# Thermogenic chromatin remodeling control and fat tissue communication

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $503,865

## Abstract

Summary
Obesity is a current major health problem associated with life threatening complications such as cardiovascular
disease, type 2 diabetes and cancer. Obesity is managed with dietary regimens that selectively reduce energy
intake and/or exercise programs focused on energy expenditure. These treatments have high failure and
relapse rates urging new strategies focused on drug-targeted therapies. Recent findings in humans showing
that activation of brown and beige thermogenic function can increase energy expenditure open a new route to
target the molecular components in these tissues that control body temperature and weight. However, the
regulatory mechanisms of the components that control thermogenic gene expression and whole body energy
balance are not completely understood. The transcription factor YY1 controls the thermogenic function in
brown and beige fat through transcriptional and epigenetic changes in genes encoding for this metabolic and
energetic program. Our previous studies found that mice deficient in the transcription factor YY1 in adipose
tissue are strongly protected against diet-induced obesity. Mechanistically, this protection is caused by the fact
that YY1 can repress brown fat secreted proteins that activate beige fat thermogenic activity. In this grant
renewal, we propose studies that will focus on two main processes in thermogenic adipocytes. (1) Define the
specific YY1 activation function through the INO80 complex that controls mitochondrial bioenergetic gene
expression, and (2) define the YY1 repression function that controls brown fat secreted proteins that activate
beige adipose thermogenic function. Because both regulatory processes are directly linked to energy
expenditure they have strong significance towards potential treatments for metabolic diseases. The major goal
of this application is to identify the transcriptional and epigenetic mechanisms, focusing on the YY1/INO80
chromatin remodeling complex and secreted proteins, underlying the brown and beige adipose thermogenic
function which promotes energy expenditure and protects against obesity. Three different aims are proposed,
1) Transcriptional and epigenetic regulatory analysis of how the YY1/INO80 chromatin remodeling complex
controls mitochondrial/thermogenic and secreted proteins gene expression programs in brown adipose tissue
(Specific Aim 1), 2) Metabolic and bioenergetic analysis mediated by the YY1/INO80-dependent thermogenic
and secreted gene expression programs in brown and beige adipose cells (Specific Aim 2) and, 3) Energy and
metabolic analysis in response to cold- and diet-induced thermogenesis mediated through the YY1/INO80
transcriptional complex and GDF15 secreted protein (Specific Aim 3). The outcomes from this application will
identify the transcriptional and epigenetic mechanisms that control adjustable thermogenesis in response to
cold and overnutrition driven through the YY1/INO80 chromatin remodeling complex. Since obesity is linked to...

## Key facts

- **NIH application ID:** 10133056
- **Project number:** 5R01DK081418-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pere Puigserver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $503,865
- **Award type:** 5
- **Project period:** 2008-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133056

## Citation

> US National Institutes of Health, RePORTER application 10133056, Thermogenic chromatin remodeling control and fat tissue communication (5R01DK081418-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10133056. Licensed CC0.

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