Jatrorrhizine retard obesity by modulating transcription factor c-Jun/c-Fos to downregulate Mmp12-mediated inflammation

Abstract

Obesity is a systemic, chronic, low-grade inflammatory disease. Nutritional obesity, in particular, is also accompanied by inflammation and metabolic disorders, which are the primary causes of malignant metabolic diseases. Rhizoma Coptidis (Coptis Chinensis Franch) (RC), a traditional Chinese medicine, is primarily used for its anti-inflammatory and anti-diarrheal properties. Our previous studies have shown that RC can reduce body weight and lower fat levels, demonstrating its potential to improve nutritional obesity.However, the effects and mechanisms of the active small molecules in RC extracts in treating obesity-induced chronic inflammation need to be further investigated. In this study, we investigated the ameliorative effect and mechanism study of the monomeric jatrorrhizine (JAT) extracted from RC on high-fat diet-induced obese mice. First, JAT could dose-dependently reduce body weight and decrease the expression of inflammatory factors such as IL6, IL1β, and TNFα in the tissues of obese mice.Secondly, transcriptomics and bioinformatics studies of epididymal white adipose tissue (eWAT) identified Mmp12 as a key target through which JAT may alleviate obesity. Next, the effect of JAT on c-Jun/c-Fos promoter activity, which in turn down-regulates the transcript and protein levels of Mmp12, was analyzed and determined by qPCR, transcription factor prediction, single fluorescent promoter activity assay, Cell thermodynamic stability analysis (CETSA), molecular dynamics simulation mimicry, circular dichroism (CD) and Co-Immunoprecipitation (Co-IP). In conclusion, JAT may ameliorate high-fat diet-induced obesity and its associated inflammation through the c-Jun/c-Fos-Mmp12 axis.