Updated project metadata. Obesity leads to the development of non-alcoholic fatty liver disease (NAFLD) and associated alterations to the plasma proteome. To elucidate the underlying changes associated with obesity, we performed liquid chromatography-tandem mass spectrometry in the liver and plasma of obese leptin-deficient ob/ob mice. We quantified 7173 and 555 proteins in the liver and plasma, respectively. The abundance of proteins related to fatty acid metabolism were increased, alongside peroxisomal proliferation in ob/ob liver. Putatively secreted proteins and the secretory machinery were also dysregulated in the liver, which was mirrored by a substantial alteration of the plasma proteome. Greater than 50% of the plasma proteins were differentially regulated, including NAFLD biomarkers, lipoproteins, the 20S proteasome, and the complement and coagulation cascades of the immune system. Integration of the proteomes identified proteins that were concomitantly regulated in the liver and plasma in obesity, suggesting the systemic abundance of these plasma proteins are regulated by secretion from the liver. These analyses yield a comprehensive insight into obesity and provide an extensive resource for obesity research in a prevailing model organism.