2065-LB: Slug Regulates Adipogenesis and Adipose Tissue Growth

Adipose stem cell commitment, proliferation, and differentiation critically regulate adipose tissue development and homeostasis. Transcription factor Slug, also known as Snai2, is well known to promote epithelial-mesenchymal transition and cell motility. Slug also emerges as an important regulator of body weight and metabolism. In the hypothalamus, Slug promotes leptin resistance, leading to obesity. In the liver, hepatic Slug promotes de novo lipogenesis and fatty liver disease. In this study, we observed that Slug is expressed in adipose stromal vascular fraction cells (SVFs). SVFs contains adipose stem cells/preadipocytes. To determine the fate of Slug-expressing SVFs, we generated Slug-Cre and Slug-CreERT (tamoxifen-dependent) drivers. The drivers were crossed with Rosa26-mTmG or Rosa26-tdTomato reporter mice to generate Slug-expressing cell lineage-tracing models. The Slug-Cre based tracing paradigm revealed that Slug-expressing stem cells generate the majority of white adipocytes and brown adipocytes in mice. The Slug-CreERT models demonstrated that in adult mice, Slug-expressing SVFs play an important role in regulating adipose tissue regeneration and maintenance. To examine Slug function, we generated adipose stem cell-specific Slug knockout mice by crossing Slug^f/f mice with PDGFRα-Cre drivers. Body weight was lower in Slug mutant mice relative to Slug^f/f mice on a high fat diet (HFD). Likewise, whole body deletion of Slug also protected against HFD-induced obesity and insulin resistance. In conclusion, our results suggest that Slug directly regulates adipose stem cell behavior, adipogenesis, adipose growth, and adipose function.