Si–Ni-SAN ameliorates obesity through AKT/AMPK/HSL pathway-mediated lipolysis: Network pharmacology and experimental validation

Si-Ni-San (SNS) is a famous Chinese herbal formula used in China for thousands of years. It has clinical effects on a variety of lipid metabolism disorders, but the ameliorating effects of SNS on obesity and underlying mechanisms remained poorly elucidated.This study aims to explore the therapeutic effect and mechanism of SNS on obesity from multiple perspectives in vitro and in vivo.The high-fat diet (HFD)-induced obesity mouse model was established to evaluate the effect of SNS. Then network pharmacologic methods were performed to predict underlying mechanisms, and the core pathways were verified in animal and cell studies.Our results demonstrated that SNS significantly reduced body weight, body fat content, white adipose tissue (WAT) expansion in obese mice, and lipid accumulation in primary mouse embryonic fibroblasts (MEFs) cells. Network pharmacologic analysis identified 66 potential therapeutic targets, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these genes revealed that the most important signaling pathway includes AMP-activated protein kinase (AMPK) signaling pathway, regulation of lipolysis in adipocytes, lipid and atherosclerosis. Western blot assay confirmed that SNS activated hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) activity and promoted lipolysis through AMPK signaling pathway.The results confirmed that SNS improves lipid accumulation through AKT/AMPK/HSL axis mediated lipolysis, which opens a new option for clinical treatment of obesity and associated complications.