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

Enhui Yao; Xiazhen Yang; Xuefeng Huang; Yuchen Mi; Xiaoqian Wu; Meijuan Fang; Jinhua Huang; Yan Qiu; Xiaoting Hong; Lu Peng; Jie Ren; Rui Huang; Caixia Chen; Lichao Yang; Yu Zhou; Rengong Zhuo; Xin Jin; Yun Zhao

doi:10.1016/j.phymed.2021.153843

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

Phytomedicine. 2022 Jan:94:153843. doi: 10.1016/j.phymed.2021.153843. Epub 2021 Nov 1.

Authors

Enhui Yao¹, Xiazhen Yang¹, Xuefeng Huang², Yuchen Mi³, Xiaoqian Wu³, Meijuan Fang³, Jinhua Huang¹, Yan Qiu³, Xiaoting Hong³, Lu Peng³, Jie Ren³, Rui Huang³, Caixia Chen³, Lichao Yang³, Yu Zhou³, Rengong Zhuo³, Xin Jin³, Yun Zhao⁴

Affiliations

¹ School of Medicine, Xiamen University, Xiamen 361005, China;; Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 350000, China.
² School of Medicine, Xiamen University, Xiamen 361005, China;; Zhongshan Hospital, Xiamen University, Xiamen 361005, China.
³ School of Medicine, Xiamen University, Xiamen 361005, China.
⁴ School of Medicine, Xiamen University, Xiamen 361005, China;. Electronic address: zy2008@xmu.edu.cn.

PMID: 34785414
DOI: 10.1016/j.phymed.2021.153843

Abstract

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 N-methyltransferase (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 PPARα knockdown cells and in PPARα^-/- 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 µM. Inhibition of NNMT and activation of SIRT1/AMPK/PPARα 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/PPARα in response to WDL. WDL could be further developed as a therapeutic agent for treating obesity and related metabolic diseases.

Keywords: AMP-activated protein kinase; adipose browning; nicotinamide N-methyltransferase; obesity; wedelolactone.

MeSH terms

3T3-L1 Cells
AMP-Activated Protein Kinases
Animals
Coumarins
Diet, High-Fat
Mice
Mice, Inbred C57BL
Nicotinamide N-Methyltransferase*
Obesity / drug therapy
PPAR alpha
Phytochemicals
Sirtuin 1*

Substances

Coumarins
PPAR alpha
Phytochemicals
wedelolactone
Nicotinamide N-Methyltransferase
AMP-Activated Protein Kinases
Sirt1 protein, mouse
Sirtuin 1