# Chemical interrogation of metabolic tissue crosstalk

> **NIH NIH DP1** · STANFORD UNIVERSITY · 2022 · $793,310

## Abstract

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.

## Key facts

- **NIH application ID:** 10490441
- **Project number:** 5DP1DK130641-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jonathan Z Long
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $793,310
- **Award type:** 5
- **Project period:** 2021-09-17 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490441

## Citation

> US National Institutes of Health, RePORTER application 10490441, Chemical interrogation of metabolic tissue crosstalk (5DP1DK130641-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10490441. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*