# Deciphering the physiology of neonatal beige adipocytes

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $470,918

## Abstract

Beige adipocytes dissipate energy via non-shivering thermogenesis. Identifying these inducible
thermogenic adipocytes has raised the prospect of treating obesity and metabolic diseases.
Recent findings that beige adipocytes develop in neonatal inguinal white adipose tissue (iWAT)
and can be reactivated into functional beige adipocytes in adulthood offer the potential for
targeting these cells in metabolic diseases. Our study focuses on gaps in understanding the
mechanisms of induction and functional characteristics of neonatal beige adipocytes. We
demonstrate that hepatic ketogenesis, which is temporally induced to support metabolic
demands, drives neonatal beige adipogenesis. Our new data showed that the metabolism of
ketone bodies is required to induce beige genes. Aim 1 will determine the role of ketone body
metabolism in iWAT in neonatal beige adipocyte homeostasis. Ketone bodies are potent
modifiers of histones by repressing class I histone deacetylases. Our ChIP-seq analysis in
neonatal iWAT showed higher acetyl histone H3 (H3K27ac), an epigenetic gene activation
marker in the chromatin regions of beige genes. The motif search of H3K27ac enriched
chromatin regions revealed a higher representation of GA binding protein a (GABPa) motifs. A
recent study showed that GABPa induces glycolytic beige adipocytes in adult mice. However,
GABPa target genes in adipocytes and its role in neonatal beige adipogenesis is unclear. Aim 2
will investigate whether GABPa is the molecular driver of neonatal beige adipogenesis. Further
analysis showed elevated levels of several glycolytic genes in neonatal iWAT. Given the limited
fat stores in neonates, we postulate that thermogenesis in neonatal beige adipocytes is fueled
by glucose. By extension, we propose that glucose utilization in beige adipocytes promotes
metabolic homeostasis in neonates. Aim 3 will characterize the thermogenic and metabolic
features of neonatal beige adipocytes. Overall, we hypothesize that ketone bodies
epigenetically activate GABPa in neonatal iWAT to induce beige adipocytes that utilize
glucose for thermogenesis, promoting metabolic homeostasis. Our study will provide
deeper insights into the trigger (ketone bodies), molecular driver (GABPa), and function of
neonatal beige adipocytes. Given that neonatal beige adipocytes could be rejuvenated in
adulthood, our study may lead to novel targets to induce them in treating obesity and metabolic
diseases.

## Key facts

- **NIH application ID:** 10800341
- **Project number:** 1R01DK134581-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sadeesh Kumar Ramakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $470,918
- **Award type:** 1
- **Project period:** 2024-03-13 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800341

## Citation

> US National Institutes of Health, RePORTER application 10800341, Deciphering the physiology of neonatal beige adipocytes (1R01DK134581-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10800341. Licensed CC0.

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