Exploring the Multi-Tissue Crosstalk Relevant to Insulin Resistance Through Network-Based Analysis

Insulin resistance (IR) is a precursor event that occurs in multiple organs and underpins many metabolic disorders. However, due to the lack of effective means to systematically explore and interpret disease-related tissue crosstalk, the tissue communication mechanism in pathogenesis of IR has not been elucidated yet. To solve this issue, we profiled all proteins in white adipose tissue (WAT), liver, and skeletal muscle of a high fat diet induced IR mouse model via proteomics. A network-based approach was proposed to explore IR related tissue communications. The cross-tissue interface was constructed, in which the inter-tissue connections and also their up and downstream processes were particularly inspected. By functional quantification, liver was recognized as the only organ that can output abnormal carbohydrate metabolic signals, clearly highlighting its central role in regulation of glucose homeostasis. Especially, the CD36–PPAR axis in liver and WAT was identified and verified as a potential bridge that links cross-tissue signals with intracellular metabolism, thereby promoting the progression of IR through a PCK1-mediated lipotoxicity mechanism. The cross-tissue mechanism unraveled in this study not only provides novel insights into the pathogenesis of IR, but also is conducive to development of precision therapies against various IR associated diseases. With further improvement, our network-based cross-tissue analytic method would facilitate other disease-related tissue crosstalk study in the near future.