IL-17A Regulates Adipose Tissue Macrophage Polarization To Mediate Bpa-induced Adipose Tissue Inflammation And Insulin Resistance

Background BPA is a synthetic polymeric monomer material that has caused widespread exposure mainly in the manufacture of thermal paper,food containers and electronic products.As a classic environmental endocrine disruptor,it has been shown to be associated with obesity and insulin resistance（IR）.Immunometabolic studies have shown that obesity is a systemic chronic inflammatory state,mainly manifested by a large infiltration of macrophages in adipose tissue（AT）.The infiltrating adipose tissue macrophages（ATM）can be classified into classically activated M1 macrophages and selectively activated M2 macrophages according to their phenotypes,and it has been shown that the phenotypes of ATM under different microenvironments are polarized and involved in the development of inflammation and IR.IL-17 A is a pro-inflammatory cytokine,and recent studies have found that IL-17 A is significantly associated with obesity.However,the relationship between IL-17 A and ATM polarization has not been established,and the regulatory role of both in BPA-induced obesity and IR and the specific mechanisms are unclear.Objective Wild type（WT）and IL-17 A knockout（KO）mice were used to investigate the regulatory effects of IL-17 A on BPA exposure-induced inflammation and IR in AT,and the mechanism of inhibiting pro-inflammatory polarization of ATM,to provide an experimental basis for elucidating the mechanism of BPA exposure-induced obesity and IR,and to provide new targets for the prevention and treatment of BPA exposure hazards.Research methods Four-week-old,specific pathogen free（SPF）grade C57BL/6J WT and IL-17 A KO male mice were randomly divided into normal control diet（NCD）,high fat diet（HFD）and HFD+1000n M BPA groups after one week of adaptive feeding,6mice/group.BPA was ingested via drinking water,and after 8 and 16 weeks of exposure,glucose tolerance tests（GTT）and insulin tolerance test（ITT）were performed;blood was collected to isolate serum,and enzyme-linked immunosorbent assay（ELISA）to detect serum insulin（FI）,inflammatory factors TNF-α and IL-1β;Histopathologic（HE）staining was performed to observe the inflammatory cell infiltration and adipocyte size in the AT,immunohistochemistry（IHC）was used to detect the expression of inflammatory factors IL-1β,TNF-α and MCP-1 in AT,flow cytometry（FCM）to detect the number of M1 and M2 ATM in vascular stromal fragments,q RT-PCR to analyze CD11 c,CD206,i NOS,Arg-1 m RNA levels,and western blot（WB）to detect the inflammatory signaling pathway JNK-NF-κB protein,insulin signaling pathway IRS-1-PI3K-AKT protein expression in AT.ResultsCompared with WT mice,IL-17 A KO mice with BPA exposure induced slow body weight gain,decreased epididymal fat factor,significantly reduced inflammatory cell infiltration in AT,smaller adipocyte volume,and downregulated expression of inflammatory factors IL-1β,TNF-α,and MCP-1 in adipose tissue.And found reduced levels of phosphorylation of NF-κB,IKKβ,IκBα,and JNK proteins of inflammatory signaling pathways.At the same time,fasting blood glucose（FG）,FI,insulin resistance index(Homeostasis model assessment（HOAR）-IR were significantly decreased,glucose tolerance impairment in mice was significantly improved,insulin sensitivity was restored,and the phosphorylation level of IRS1-PI3K-AKT protein of insulin signaling pathway was increased.The proportion of M1-type ATM in AT decreased significantly,and the levels of M1-type signature factors CD11 c and i NOS m RNA were significantly downregulated,while the proportion of M2-type ATM increased significantly,and the levels of M2-type signature factors CD206 and Arg-1 m RNA were significantly upregulated.It indicates that IL-17 A KO significantly ameliorated BPA exposure-induced adipose tissue inflammation and IR,while inhibiting the polarization of ATM to M1 type and promoting polarization to M2 type.Conclusions1.IL-17 A KO inhibited environmental low-dose BPA exposure-induced weight gain in mice.2.IL-17 A KO inhibited BPA exposure-induced polarization of ATM to M1 type and interfered with activation of JNK-NF-κB signaling pathway to attenuate BPA exposure-induced adipose tissue inflammation.3.IL-17 A KO restores the IRS1-PI3K-AKT insulin signaling pathway,reverses environmental low-dose BPA exposure-induced glucose intolerance in obese mice,enhances insulin sensitivity,and thus improves IR.