5-methoxytryptamine improves hepatic inflammation and insulin resistance via macrophage CXCL14-dependent AHR activation.

Insulin resistance and hepatic steatosis are central to metabolic disorders like obesity and type 2 diabetes, often driven by chronic hepatic inflammation. Current treatments often fall short in fully addressing the complex interplay of inflammation and metabolic dysfunction. Tryptophan metabolism is increasingly recognized for its role in glucolipid metabolism and insulin sensitivity. The tryptophan metabolite 5-methoxytryptamine (5MT), found to be decreased in high-fat diet (HFD) and db/db mice and restored by the DPP-4 inhibitor sitagliptin, suggests a potential link to metabolic homeostasis and a novel therapeutic target.

Researchers investigated the effects of 5-methoxytryptamine (5MT) in two established mouse models of metabolic dysfunction: high-fat diet (HFD)-fed mice and genetically diabetic db/db mice. They administered 5MT to these models and assessed improvements in insulin resistance and hepatic steatosis. To elucidate the mechanism, specific inhibition of the aryl hydrocarbon receptor (AHR) was performed in HFD mice. Further, transcriptome sequencing of hepatic macrophages was conducted to identify gene expression changes, followed by validation. A critical step involved using myeloid-specific knockout mice for C-X-C motif chemokine ligand 14 (Cxcl14) to confirm its role in 5MT's effects on hepatic inflammation and insulin resistance.

5-methoxytryptamine (5MT) treatment significantly ameliorated both insulin resistance and hepatic steatosis in high-fat diet (HFD)-fed and db/db mice. This beneficial effect was found to be dependent on the aryl hydrocarbon receptor (AHR), as specific inhibition of AHR attenuated 5MT's improvements in insulin resistance in HFD mice. Transcriptome sequencing and subsequent validation revealed that 5MT robustly upregulated the expression of C-X-C motif chemokine ligand 14 (Cxcl14) specifically in hepatic macrophages. The crucial role of Cxcl14 was confirmed when myeloid-specific knockout of Cxcl14 demonstrated that 5MT's ability to inhibit hepatic inflammatory response and improve insulin resistance was entirely dependent on macrophage CXCL14. Mechanistically, 5MT promoted the AHR-mediated transcriptional activation of Cxcl14.