdar Dhrubajyoti; Mukherjee Sutapa; Majumdar Subeer S; Mukhopadhyay Satinath; Chaudhuri Mihir K^*; Bhattacharya Samir^*

来源：Biochemical and Biophysical Research Communications, 2018, 501(3): 771-778.

DOI：10.1016/j.bbrc.2018.05.068

• Adipopcyte
• ATM
• Insulin sensitivity
• Macrophage
• NF kappa B
• SIRT1

Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O-2)(2) (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFN gamma. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFN gamma promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFN gamma levels, we found that it was due to the inactivation of NF kappa B because of its deacetylation by SIRT1. Since NF kappa B is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes.

• 出版日期2018-6-27