Lactiplantibacillus plantarum Attenuates Diet-Induced Obesity and Insulin Resistance Through Gut Microbiota-Driven PPAR/PI3K-Axis Modulation

LPPerfectus001 (LPP; GDMCC 62334) is a strain isolated from traditional pickled vegetables and identified as Lactiplantibacillus plantarum by 16s rRNA sequencing and biochemical analysis. Whole-genome sequencing and functional prediction revealed that it is rich in carbohydrate metabolism and lipid metabolism genes, as well as short-chain fatty acid synthesis genes. Preliminary experiments on high-sugar and high-fat zebrafish showed that LPP has the potential to improve glucose and lipid metabolism. Subsequently, in a high-fat/high-fructose obese rat experiment, a 7-week intervention with LPP was conducted. Without altering energy intake, the high-dose LPP (LPPH) significantly reduced body weight and fat mass ( p < 0.05), improved insulin sensitivity (reduced HOMA-IR and fasting blood glucose, p < 0.01) and normalised lipid profiles, thereby enhancing glucose homeostasis. This intervention reversed gut microbial dysbiosis by enriching beneficial bacteria ( Akkermansia and Lactobacillus ) and suppressing pathogens ( Klebsiella pneumoniae and Ruminococcus ), while also increasing short-chain fatty acids (butyrate/acetate) associated with improved metabolism. Transcriptome analysis revealed that LPPH remodelled adipose tissue through the PPAR signalling pathway (downregulating Pparg and upregulating Cpt1a ) and activated the hepatic PI3K-Akt signalling pathway to enhance insulin sensitivity. These results suggest that LPPH alleviates metabolic disorders by synergistically regulating the gut microbiota-fat-liver axis (independent of appetite suppression), making it a promising probiotic therapy for the treatment of obesity-related metabolic disorders. Graphical Lactobacillus plantarum LPPerfectus001 (LPPH) reduced weight and fat, improved insulin sensitivity and normalised lipids in high-fat/fructose-fed rats without altering energy intake. It restored gut microbiota (↑Akkermansia, ↓pathogens), elevated SCFAs and modulated adipose, liver and muscle metabolism via PPAR, PI3K-Akt and AMPK pathways, demonstrating therapeutic potential for metabolic disorders.