Lactobacillus rhamnosus GG Supernatant Improves GLP-1 Secretion Through Attenuating L Cell Lipotoxicity and Modulating Gut Microbiota in Obesity

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.