Leukotriene A4 hydrolase deficiency protects mice from diet-induced obesity by increasing energy expenditure through neuroendocrine axis

Abstract

Obesity is a health problem worldwide, and brown adipose tissue (BAT) is important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4H), a key enzyme in the synthesis of the lipid mediator leukotriene B4 (LTB4), in diet-induced obesity. LTA4H-deficient (LTA4H-KO) mice fed a high-fat diet (HFD) showed a lean phenotype, and bone-marrow transplantation studies revealed that LTA4H-deficiency in non-hematopoietic cells was responsible for this lean phenotype. LTA4H-KO mice exhibited greater energy expenditure, but similar food intake and fecal energy loss. LTA4H-KO BAT showed higher expression of thermogenesis-related genes. In addition, the plasma thyroid-stimulating hormone and thyroid hormone concentrations, as well as HFD-induced catecholamine secretion, were higher in LTA4H-KO mice. In contrast, LTB4 receptor (BLT1)-deficient mice did not show a lean phenotype, implying that the phenotype of LTA4H-KO mice is independent of the LTB4/BLT1 axis. These results indicate that LTA4H mediates the diet-induced obesity by reducing catecholamine and thyroid hormone secretion.