GLP-1RAs attenuated obesity and reversed leptin resistance partly via activating the microbiome-derived inosine/A2A pathway

Extensive evidence has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorate obesity. Our previous studies revealed that (Ex-4) 2 -Fc, a long-acting GLP-1RA we developed, depends on the leptin pathway to treat obesity. However, the mechanisms linking (Ex-4) 2 -Fc and leptin resistance remain largely unclear. To address this question, we explored the mechanism of GLP-1RAs from the perspective of the gut microbiota, as increasing evidence indicates an important link between the gut microbiota and obesity. This study aimed to explore the potential role of the gut microbiota in the treatment of GLP-1RAs. We found that (Ex-4) 2 -Fc treatment reshaped obesity-induced gut microbiota disturbances and substantially increased the abundance of Akkermansia muciniphila ( Am ). In addition, (Ex-4) 2 -Fc did not respond well in antibiotic-treated (ATB) Obese mice. Subsequent studies have shown that this defect can be overcome by gavage with Am . In addition, we found that Am enhanced (Ex-4) 2 -Fc therapy by producing the metabolite inosine. Inosine regulates the macrophage adenosine A2A receptor (A2A) pathway to indirectly reduce leptin levels in adipocytes Thus, elucidating the role of metabolites in regulating the leptin pathway will provide new insights into GLP-1RAs therapy and may lead to more effective strategies for guiding the clinical use of antidiabetic agents. Graphical abstractThis study revealed that GLP-1RAs partially reversed obesity-induced hypothalamic leptin antagonism through microbiota-driven inosine and provided new insights into guiding the clinical use of antidiabetic agents.