B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity

Immune-derived opioid peptides have been implicated in immune regulation and inflammatory processes. Here, we investigate the effects of nociceptin/orphanin FQ (N/OFQ) on metabolic function and inflammation in obesity. Selectively targeting N/OFQ, encoded by the Pnoc gene, in B cells mitigates the adverse metabolic effects of diet-induced obesity and enhances insulin sensitivity and glucose tolerance. Notably, B cell-specific Pnoc knockout mice display a marked reduction in markers of immune cell migration and diminished macrophage recruitment in adipose tissue and liver. Mechanistically, we identify that N/OFQ promotes macrophage recruitment and metabolic inflammation, exacerbating glucose intolerance and insulin resistance during obesity. Overall, the immunomodulatory properties exhibited by the N/OFQ-NOP system render it a promising therapeutic target for mitigating metabolic inflammation. Gene expression profiling analysis of RNA-seq data from visceral adipose tissue (eWAT) of Pnoc∆CD19 and littermate control animals (CD19-Cre). Organs were collected after 17 weeks of high-fat diet feeding.

免疫源性阿片肽已被证实参与免疫调控与炎症反应进程。本研究探讨了痛敏肽/孤啡肽FQ（nociceptin/orphanin FQ, N/OFQ）在肥胖状态下对代谢功能与炎症的调控效应。在B细胞中特异性靶向Pnoc基因编码的N/OFQ，可减轻饮食诱导肥胖所致的不良代谢影响，并改善胰岛素敏感性与葡萄糖耐量。值得注意的是，B细胞特异性Pnoc敲除小鼠的免疫细胞迁移标志物水平显著降低，且脂肪组织与肝脏内的巨噬细胞招募过程受到明显抑制。机制层面的研究证实，N/OFQ可促进巨噬细胞招募与代谢性炎症，进而加剧肥胖状态下的葡萄糖耐受不良与胰岛素抵抗。综上，N/OFQ-NOP系统所展现出的免疫调控特性，使其成为缓解代谢性炎症的极具潜力的治疗靶点。本研究对Pnoc∆CD19小鼠及同窝CD19-Cre对照动物的内脏脂肪组织（eWAT）的RNA测序数据进行了基因表达谱分析，所有组织样本均于小鼠接受17周高脂饮食喂养后采集。