Insulin receptor signaling regulates blood glucose homeostasis. Obesity, among other conditions, decreases insulin receptor signaling, resulting in increased blood glucose, increased insulin levels, and a host of adverse health effects. Our goal is to understand, at a systems-level, the mechanisms underlying high-fat diet or inflammation induced insulin resistance, as this knowledge should enable the identification of improved therapeutic options to regulate insulin senstivity. To this end, we are using mass spectrometry based proteomics to quantify signaling networks in multiple biological systems ranging from in vitro cell culture to mouse models and eventually human tissues. This data will be coupled to phenotypic outcome (e.g. glucose uptake, quantification of insulin-responsive transcripts) and to other systems-level datasets to develop computational models reflecting the complexity of the response to high-fat diet or other insulin resistance mediating conditions.