# Defining mechanisms of succinate regulation over adipose tissue thermogenesis

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $95,587

## Abstract

Defining mechanisms of succinate regulation over adipose tissue thermogenesis
PROJECT SUMMARY:
Obesity is a major risk factor for type-2 diabetes, cardiovascular disease, and many cancers. Thermogenic brown
and beige adipose tissues can catabolize stored fat and are potently anti-obesogenic. The anti-obesity activity
of thermogenic adipocytes requires activation by peripheral signals, and the identification of these activating
mechanisms is key to leveraging the therapeutic activity of these cells.
We recently discovered that the mitochondrial metabolite succinate is a potent molecular activator of
thermogenic respiration in brown and beige adipocytes. Remarkably, these cells can utilize succinate to drive
thermogenesis by sequestering it from the circulation, which is a newfound unique activity of thermogenic
adipocytes. Our current objective is to investigate the molecular mechanisms that control this newfound pathway
of succinate-dependent thermogenesis, and to also determine its physiological consequences.
To build on our identification of the succinate thermogenesis pathway we propose specific hypotheses to test
that will determine the mechanisms through which brown and beige adipocytes acquire and utilize succinate to
control their anti-obesity activity. Based on extensive preliminary data, we hypothesize an essential role for the
plasma membrane transporter monocarboxylate transporter 1 (MCT1) in controlling succinate uptake specifically
in brown adipocytes. Our findings have led us to hypothesize that MCT1 is subject to unique regulation in
thermogenic adipocytes that re-purposes its activity to facilitate succinate uptake.
In Aim 1 using a combination of genetic, biochemical, and mass spectrometry approaches, we will establish the
quantitative contribution and mechanisms through which MCT1 is repurposed to drive succinate uptake in brown
and beige adipocytes, and the molecular consequences of inhibiting this pathway. In Aim 2, using a new mouse
model of MCT1 ablation in thermogenic fat (MCT1 TF-KO already in the lab) we will establish the in vivo
physiological consequences of selective inhibition of succinate uptake by thermogenic adipocytes. In Aim 3 we
will establish the mechanisms through which succinate controls thermogenic respiration in brown and beige
adipocytes. We will build on our discovery that the thermogenic activity of succinate requires its oxidation,
consequent generation of reactive oxygen species, and modification of cysteine residues on proteins. We will
apply new mass spectrometry approaches developed by our lab to map succinate-induced ROS modifications
of thermogenic proteins. In addition, we will use newly developed loss of function genetic models of the major
thermogenic effectors to establish their relative importance for succinate-induced energy expenditure.
Together, we will determine the mechanisms of adipose tissue succinate uptake and thermogenesis, and its
causal role in manipulating metabolic disease. We p...

## Key facts

- **NIH application ID:** 10440227
- **Project number:** 3R01DK123095-03S1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Edward Thomas Chouchani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $95,587
- **Award type:** 3
- **Project period:** 2019-09-13 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440227

## Citation

> US National Institutes of Health, RePORTER application 10440227, Defining mechanisms of succinate regulation over adipose tissue thermogenesis (3R01DK123095-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440227. Licensed CC0.

---

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