Epigenetic regulation of peri-weaning white adipocyte browning via ETS transcription factor GABPalpha

Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in the neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contributes to >50% of beige adipocytes in adults. Neonatal beige is distinct from the recruited beige in that they develop independent of temperature and sympathetic innervation through mechanisms that remain poorly defined. Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 mice 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. Results: We found that the recruitment of acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer of UCP1 was increased in iWAT of P20 mice. We performed H3K27ac ChIP-seq in iWAT of P3 and P20 mice and found that P20 mice had strong H3K27ac peak signals at beige adipocyte markers such as Ucp1, Cidea1 and Cox8b. Moreover, RNA-seq analysis revealed that iWAT of P20 mice displayed pathways that are highly enriched with signatures of beige adipocytes including oxidative phosphorylation and mitochondrial metabolism. Mechanistically, we identify GA-binding protein alpha (GABP) that controls beige adipose tissue development. Our study also uncovers that the neonatal beige adipocytes possesses distinct characteristics from the canonical beige fat in their enhanced glucose oxidation. Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes and recruits a distinct form of thermogenic cells required for energy and metabolic homeostasis. Therefore, understanding the mechanisms underlying the temporal induction of neonatal beige adipocytes and characterizing their metabolic identity will help us harness their therapeutic potential.