Excess high-fat diet (HFD) intake predisposes the occurrence of obesity-associated heart injury, but the mechanism is elusive. Fisetin (FIS), as a natural flavonoid, has potential activities to alleviate obesity-induced metabolic syndrome. However, the underlying molecular mechanisms of FIS against HFD-induced cardiac injury remain unclear. The present study was to explore the protective effects of FIS on cardiac dysfunction in HFD-fed mice. We found that FIS alleviated HFD-triggered metabolic disorder by reducing body weight, fasting blood glucose and insulin levels, and insulin resistance. Moreover, FIS supplements significantly alleviated dyslipidemia in both mouse hearts and cardiomyocytes stimulated by metabolic stress. FIS treatment abolished HFD-induced inflammatory response in heart tissues through suppressing TNF receptor-1/TNF receptor-associated factor-2 (Tnfr-1/Traf-2) signaling. Furthermore, FIS induced a strong reduction in the expression of fibrosis-related genes, contributing to the inhibition of fibrosis by inactivating transforming growth factor (Tgf)-β1/Smads/Erk1/2 signaling. Collectively, these results demonstrated that FIS could be a promising therapeutic strategy for the treatment of obesity-associated cardiac injury.

过量摄入高脂饮食（HFD）容易导致肥胖相关性心脏病的发生，但该机制尚不清楚。非瑟酮（FIS）作为天然类黄酮，具有减轻肥胖引起的代谢综合征的潜在活性。然而，FIS对抗HFD引起的心脏损伤的潜在分子机制仍不清楚。本研究旨在探讨FIS对HFD喂养小鼠心脏功能障碍的保护作用。我们发现，FIS可以通过减轻体重，空腹血糖和胰岛素水平以及胰岛素抵抗来缓解HFD触发的代谢紊乱。此外，FIS补充剂可显着减轻代谢应激刺激的小鼠心脏和心肌细胞的血脂异常。FIS治疗通过抑制TNF受体-1 / TNF受体相关因子2（Tnfr-1 / Traf-2）信号传导，消除了HFD诱导的心脏组织炎症反应。此外，FIS诱导了纤维化相关基因的表达大大降低，从而通过失活转化生长因子（Tgf）-β1/ Smads / Erk1 / 2信号传导来抑制纤维化。总体而言，这些结果表明，FIS可能是治疗肥胖相关性心脏损伤的有前途的治疗策略。