Acarbose improves obesity-induced insulin resistance and immune homeostasis by directly regulating gut microbiota and macrophages inflammation
Acarbose was reported to alleviate obesity-induced insulin resistance IR and regulate the gut microbiota community; however, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of acarbose remains unknown. In this study, we reported that acarbose treatment was able to significantly improve high fat diet (HFD) induced IR and inflammation states in adipose tissue and intestine by influencing the survival and pro-inflammatory function of M1 macrophages. Furthermore, we revealed that acarbose exert anti-inflammatory effects partly in a gut-microbiota dependent manner by microbiota clearance experiments. 16S rRNA sequencing and metabolomic researches identified that acarbose could enhance the proliferation of propionic acid (PA)-producing Parasutterella excrementihominis (PARA). As the vital metabolic mediator, PA regulated the pro-inflammatory and anti-inflammatory balance of M1/M2 macrophages by GPR4/NLRP3 signaling pathway. In addition, in vivo studies of NBD fluorescence labeled acarbose verified that acarbose directly inhibited the macrophage inflammatory response in adipose tissue via being captured by intestinal macrophage due to the aggravated intestinal permeability in HFD mice. We also validated this result in bone-marrow derived macrophage (BMDM) and human macrophages in vitro. Mechanistically, acarbose may suppressed mTOR signaling pathway and the following autophagy/mitochondrial function of M1 macrophage by activating GPR120, thereby reducing its survival and the secretion of pro-inflammatory cytokines. In conclusion, these findings presented that acarbose improved obesity-induced IR by maintaining beneficial microbiota and direct inhibited action on M1 macrophages. Overall design: Control sample: M1 bone-marrow derived macrophage; Exprimental sample: Acarbose treated M1 bone-marrow derived macrophage