Piper longum ameliorates obesity by regulating gut microbiota and promoting adipose thermogenesis

Obesity, a global health issue, involves abnormal fat accumulation and metabolic dysfunction. Piper longum L., a medicinal-edible herb, exhibits anti-obesity potential with unclear mechanisms.

This study investigates how the ethanol extract of P. longum (EEPL) exerts anti-obesity effects by regulating adipose thermogenesis and gut microbiota.

Multi-omics analyses identified the role of the transient receptor potential vanilloid subfamily 1 (TRPV1) / calcium/calmodulin dependent protein kinase Ⅱβ (CaMK2β) / AMP-activated protein kinase (AMPK) pathway in brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. Using 3T3-L1 adipocytes and obese mouse models, we explored EEPL's thermogenesis mechanism via this pathway. Moreover, we performed 16S rRNA sequencing to evaluate its effects on gut microbiota, and Mendelian randomization (MR) analysis was conducted to assess the causal relationship between gut microbiota and obesity.

Bioinformatics analyses revealed AMPK pathway as a key driver of BAT activation and WAT browning. In vitro and in vivo experiments showed EEPL activates the TRPV1/CaMK2β/AMPK pathway to promote WAT browning and BAT activation, thereby improving obesity in mice. EEPL restored obese mice's gut microbiota homeostasis (reversed Bacteroidota reduction/Firmicutes increase), elevated fecal acetate/propionate, and reduced food intake via promoting GLP-1 secretion. MR analysis confirmed microbiota-obesity causality, suggesting Bacteroidota's Gillisia may regulate fatty acid oxidation/energy expenditure via pyruvate-propionate balance, consistent with EEPL's effects on Bacteroidota and short-chain fatty acids (SCFAs).

EEPL exerts dual anti-obesity effects by enhancing adipose thermogenesis and regulating gut microbiota homeostasis. This study provides evidence for obesity treatment and EEPL-based anti-obesity preparation development and application.