5-methoxytryptamine improves hepatic inflammation and insulin resistance in a macrophage C-X-C motif chemokine ligand 14 dependent manner

Accumulating evidence indicates that tryptophan metabolism plays important roles in insulin resistance, and glucolipid metabolism. Our preliminary study revealed a significant decrease in the serum levels of the tryptophan metabolite 5-methoxytryptamine (5MT), in both high-fat diet (HFD)-fed and db/db mice. Notably, these levels were restored following treatment with the hypoglycemic agent, the dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin, suggesting a potential relationship between 5MT and metabolic homeostasis. In the current study, we demonstrated that 5MT treatment ameliorated insulin resistance and hepatic steatosis in HFD and db/db mice. Specific inhibition of the aryl hydrocarbon receptor (AHR) attenuated the beneficial effects of 5MT on insulin resistance in HFD mice. Transcriptome sequencing and subsequent validation revealed that 5MT significantly upregulated the expression of C-X-C motif chemokine ligand 14 (Cxcl14) in hepatic macrophages. Myeloid-specific knockout of Cxcl14 demonstrated that 5MT inhibited hepatic inflammatory response to improve insulin resistance in a macrophage CXCL14-dependent manner. Furthermore, molecular mechanism exploration revealed that 5MT promoted the AHR-mediated transcriptional activation of Cxcl14, which inhibited glycolysis in macrophages, subsequently suppressing their proinflammatory classical activation (M1 phenotype). Collectively, these data reveal a novel beneficial role of 5MT in insulin resistance and metabolic homeostasis, providing a rationale for new therapeutic strategies targeting insulin resistance-associated metabolic disorders, such as obesity and diabetes.