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. 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.