Western diet (WD), characterized by a high intake of fats and sugary drinks, is a risk factor for male reproductive impairment. However, the molecular mechanisms underlying this remain unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is highly expressed in extra-oral tissues, particularly in the testes. Here, we investigated to determine the effects of WD intake on male reproduction and whether TAS1R3 mediates WD-induced impairment in male reproduction. Male C57BL/6 J wild-type (WT) and Tas1r3 knockout (KO) mice were fed either a normal diet and plain water (ND) or a 60 % high-fat-diet and 30 % (w/v) sucrose water (WD) for 18 weeks (n = 7–9/group). Long-term WD consumption significantly impaired sperm count, motility and testicular morphology in WT mice with marked Tas1r3 overexpression, whereas Tas1r3 KO mice were protected from WD-induced reproductive impairment. Testicular transcriptome analysis revealed downregulated AMP-activated protein kinase (AMPK) signaling and significantly elevated AMPK-targeted nuclear receptor 4A1 (Nr4a1) expression in WD-fed Tas1r3 KO mice. In vitro studies further validated that Tas1r3 knockdown in Leydig cells prevented the suppression of Nr4a1 and downstream steroidogenic genes (Star, Cyp11a1, Cyp17a1, and Hsd3b1) caused by high glucose, fructose, and palmitic acid levels, and maintained the levels of testosterone. Additionally, we analyzed the public human dataset to assess the clinical implications of our findings and confirmed a significant association between TAS1R3 and male-infertility-related diseases. Our findings suggest that TAS1R3 regulates WD-induced male reproductive impairment via the AMPK/NR4A1 signaling and can be a novel therapeutic target for male infertility.

西方饮食（WD）的特点是摄入大量脂肪和含糖饮料，是男性生殖障碍的危险因素。然而，其背后的分子机制仍不清楚。味觉受体 1 型成员 3 (TAS1R3) 由 WD 配体激活，在口腔外组织中高度表达，特别是在睾丸中。在此，我们研究了 WD 摄入量对男性生殖的影响以及 TAS1R3 是否介导 WD 引起的男性生殖损伤。雄性 C57BL/6 J 野生型 (WT) 和Tas1r3敲除 (KO) 小鼠喂食正常饮食和白开水 (ND) 或 60% 高脂肪饮食和 30% (w/v) 蔗糖水 ( WD）持续 18 周（n = 7-9/组）。长期食用 WD 会显着损害Tas1r3明显过表达的 WT 小鼠的精子数量、活力和睾丸形态，而Tas1r3 KO 小鼠则免受 WD 诱导的生殖损伤。睾丸转录组分析显示，在 WD 喂养的Tas1r3 KO 小鼠中，AMP 激活蛋白激酶 (AMPK) 信号传导下调，AMPK 靶向核受体 4A1 ( Nr4a1 ) 表达显着升高。体外研究进一步证实， Leydig 细胞中Tas1r3 的敲除可以阻止高葡萄糖、果糖和棕榈酸水平引起的Nr4a1和下游类固醇生成基因（Star、Cyp11a1、Cyp17a1和Hsd3b1 ）的抑制，并维持睾酮水平。此外，我们分析了公共人类数据集，以评估我们研究结果的临床意义，并证实 TAS1R3 与男性不育相关疾病之间存在显着关联。我们的研究结果表明，TAS1R3 通过 AMPK/NR4A1 信号传导调节 WD 引起的男性生殖障碍，并且可以成为男性不育症的新治疗靶点。