<i>Ganoderma lucidum</i> Polysaccharides Alleviate High-Fat Diet-Induced Obesity by Promoting Lipolysis and Inhibiting Inflammation through <i>Lactobacillus johnsonii</i> –Butyrate Axis

<i>Ganoderma lucidum</i> polysaccharides (GLPs) exert antiobesity effects that are linked to gut-microbiota modulation, yet the underlying mechanisms remain elusive. Here, we show that GLPs raise the fecal butyrate level, which in turn inhibits high-fat diet (HFD)-induced weight gain, fat accumulation, adipocyte hypertrophy, and elevated serum triglyceride by promoting adipose triglyceride lipase (ATGL) expression to activate lipolysis. GLPs and butyrate also strengthen the intestinal barrier, reflected by elevated tight junction proteins and goblet cells, leading to reduced serum lipopolysaccharide-binding protein (LBP) and attenuated white-adipose-tissue (WAT) inflammation. The intestinal barrier enhancement involves FABP4-PPARγ signaling. In addition, the butyrate-enhancement and antiobesity effects of GLPs are abolished after antibiotic-mediated microbiota depletion. Notably, GLPs selectively enrich the abundance of <i>Lactobacillus</i>, especially <i>Lactobacillus johnsonii</i>, whose supplementation alone increases fecal butyrate and recapitulates GLPs-induced benefits by reinforcing gut barrier integrity and lipolysis. Collectively, our findings identify the <i>L. johnsonii</i>-butyrate axis as a central target through which GLPs attenuate obesity and associated inflammation.