Novel identified micropeptide LEAO reshapes plasticity of adipose tissue to improve metabolic homeostasis

Adipose tissue exhibits remarkable plasticity, defined as its capability of adapting to various environments and energy demands by undergoing shifts in phenotypic, metabolic characteristics, and structure. However, obesity often results in diminished adipose tissue plasticity. Long non-coding RNA (lncRNA) is a class of RNA defined as being more than 200 nucleotides long and lacking protein-coding capability. With advancements in ribosome profiling, mass spectrometry, and other research technologies, an increasing number of studies have confirmed that short open reading frames (less than 300 nucleotides) within lncRNAs have the capacity to encode functional micropeptides. In our study, we initially identified a biologically active micropeptide, lncRNA Esrp2-as-ORF1(LEAO), encoded by lncRNA Esrp2-as in mice. In diet-induced obesity (DIO)mice, this micropeptide demonstrates the ability to induce fat browning, enhance adipose tissue plasticity, and subsequently improve metabolic homeostasis. Additionally, we observed that the micropeptide LEAO exerts its effects on adipocytes by stimulating IL6 secretion in adipose tissue macrophages. In summary, LEAO may have therapeutic potential for obesity-related metabolic diseases.