Yao Enhui, Yang Xiazhen, Huang Xuefeng, Mi Yuchen, Wu Xiaoqian, Fang Meijuan, Huang Jinhua, Qiu Yan, Hong Xiaoting, Peng Lu, Ren Jie, Huang Rui, Chen Caixia, Yang Lichao, Zhou Yu, Zhuo Rengong, Jin Xin, Zhao Yun
School of Medicine, Xiamen University, Xiamen 361005, China;; Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 350000, China.
School of Medicine, Xiamen University, Xiamen 361005, China;; Zhongshan Hospital, Xiamen University, Xiamen 361005, China.
Phytomedicine. 2022 Jan;94:153843. doi: 10.1016/j.phymed.2021.153843. Epub 2021 Nov 1.
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.
The present study aimed to investigate the effect of WDL on obesity and EE in diet-induced obese (DIO) mice and its underlying mechanism.
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.
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.
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.
肥胖是多种代谢紊乱的病因，其发病率在全球范围内迅速上升。当能量摄入超过能量消耗（EE）时，肥胖就会发生。去甲蟛蜞菊内酯（WDL）是从鳢肠中天然分离出的一种化合物，具有多种药理活性。然而，关于WDL对肥胖和能量消耗的影响知之甚少。
本研究旨在探讨WDL对饮食诱导肥胖（DIO）小鼠肥胖和能量消耗的影响及其潜在机制。
通过高脂饮食诱导肥胖小鼠。通过检测体重、脂肪量、能量消耗、葡萄糖耐量以及肝和肾损伤来评估WDL对肥胖小鼠的影响。将3T3-L1细胞分化为成熟脂肪细胞，并在体外与WDL孵育。采用免疫组织化学、蛋白质印迹法和实时定量PCR评估脂肪褐变。使用荧光测定法评估WDL对烟酰胺N-甲基转移酶（NNMT）的抑制效率。
WDL减少了DIO小鼠的脂肪量，抑制了体重增加，并改善了与肥胖相关的代谢紊乱。WDL处理促进了DIO小鼠和3T3-L1细胞中的脂肪褐变并增强了能量消耗。在AMPK拮抗剂或PPARα基因敲低的细胞以及PPARα基因敲除小鼠中，这些作用消失。此外，我们确定WDL的靶点是NNMT，这是调节能量代谢的一个有吸引力的靶点。WDL以极低的IC50（0.03 μM）抑制NNMT。抑制NNMT和激活SIRT1/AMPK/PPARα解释了WDL如何通过促进脂肪褐变来逆转肥胖。
我们的研究结果证明了WDL在促进脂肪褐变、增强能量消耗和减轻肥胖方面的新作用，并揭示了其潜在机制，包括抑制NNMT以及随后响应WDL激活SIRT1/AMPK/PPARα。WDL可进一步开发为治疗肥胖及相关代谢疾病的药物。
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