Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, United States.
Pittsburgh Liver Research Centre, University of Pittsburgh, Pittsburgh, PA, United States.
Front Endocrinol (Lausanne). 2024 May 3;15:1385811. doi: 10.3389/fendo.2024.1385811. eCollection 2024.
Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms.
We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays.
We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20.
Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.
产热米色脂肪细胞可将能量以热量的形式消耗掉，在新生儿和成人中都有发现。最近的研究表明，新生儿米色脂肪细胞具有高度的可塑性，在成人米色脂肪细胞中占比超过 50%。与通过温度和交感神经支配募集而来的米色脂肪细胞不同，新生儿米色脂肪细胞的发育是通过尚未明确的机制独立进行的。
我们通过成像、全基因组 RNA-seq 分析、ChIP-seq 分析、qRT-PCR 验证和生化测定，对 C57BL6 新生后 3 天和 20 天（P3 和 P20）腹股沟白色脂肪组织（iWAT）中的新生儿米色脂肪细胞进行了表征。
我们发现 P20 小鼠 iWAT 中米色特异性基因 UCP1 的启动子和增强子区域上乙酰化组蛋白 H3 赖氨酸 27（H3K27ac）增加。此外，P3 和 P20 小鼠 iWAT 的 H3K27ac ChIP-seq 分析显示，P20 小鼠 iWAT 中米色脂肪细胞相关基因上存在强烈的 H3K27ac 信号。P20 iWAT 的 H3K27ac ChIP-seq 和 RNA-seq 分析的整合揭示了米色脂肪细胞的表观遗传活性特征，包括氧化磷酸化和线粒体代谢。我们发现 GABPα 结合区域在 P20 iWAT 的表观遗传活性染色质区域中富集，特别是在米色基因上，并证明 GABPα 是米色脂肪细胞分化所必需的。此外，转录组分析和葡萄糖氧化测定显示，P20 新生 iWAT 的糖酵解活性增加。
我们的研究结果表明，表观遗传机制通过 GABPα 调节围产期米色脂肪细胞的发育。进一步的研究旨在更好地理解调节 GABPα 表观遗传激活的上游机制，并对新生儿米色脂肪细胞的代谢特征进行分析，这将有助于我们在代谢性疾病中利用其治疗潜力。
