Treatment with celastrol protects against obesity through suppression of galanin-induced fat intake and activation of PGC-1a/GLUT4 axis-mediated glucose consumption
Treatment with celastrol protects against obesity through suppression of galanin-induced fat intake and activation of PGC-1a/GLUT4 axis-mediated glucose consumption
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DOI：
10.1016/j.bbadis.2019.02.002
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Bo, Ping
中科院分区：
文献类型：
--
作者：
Fang, Penghua;He, Biao;Bo, Ping
超重和肥胖可能会导致多种代谢并发症，包括2型糖尿病和高脂血症。尽管医学多年来取得了进步，但目前还没有针对肥胖症的高效药物治疗方法。天然化合物雷公藤红素是从雷公藤植物根部提取的五环三萜，具有多种生物活性，包括抗糖尿病和抗肥胖作用。尽管雷公藤红素可以减少食物摄入和肥胖，但雷公藤红醇的详细机制目前仍不清楚。在此，我们打算确定雷公藤红素对肥胖的影响及其潜在机制。在本研究中，饮食诱导的肥胖小鼠在最后 21 天用 100 pg/kg/d 雷公藤红素处理，3T3-L1 细胞用雷公藤红素处理 6 小时。目前的研究结果表明，雷公藤红醇可抑制脂肪摄入，并通过抑制高脂饮食小鼠下丘脑中的甘丙肽及其受体表达来导致体重减轻。更重要的是，除了这些直接的抗肥胖活性之外，雷公藤红醇还增强脂肪细胞和骨骼肌中 PGC-1a 和 GLUT4 的表达，从而通过 AKT 和 P38 MAPK 激活增加葡萄糖摄取。雷公藤红素还通过 CREB/PGC-1a 途径抑制糖异生活性。总之，雷公藤红素的减肥作用是由甘丙肽引起的食物消耗减少所驱动的。因此，本研究有助于我们了解雷公藤红素的抗肥胖作用，并为临床上利用雷公藤红素治疗肥胖提供了可能。
Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus and hyperlipidemia. Despite years of progress in medicine, there are no highly effective pharmacological treatments for obesity. The natural compound celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, exerts various bioactivities including anti-diabetic and anti-obese effects. Although celastrol could decrease food intake and obesity, the detailed mechanism for celastrol is still unclear as yet. Herein, we intended to determine the effect of celastrol on obesity and the underlying mechanisms. In the present study, diet-induced obese mice were treated with 100 pg/kg/d celastrol for the last 21 days, and 3T3-L1 cells were treated with celastrol for 6 h. The present findings showed that celastrol suppresses fat intake, and leads to weight loss by inhibiting galanin and its receptor expression in the hypothalamus of mice fed a high-fat diet. More importantly, in addition to these direct anti-obesity activities, celastrol augmented the PGC-la and GLUT4 expression in adipocytes and skeletal muscles to increase glucose uptake through AKT and P38 MAPK activation. Celastrol also inhibited gluconeogenic activity through a CREB/PGC-la pathway. In conclusion, the weight-lowering effects of celastrol are driven by decreased galanin-induced food consumption. Thus, this study contributes to our understanding of the anti-obese role of celastrol, and provides a possibility of using celastrol to treat obesity in clinic.