Wednesday, April 2, 2025
4/2/2025
Deciphering the physiology of neonatal beige adipocytes - 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.
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