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.

Objective To compare effectiveness,performance,and complications between ultrasound-guided selective cervical nerve root block and interscalene brachial plexus block for patients undergoing arthroscopic surgery in perioperative period.Methods Seventy patients scheduled for arthroscopic surgery,25 males and 45 females,aged 18-75 years,were randomly divided into two groups.They were given either selective cervical nerve root block (group S,n =35) or interscalene brachial plexus block (group ISB,n=35).In group S,C5 and C6 nerve roots were given 0.5％ ropivacaine 5 ml respectively;In group ISB,patients were given 0.5％ ropivacaine 10 ml under ultrasound guidance.The primary outcome:VAS score and forearm modified Bromage scale (MBS) score were recorded at 4,12 and 24 hours after surgery;Secondary outcomes:cumulative tramadol consumption,the patients' satisfaction rate and adverse effects were recorded.Results The VAS scores in group S was significantly lower than that in group ISB at 12 hours after surgery (1.7±0.8 vs 3.6±0.7,P＜0.05).The forearm MBS scores in group S was significantly higher than that in group ISB 4 hours after surgery (P＜0.01).Compared with group ISB,the amount of tramadol consumption was lower at 24 hours after surgery [(37.5±35.9) mg vs (112.5±43.5) mg,P＜0.05)].The satisfaction rate of group S was higher than group ISB (88％ vs 56％,P＜0.05).There was no significant difference in side effects between the two groups.Conclusion In arthroscopic surgery,the selective cervical nerve root block is superior to the brachial plexus block.