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Acarbose improves obesity-induced insulin resistance and immune homeostasis by directly regulating gut microbiota and macrophages inflammation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE232578 | GEO | 2024/11/04

REPOSITORIES: GEO

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Project description:A favourable immunotherapeutic strategy in the treatment of chronic inflammatory disease, is to dampen the pro-inflammatory macrophage response and upregulate the anti-inflammatory macrophage response. Previous studies have shown that Arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response with an essential role in IL-10 signalling. Here we show that IL-10 in the presence of LPS increased Arg2 expression in human macrophages and peripheral blood mononuclear cells. Target site blockers (TSBs) (locked nucleic acid antisense oligonucleotides) specifically designed to target the 3’ UTR of Arg2 messenger RNA were used to inhibit binding of specific microRNAs thus enhancing Arg2 expression. Eleven Arg2-TSBs were screened and the TSB targeting miR-155 (TSB-155) and the TSB targeting miR-3202 (TSB-3202) were found to increase Arg2 expression in human macrophages resulting in decreased gene expression and cytokine production of TNF-α and CCL2. In addition, following TSB-3202 stimulation, there were statistically significant increases in the ‘M2-like’ macrophage marker, CD206; and CD16, associated with an IL-10 response, and a decrease in the ‘M1-like’ macrophage marker, HLA-DR, indicating a shift in the macrophage phenotype. Proteomic analysis demonstrated that multiple pro-inflammatory responsive proteins including Signal Transducer and Activator of Transcription 1 (STAT-1), Toll-like receptors, Signalling Lymphocytic Activation Molecule F7 (SLAMF7) and Interferon Induced Protein with Tetratricopeptide Repeats 3 (IFIT3), were downregulated by TSB-155 and TSB-3202 while Sequestomsome-1 (SQSTM1) was increased after treatment. In silico analysis of significantly dysregulated proteins predicted that TSB-3202 supressed several upstream pro-inflammatory regulators including STAT-1 and Interferon α2 (IFNA2) while enhancing anti-inflammatory associated interleukin 1 receptor antagonist (IL1RN) and STAT-3. Proteomic data was validated by confirming increased levels of SQSTM1, decreased levels of phosphoylated-STAT-1 and STAT-1, and downregulation of Ifit3 and Slamf7 by TSB treatment. In conclusion, upregulation of Arg2 protein by TSBs inhibits several pro-inflammatory signalling proteins resulting in reduced pro-inflammatory cytokine secretion, reduced ‘M1-like’ marker expression and enhanced ‘M2-like’ macrophage marker expression. Arg2 is a promising novel therapeutic target to modulate inflammatory signalling in macrophages.

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Acarbose improves obesity-induced insulin resistance and immune homeostasis by directly regulating gut microbiota and macrophages inflammation

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