Obesity is a risk factor for the development of secondary complications including dyslipidemia, non-alcoholic fatty liver disease, cardiovascular disease and type 2 diabetes. An accumulation of lipid in the liver, which is clinically known as hepatic steatosis, is a pathologic abnormality that is common in obese and type 2 diabetes patients. Hepatic steatosis occurs when fatty acid supply outweighs fatty acid demand and occurs in a time-course that usually precedes the induction insulin resistance and type 2 diabetes. We hypothesised that the protein and lipid secretome is altered with the development of hepatic steatosis and that this altered secretome contributes to the development of insulin resistance. In this presentation, we describe how ‘omics’ approaches are used to delineate the hepatocyte protein and lipid secretome in health and obesity. Further, we report on the pre-clinical validation of several liver secreted factors that cause insulin resistance and disturbances in systemic metabolic homeostasis.