Licoisoflavone A improves adipose tissue dysfunction in response to diet induced obesity by promoting METTL3 expression

As developing obese adipose tissue, adipocytes suffer pathological changes from inert energy storage to excessive and active endocrine organ in association with disease hazard. METTL3, as an RNA methyltransferase of key importance in adipose tissue development, functional preservation and metabolic homeostasis, is remarkably complex. Licoisoflavone A (LIC-A) is a prenylated flavonoid compound of licorice that has been suggested to display antiinflammatory, -hypertrophic, and -proliferative activities; it remains unknown whether it can directly modulate expression of METTL3 and impact functions of adipose tissue in obesity. Here in our study, 16 candidates in the top ranking molecules were screened out in the process of the molecular docking between our TCM formula Fangjihuangqin Decoction and protein METTL3 (PDB: 5TEY). Among them, LIC-A was considered as a potential upstream regulatory molecule of METTL3 and obviously promote the expression of METTL3. The effects of TNF- and LPS treatments on the inhibition of adipogenesis were successfully recovered by LIC-A treatment in the adipogenic 3T3-L1 cells, via the regulation of adipogenic cytokines, as well as the expression of inflammatory factors. These protective effects were similarly abolished with METTL3 knockdown, suggesting the role of LIC-A relies on METTL3. Moreover, in vivo data demonstrated that administration of LIC-A could significantly recover the body weight lipid metabolism, insulin resistance and gluconeogenesis in mice with reduced adipose depostion as well as abated systemic inflammation. In conclusion, our study suggested that LIC-A could be the key component in preserving the homeostasis of adipose tissues through regulating METTL3 expression, indicating LIC-As promising treatment potential for obesity-related metabolic diseases.