Poria cocos polysaccharides alleviate obesity-related adipose tissue insulin resistance via gut microbiota-derived short-chain fatty acids activation of FGF21/PI3K/AKT signaling.

Obesity is a chronic condition that increases the risk of metabolic disorders, with intestinal dysbiosis and adipose tissue insulin resistance (Adipose-IR) playing key roles in its pathogenesis. Poria cocos polysaccharides (PCP), derived from traditional Chinese medicine, have shown potential in improving glucose metabolism and modulating gut microbiota. However, whether PCP can alleviate obesity-induced Adipose-IR and its dependence on gut microbiota remain unclear. This study investigated the effects of PCP on Adipose-IR in high-fat diet (HFD)-induced obese mice. PCP supplementation reduced body weight, adipose tissue mass, and improved glucose tolerance and lipid metabolism. Histological analysis showed alleviation of adipocyte hypertrophy and colonic barrier damage. PCP also modulated gut microbiota, enhancing the abundance of Lactobacillus, Allobaculum, and Phascolarctobacterium, and increased fecal short-chain fatty acids (SCFAs). These changes activated fibroblast growth factor 21 (FGF21), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter 4 (GLUT4) expression, improving insulin sensitivity. Antibiotic treatment and fecal microbiota transplantation (FMT) further confirmed that PCP's effects on glucose and lipid metabolism are gut microbiota-dependent. Our findings suggest that PCP may serve as a prebiotic agent to alleviate obesity-induced Adipose-IR and metabolic disorders, supporting its potential for functional food development.