# Defining mechanisms of extracellular succinate regulation over metabolic tissue function

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $650,788

## Abstract

PROJECT SUMMARY
Succinate, a mitochondrial metabolite, has recently emerged as a major regulator of metabolic physiology and
inflammation. Much of this succinate-dependent signaling occurs through its release from cells and subsequent
activation of its cognate GPCR, SUCNR1. We discovered that diminished brown adipocyte activity, and the
obesogenic Western Diet, lowers succinate uptake capacity by brown fat and leads to chronic accumulation of
extracellular succinate in the liver, leading to SUCNR1-mediated tissue fibrosis and inflammation. We also
defined a succinate transport mechanism in muscle and adipose cells via plasma membrane monocarboxylate
transporter 1 (MCT1).
The major discovery of our previous grant period is that secretion of succinate from metabolic tissues can play
both protective and pathogenic roles in metabolic health, both via SUCNR1. What is unclear is which
characteristics determine whether succinate will act in pro- or anti-pathogenic manner? Therefore, in the next
stage of our project, we ask what mechanisms determine protective versus pathogenic regulation by
extracellular succinate? We hypothesize that succinate activates divergent molecular mechanisms within
specific cell types depending on length of exposure (acute vs. chronic), leading to distinct physiological
consequences. To test this hypothesis and answer the proposed question, we aim to (1) Determine the cell-
type specific consequences of acute versus chronic succinate-mediated SUCNR1 activation in the liver. (2)
Determine the intracellular, downstream mechanism of SUCNR1 activation; and (3) Investigate the MCT1-
mediated mechanism of succinate transport in the liver.
Proposed aims will address the critical gap in our understanding of the differential mechanisms that are
activated by chronic and acute exposure to succinate, a major metabolic regulator of metabolic health and
disease. Building on the critical discoveries in our initial grant period, the current proposal will define the
consequences of succinate exposure in the liver, but it is likely that similar pathways will be activated in other
tissues of interest in metabolic disorders. Therefore, our work will address how obesity and associated
pathologies develop and may lead to identification of candidates for further pharmacological development.

## Key facts

- **NIH application ID:** 10801130
- **Project number:** 2R01DK123095-06
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Edward Thomas Chouchani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,788
- **Award type:** 2
- **Project period:** 2019-09-13 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801130

## Citation

> US National Institutes of Health, RePORTER application 10801130, Defining mechanisms of extracellular succinate regulation over metabolic tissue function (2R01DK123095-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10801130. Licensed CC0.

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