Liver ACOX1 Regulates Levels of Circulating Lipids that Promote Metabolic Health through Adipose Remodeling

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 describe a liver-adipose signaling axis regulating metabolic health based on the control of circulating lipids by hepatic peroxisomal b-oxidation. Liver-specific knockout of <i>Acox1</i> (<i>Acox1</i>-LKO) counteracted diet-induced obesity by increasing energy expenditure and protected against obesity-associated adipose tissue inflammation and systemic insulin resistance in mice. Serum from <i>Acox1</i>-LKO mice promoted browning in cultured white adipocytes. Global serum lipidomics revealed increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that our results show promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in white adipocytes. This work identifies hepatic peroxisomal b-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.