Chemical interrogation of metabolic tissue crosstalk

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PROJECT SUMMARY. Peripheral metabolic tissues engage in pervasive inter-organ crosstalk to maintain systemic glucose and lipid homeostasis. This long-range intercellular communication is mediated by blood borne, secreted polypeptides. Over the last decade, there has been renewed interest in identifying additional proteins secreted from metabolic tissues. This is because the collection of secreted proteins (e.g., secretome) from metabolic cell types is large and also poorly characterized, and therefore many additional polypeptides that mediate peripheral tissue crosstalk likely remain to be discovered. It is not unreasonable to imagine that many of these orphan factors represent new signaling pathways and consequently potentially new therapeutic targets for obesity, diabetes, and related metabolic disorders. Typically, approaches to this problem have relied on surrogate methods that attempt to predict, rather than directly measure, in vivo polypeptide secretion events. In recent work, we have introduced an in vivo chemical methodology that enables a radically different strategy: to measure metabolic tissue secretomes directly in living animals (Wei et al., Nat. Chem. Biol. 2020). Importantly, this chemical strategy provides unique insights into the composition and dynamics of secretomes in mice that could not have been predicted by existing in vitro or computational approaches. This proposal seeks to further develop these chemical methodologies with the goal of generating a complete endocrine map of the secreted polypeptides that mediate peripheral metabolic tissue crosstalk. To achieve this goal, we will (1) produce a 6 organ, 15-cell type atlas of peripheral metabolic tissue polypeptide secretomes and determine how these secretomes are dynamically altered by metabolic perturbations such as obesity, diet, environmental temperature, and physical activity; (2) develop new in vivo chemistries that enable high-resolution mapping of secreted polypeptide fragments produced via proteolytic cleavage events; and (3) integrate metabolic tissue secretomes into endocrine circuits through in vivo chemical pulse-chase approaches. Successful completion of this high-risk, high-reward project will provide a chemical toolbox for dissecting cellular secretomes, open potentially important new areas in tissue crosstalk, and ultimately enable the long-term vision of “capturing” the pathways of tissue crosstalk to combat obesity, type 2 diabetes, and related metabolic disorders.