The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω−3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.

过氧化物酶体 β-氧化酶酰基辅酶 A 氧化酶 1 （ACOX1） 的肝脏基因表达，该酶可分解代谢甚长链脂肪酸 （VLCFA），在肥胖的情况下增加，但该途径如何影响全身能量代谢仍不清楚。在这里，我们表明肝脏 ACOX1 介导的β氧化调节参与代谢稳态的器官间通讯。Acox1 的肝脏特异性敲除 （Acox1-LKO） 可保护小鼠免受饮食诱导的肥胖、脂肪组织炎症和全身胰岛素抵抗的影响。来自 Acox1-LKO 小鼠的血清可促进培养的白色脂肪细胞的褐变。全球血清脂质组学显示几种 ω-3 VLCFA （C24-C28） 的循环水平增加，这些物质具有以前未表征的生理作用，通过激活脂肪细胞中的脂质传感器 GPR120 促进褐变、线粒体生物发生和 Glut4 易位。这项工作确定肝脏过氧化物酶体 β-氧化是代谢稳态的重要调节因子，并表明操作 ACOX1 或其底物可以治疗肥胖相关的代谢紊乱。