Wang Xu, Lv Xinrui, Qi Yaxin, Wang Sipu, Yang Mo, Wang Bangmao, Cao Hailong, Zhang Jie, Xu Xin
Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, 300052, China.
Probiotics Antimicrob Proteins. 2025 May 14. doi: 10.1007/s12602-025-10564-9.
Obesity is associated with decreased secretion of glucagon-like peptide-1 (GLP-1), which may result from lipotoxic damage to L cells caused by elevated levels of free fatty acids (FFAs). Although the probiotic Lactobacillus rhamnosus GG (LGG) exhibits anti-apoptotic properties, its potential to protect L cells from lipotoxic damage remains uncertain. This study investigated the impact of LGG supernatant (LGGs) on NCI-H716 cells treated with palmitic acid (PA) to mimic lipotoxic injury, focusing on cell apoptosis and function. Transcriptome sequencing was used to explore the mechanism of the action of LGGs. Additionally, the effects of LGGs on body weight, glucose tolerance, GLP-1 secretion, and gut microbiota were assessed in a diet-induced obese mouse model. PA induced L cell apoptosis and decreased the level of prohormone convertase 1 (PC1) in a concentration- and time-dependent manner, leading to intracellular accumulation of proglucagon (GCG). LGGs significantly restored PA-induced downregulation of PC1, GCG accumulation, and cell apoptosis, mainly by inhibiting endoplasmic reticulum stress and downregulating the ATF3/Chop pathway. Overexpression of Chop or ATF3 partially reversed the protective effect of LGGs. Additionally, in the mouse model, LGGs improved obesity, insulin resistance, and glucose tolerance, and restored GLP-1 secretion, which may be related to LGGs' inhibition of the ATF3/Chop pathway in L cells, regulation of gut microbiota composition, and enhancement of short-chain fatty acid production. Overall, LGGs can ameliorate high-fat diet-induced impairment of GLP-1 secretion by inhibiting lipotoxicity-mediated damage through the ATF3/Chop pathway and modulating the gut microbiota.
肥胖与胰高血糖素样肽-1（GLP-1）分泌减少有关，这可能是由于游离脂肪酸（FFA）水平升高对L细胞造成脂毒性损伤所致。尽管益生菌鼠李糖乳杆菌GG（LGG）具有抗凋亡特性，但其保护L细胞免受脂毒性损伤的潜力仍不确定。本研究调查了LGG上清液（LGGs）对用棕榈酸（PA）处理以模拟脂毒性损伤的NCI-H716细胞的影响，重点关注细胞凋亡和功能。转录组测序用于探索LGGs的作用机制。此外，在饮食诱导的肥胖小鼠模型中评估了LGGs对体重、葡萄糖耐量、GLP-1分泌和肠道微生物群的影响。PA以浓度和时间依赖性方式诱导L细胞凋亡并降低激素原转化酶1（PC1）水平，导致胰高血糖素原（GCG）在细胞内积累。LGGs主要通过抑制内质网应激和下调ATF3/Chop途径，显著恢复了PA诱导的PC1下调、GCG积累和细胞凋亡。Chop或ATF3的过表达部分逆转了LGGs的保护作用。此外，在小鼠模型中，LGGs改善了肥胖、胰岛素抵抗和葡萄糖耐量，并恢复了GLP-1分泌，这可能与LGGs抑制L细胞中的ATF3/Chop途径、调节肠道微生物群组成以及增强短链脂肪酸产生有关。总体而言，LGGs可以通过抑制ATF3/Chop途径介导的脂毒性损伤和调节肠道微生物群，改善高脂饮食诱导的GLP-1分泌受损。
