Trans-omic analysis reveals fed and fasting insulin signal across phosphoproteome, transcriptome, and metabolome

SUMMARY The concentration and temporal pattern of insulin selectively regulate multiple cellular functions. To understand how insulin dynamics are interpreted by cells, we constructed a trans-omic network of insulin action in FAO hepatoma cells from three networks—a phosphorylation-dependent cellular functions regulatory network using phosphoproteomic data, a transcriptional regulatory network using phosphoproteomic and transcriptomic data, and a metabolism regulatory network using phosphoproteomic and metabolomic data. With the trans-omic regulatory network, we identified selective regulatory networks that mediate differential responses to insulin. Akt and Erk, hub molecules of insulin signaling, encode information of a wide dynamic range of dose and time of insulin. Down-regulated genes and metabolites in glycolysis had high sensitivity to insulin (fasting insulin signal); up-regulated genes and dicarboxylic acids in the TCA cycle had low sensitivity (fed insulin signal). This integrated analysis enables molecular insight into how cells interpret physiologically fed and fasting insulin signals. Highlights We constructed a trans-omic network of insulin action using multi-omic data. The trans-omic network integrates phosphorylation, transcription, and metabolism. We classified signaling, transcriptome, and metabolome by sensitivity to insulin. We identified fed and fasting insulin signal flow across the trans-omic network.