Nelfb promotes dermal white adipose tissue formation through RNA polymerase II-mediated adipogenic gene regulation

Dermal white adipose tissue (dWAT) is crucial for skin homeostasis, contributing to hair follicle regeneration, immune defense and skin wound healing. dWAT is formed and maintained by the differentiation of adipocyte precursors found in the dermis of the skin. While transcription factors that control adipocyte differentiation have been well characterized, other aspects of transcription control, such as pausing/elongation, are poorly understood. Here, we show that deletion of the transcriptional pause factor, Nelfb, from preadipocyte lineages in mice led to a failure of dWAT and other fat depot formation, perinatal lethality and reduced expression of adipogenic genes. Nelfb promotes an open chromatin structure and stabilizes RNA Polymerase II binding to Pparg, Cebpa, Krox20 and Stat3 to allow their transcription, which is necessary for adipocyte differentiation. Retroviral expression of Pparg in Nelfb-depleted cells restored adipocyte differentiation in cultured cells, while treatment of Nelfb-deleted mice with the Pparg agonist, rosiglitazone, allowed for dWAT formation and prolonged lifespan. These findings highlight the essential role of Nelfb in promoting the expression of key adipogenic genes that are necessary for dWAT formation and adipocyte differentiation.