Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling

• Published in: Nature communications Vol. 15; no. 1; pp. 4214 - 16
• Main Authors: Lu, Dongliang, He, Anyuan, Tan, Min, Mrad, Marguerite, El Daibani, Amal, Hu, Donghua, Liu, Xuejing, Kleiboeker, Brian, Che, Tao, Hsu, Fong-Fu, Bambouskova, Monika, Semenkovich, Clay F., Lodhi, Irfan J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 14; 14/19; 38/91; 631/443/319/1642/393; 631/443/319/2723; 631/80/86/2365; 64/60; 692/4017; 96; 96/95; Acyl-CoA Oxidase - genetics; Acyl-CoA Oxidase - metabolism; Adipocytes; Adipose tissue; Adipose Tissue - metabolism; Animals; Biogenesis; Body fat; Browning; Coenzyme A; Coenzymes; Diet, High-Fat; Energy Metabolism; Enzymes; Fatty acids; Fatty Acids - metabolism; Gene expression; Homeostasis; Humanities and Social Sciences; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Male; Metabolic disorders; Metabolic rate; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Obesity; Obesity - genetics; Obesity - metabolism; Oxidation; Oxidation-Reduction; Physiology; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Substrates; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48471-2

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. The peroxisomal β-oxidation enzyme ACOX1 increases in liver with obesity, but the physiological significance is unclear. Here, the authors show that liver-specific knockout of Acox1 leads to accumulation of omega-3 VLCFAs that promote metabolic health through activation of GPR120 in adipose tissue.