# HDAC1 regulates thermogenic program via H3K27 deacetylation

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $377,935

## Abstract

Project Abstract
Obesity develops when a persistent imbalance between energy intake and energy expenditure occurs.
Adaptive thermogenesis, in which brown adipose tissue (BAT) functions to dissipate energy as heat due to the
unique expression of UCP1, is an integral part of overall energy expenditure. There are two types of brown
adipocytes in rodents. Traditional brown adipocytes are located in discrete areas, whereas inducible beige
adipocytes are dispersed in WAT and can be induced by cold exposure or β adrenergic activation. While
numerous studies have been devoted to the evaluation of genetic factors in regulation of brown/beige cell
function, much is unknown about epigenetic regulations including histone acetylation in this process. Evidence
converges to suggest that epigenetic events, including histone acetylation, figure prominently in the
development of obesity. Recent studies reported that class I HDAC inhibitor (HDACi) ameliorates obesity in
mice. However, the exact member of the HDAC family and the precise mechanism whereby class I HDACi
exerts these beneficial effects are not known. Histone deacetylase 1 (HDAC1) functions to remove acetyl
groups from lysine residues in histone, thereby silencing gene expression. Our published and preliminary data
suggest that HDAC1 deficiency promotes brown adipocyte thermogenic program and white adipocyte lipolysis
via increasing histone lysine 27 (H3K27) acetylation (H3K27ac). Therefore, we hypothesize that HDAC1
regulates adaptive thermogenesis, lipolysis, energy metabolism and obesity in genetic models. Aim 1 will
determine the role of HDAC1 in regulation of adaptive thermogenesis, energy metabolism and diet-induced
obesity in genetic models. We have generated genetic mice with brown/beige adipocytes deficient or
overexpressing HDAC1 and will characterize the phenotypes of cold-induced thermogenesis and diet-induced
obesity in these mice. We will further investigate the orphan nuclear receptor NR4A1, identified via ChIP-Seq,
as a downstream signal mediating H3K27ac-induced thermogenic program due to HDAC1 deficiency. Aim 2
will determine whether HDAC1 regulates lipolysis via a NR4A1-mediated lipolytic program. We have generated
genetic models with fat (white and brown)-specific HDAC1 deletion or overexpression. We will determine: a)
whether adipocyte-specific deletion of HDAC1 enhances, whereas specific overexpression of HDAC1 inhibits
adipocyte lipolysis; b) whether enhanced H3K27ac by HDAC1 deficiency recruits NR4A1 to the lipolytic gene
promoters, resulting in enhanced gene expression and subsequent lipolysis in white fat. Aim 3 will determine
the molecular pathway whereby β adrenergic signal regulates HDAC1 activity. We will determine: a) β
adrenergic activation disassociates a repressive complex consisting of HDAC1 and the co-repressors RIP140
and RB, which suppress the thermogenic program at basal state; and b) β adrenergic activation decreases
HDAC1 activity via acetylation by the histone C...

## Key facts

- **NIH application ID:** 9978048
- **Project number:** 5R01DK115740-03
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Hang Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,935
- **Award type:** 5
- **Project period:** 2018-07-16 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978048

## Citation

> US National Institutes of Health, RePORTER application 9978048, HDAC1 regulates thermogenic program via H3K27 deacetylation (5R01DK115740-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9978048. Licensed CC0.

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