1720-P: Epigenetic Regulator Slug Directly Promotes Beige Adipogenesis

Introduction and Objective: Brown adipose tissue and beige adipocytes are activated by cold exposure to maintain temperature homeostasis, and adipose thermogenesis also confers benefits against obesity and metabolic disease. Beige progenitor cells reside in adipose stromal vascular fraction (SVF) and proliferate and differentiate into beige adipocytes after chronic cold exposure. Slug is a transcriptional regulator and regulates stem cell behavior (stemness, proliferation, differentiation) through recruiting epigenetic modifiers. We aimed to elucidate the role of Slug in beige adipogenesis. Methods: Slug-Cre and Slug-CreERT (tamoxifen-dependent) knockin mice were generated using Crispr/Cas9 and crossed with Rosa26-mTmG or Rosa26-tdTomato reporter mice for lineage-tracing of Slug-expressing cells. Slug cells were ablated by crossing Slug-CreERT Slug mice with Cre-dependent Rosa-DIO-DTA mice, and the mice were treated with tamoxifen. Slug was deleted in beige progenitor cells by crossing Slugf/f mice with Pdgfra-Cre drivers. Beige adipocytes were identified by UCP1 expression and assessed using immunobiological and immunoblotting assays. Results: Slug-expressing SVF cells readily differentiated into beige adipocytes in vitro. After cold exposure for 10 days, approximately 80% of beige adipocytes in inguinal white adipose tissue (iWAT) were differentiated from Slug SVF cells. DTA-based ablation of Slug cells (prior to cold exposure) dramatically impaired beige adipogenesis and decreased UCP1 beige adipocytes in iWAT, resulting in cold intolerance. Likewise, deletion of Slug in SVF cells (Pdgfr-cre) also markedly impaired cold-stimulated beige adipogenesis. Conclusion: We have identified Slug-expressing SVF cells as important beige progenitor cells that are responsible for cold-stimulated beige adipogenesis. Slug and its controlled epigenetic reprogramming play a critical role in the maintenance of beige progenitor homeostasis, beige adipogenesis, and adipose thermogenesis. Disclosure L. Ju: None. Q. Kang: None. R. Zhou: None. Q. Zheng: None. L. Rui: None.