PYY-mediated appetite control and obesity alleviation through short-chain fatty acid–driven gut-brain axis modulation by Lacticaseibacillus rhamnosus HF01 isolated from Qula

Obesity driven by high-fat diets is associated with metabolic dysregulation and gut microbiota disruption. Traditional fermented dairy products, such as Qula from Qinghai Province, China, are valuable sources for isolating novel probiotics with potential therapeutic applications against obesity. This study explored the appetite-regulating mechanisms and gut microbiota modulation by Lacticaseibacillus rhamnosus HF01, a strain isolated from traditional Qula, in mice with high-fat diet-induced obesity. The L. rhamnosus HF01 improved lipid profiles, reduced BW and lipid accumulation, and modulated the hypothalamic expression of appetite-related genes (NPY, POMC), with a particular focus on PYY in appetite regulation. The L. rhamnosus HF01 stimulated PYY secretion through activation of intestinal L cells, which then activated the NPY-Y2 receptor, modulating NPY and POMC expression to regulate appetite. Additionally, L. rhamnosus HF01 reshaped the gut microbiota by increasing the abundance of key short-chain fatty acid (SCFA)-producing genera (Akkermansia, unclassified_f__Muribaculaceae, unclassified_f__Lachnospiraceae, Allobaculum, Candidatus_Saccharimonas). Elevated levels of SCFA, including butyric, isobutyric, and isovaleric acids, correlate with specific microbial taxa and activate GPR41/43 receptors, further promoting PYY secretion. These findings suggest that L. rhamnosus HF01 exerts its antiobesity effects through gut microbiota modulation, SCFA production, and GPR receptor activation, leading to PYY secretion, appetite suppression, and improved metabolic health via the gut-brain axis. The L .rhamnosus HF01 provides a promising therapeutic approach for obesity by targeting the gut-brain axis, regulating appetite through microbiota-driven SCFA production.