Modulation of the gut microbiota by Lacticaseibacillus paracasei reduces adipogenesis and metabolic dysregulation in high-fat diet-induced obese mice

The rising interest in microbiota-based therapies has positioned probiotics as promising candidates for managing obesity. This study evaluated the effects of Lacticaseibacillus paracasei in a murine model of high-fat diet (HFD)-induced obesity. Oral administration of L. paracasei significantly reduced body weight gain and adiposity without altering food intake, indicating improved energy efficiency. Probiotic supplementation enhanced insulin sensitivity and glucose tolerance, as shown by lower fasting glucose, insulin levels, and HOMA-IR. At the molecular level, L. paracasei downregulated adipogenic genes (Srebf1, Pparg, Cebpa, Fabp4) and upregulated Ucp-1, suggesting increased browning of white adipose tissue. Inflammatory markers (Tnf-α, Il-6, Mcp-1) and JNK pathway activation were decreased, while insulin signaling and lipid metabolism improved via increased Glut4 and Pparα, and modulation of adipokines. In the liver, the probiotic attenuated steatosis, reduced oxidative stress, and modulated genes related to lipid metabolism. Gut barrier integrity was improved, as indicated by higher expression of tight junction proteins, lower LPS levels, and reduced Tlr4 expression. L. paracasei also reshaped the gut microbiota, decreasing the Bacillota/Bacteroidota ratio and increasing beneficial taxa such as Akkermansia muciniphila and Lactobacillus, while reducing Clostridium spp. Additionally, it normalized obesity-associated miRNAs involved in adipogenesis and inflammation. Finally, the probiotic improved endothelial function and reduced vascular oxidative stress. These results support L. paracasei as a promising probiotic for obesity management, acting through metabolic, inflammatory, and microbiota-mediated mechanisms.