12/15-lipoxygenase (12/15-LOX) plays an essential role in oxidative conversion of polyunsaturated fatty acids into various bioactive lipid molecules. Although 12/15-LOX's role in the pathophysiology of various human diseases has been well studied, its role in weight gain is controversial and poorly clarified. Here, we demonstrated the role of 12/15-LOX in high-fat diet (HFD)-induced weight gain in a mouse model. We found that 12/15-LOX mediates HFD-induced de novo lipogenesis (DNL), triglyceride (TG) biosynthesis and the transport of TGs from the liver to adipose tissue leading to white adipose tissue (WAT) expansion and weight gain via xanthine oxidase (XO)-dependent production of H₂O₂. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing H₂O₂ production, DNL and TG biosynthesis resulting in reduced WAT expansion and weight gain. These findings infer that manipulation of 12/15-LOX metabolism may manifest a potential therapeutic target for weight gain and obesity.

12/15-脂氧合酶 (12/15-LOX) 在多不饱和脂肪酸氧化转化为各种生物活性脂质分子中起重要作用。尽管 12/15-LOX 在各种人类疾病的病理生理学中的作用已得到充分研究，但其在体重增加中的作用仍存在争议且不清楚。在这里，我们展示了 12/15-LOX 在小鼠模型中高脂肪饮食 (HFD) 诱导的体重增加中的作用。我们发现 12/15-LOX 介导 HFD 诱导的从头脂肪生成 (DNL)、甘油三酯 (TG) 生物合成以及 TG 从肝脏向脂肪组织的转运，导致白色脂肪组织 (WAT) 膨胀和通过黄嘌呤氧化酶增加体重(XO) 依赖的 H ₂ O ₂生产. 12/15-LOX 缺乏导致 cullin2 介导的 XO 泛素化和降解，从而抑制 H ₂ O ₂产生、DNL 和 TG 生物合成，从而导致 WAT 膨胀和体重增加减少。这些发现推断，对 12/15-LOX 代谢的操纵可能是体重增加和肥胖症的潜在治疗靶点。