Novel role of xanthine oxidase-dependent HO production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain.

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 HO. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing HO 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.