Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling

Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we develop a method enabling temporally controlled, cell-type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. The expression of TurboID in hepatocytes, adipocytes, and B lymphocytes enabled the characterization of cell type-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue- and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy balance and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.