ZishenWan reduces obesity in db/db mice by inhibiting p21 expression in adipose tissues.

BACKGROUND: Obesity is a major risk factor for metabolic disorders, including type 2 diabetes, metabolic syndrome, and cardiovascular diseases. Recent studies suggest that adipocyte cell cycle regulation is linked to metabolic dysfunction, making cell cycle regulatory factors potential therapeutic targets. ZishenWan (ZSW), a traditional Chinese medicinal formula composed of three herbs, has shown therapeutic potential against diabetes and obesity. This study aimed to investigate the mechanisms underlying the weight-regulatory effects of ZSW. METHODS: ZSW was orally administered to db/db mice for 5 weeks, with metformin used as a positive control. Body weight and fasting blood glucose levels were monitored weekly, and an oral glucose tolerance test was conducted at the end of the intervention. Insulin levels and serum lipid profiles were also assessed. Histological analysis was performed on adipose tissue, and epididymal adipose tissue (EAT) samples were collected for transcriptomic analysis. The findings from transcriptomic analysis were further validated using qPCR, immunohistochemistry, and western blotting. RESULTS: ZSW significantly reduced body weight, inhibited adipocyte hypertrophy, and improved insulin sensitivity and insulin secretion in db/db mice without affecting liver or kidney function. Transcriptomic analysis revealed that ZSW altered the expression of genes involved in lipid metabolism and inhibited p21 expression. Additionally, ZSW activated the PI3K/AKT/FoxO1 signaling pathway, resulting in reduced p21 expression, increased apoptosis, and enhanced UCP1 expression in EAT. CONCLUSIONS: ZSW may improve obesity-related metabolic disorders by activating the PI3K/AKT pathway and downregulating p21 expression in EAT. These effects promote adipocyte apoptosis, enhance thermogenesis, inhibit adipocyte hypertrophy, and improve insulin sensitivity.