Phytochemical wedelolactone reverses obesity by prompting adipose browning through SIRT1/AMPK/ PPARα pathway via targeting nicotinamide N-methyltransferase

Background: Obesity is the cause of multiple metabolic disorders, and its incidence has been rapidly increasing worldwide. It develops when energy intake exceeds energy expenditure (EE). Wedelolactone (WDL) is a naturally isolated compound from Eclipta prostrata L. and possesses many pharmacological activities. However, little is known about the effect of WDL on obesity and EE. Purpose: The present study aimed to investigate the effect of WDL on obesity and EE in diet-induced obese (DIO) mice and its underlying mechanism. Methods: Obese mice were induced by high fat diet. The effects of WDL on obese mice were assessed by examining body weight, fat mass, EE, glucose tolerance, and hepatic and kidney injury. 3T3-L1 cells were differentiated into mature adipocytes and incubated with WDL in vitro. Immunohistochemistry, western blotting, and real-time PCR were used to assess adipose browning. The inhibitory efficiency of WDL on nicotinamide Nmethyltransferase (NNMT) was evaluated using a fluorescence assay. Results: WDL reduced fat mass, suppressed body weight gain, and improved obesity-related metabolic disorders in DIO mice. WDL treatment promoted adipose browning and enhanced EE in both DIO mice and 3T3-L1 cells. These effects were eliminated in AMPK antagonized or PPAR alpha knockdown cells and in PPAR alpha(-/-) mice. Furthermore, we identified the target of WDL to be NNMT, an appealing target for regulating energy metabolism. WDL inhibited NNMT with an extremely low IC50 of 0.03 mu M. Inhibition of NNMT and activation of SIRT1/ AMPK/PPAR alpha explains how WDL reverses obesity by prompting adipose browning. Conclusion: Our findings demonstrate the novel effects of WDL in promoting adipose browning, enhancing EE and attenuating obesity and uncover the underlying mechanism, which includes inhibition of NNMT and subsequently activation of SIRT1/AMPK/PPAR alpha in response to WDL. WDL could be further developed as a therapeutic agent for treating obesity and related metabolic diseases.