Abstract 1521 Peroxisomal Lipid Metabolism and the Regulation of Metabolic Homeostasis

Peroxisomes house several pathways involved in lipid and reactive oxygen species (ROS) metabolism. Emerging studies suggest that peroxisomes are important regulators of energy homeostasis and that disruption of peroxisomal functions influences the risk for obesity and the associated metabolic disorders, including type 2 diabetes and hepatic steatosis. Our studies implicate peroxisome-derived lipids called plasmalogens in the regulation of brown adipocyte mitochondrial dynamics and thermogenesis. Adipose-specific knockout of the critical peroxisomal biogenesis factor Pex16 in mice impairs thermogenesis and decreases energy expenditure due to inhibition of cold-induced mitochondrial fission resulting from decreased mitochondrial membrane content of plasmalogens. Recently, we identified transmembrane 135 (TMEM135) as a critical mediator of the peroxisomal regulation of mitochondrial fission in brown adipocytes. Acute β-adrenergic receptor activation promotes association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Using loss-of-function and gain-of-function mouse models, we demonstrate that TMEM135 is an important regulator whole-body energy metabolism through its role in brown adipocyte mitochondrial fission. This work reveals a novel inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT. Our work is supported by the NIH grant R01DK132239.