Prior exposure of angiogenic factors promote cell‐autonomous brown adipogenesis of human classical brown precursor cells

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Humans contain substantial amount of classical brown fat in the neck area. In contrast to beige fat that requires stimulatory signal, classical brown fat constitutively expresses uncoupling protein 1 (UCP1), thereby significantly contributing to energy balance. Despite metabolic significance, environmental factors that alter brown fat development in humans have not been clearly established. Given the intimate relationship between brown adipogenesis and capillary network in vivo, we hypothesize that angiogenic factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) modulate brown adipogenic potential. Immortalized classical brown precursors established from human, were pre‐exposed with or without endothelial growth medium (EGM) containing VEGF and FGF2 before the induction to adipogenic differentiation. Pre‐exposure of anigoenic medium resulted in >10‐fold increases of brown signature gene expressions including UCP1, Cidea and DIO2, as well as oxygen consumption rate. In addition, exposure to angiogenic media significantly modulated brown adipogenesis via epigenetic mechanisms: 1) downregulation of histone deacetylase (HDAC) expression specifically HDAC1 and HDAC9, and 2) biogenesis of functional cluster of brown‐specific microRNAs, i.e., miR‐378, miR‐30b and miR‐193b/365. Collectively, we demonstrated that prior exposure of anigogenic environment promotes cell‐autonomous potential to convert brown precursor cells into metabolically active human brown adipocytes via epigenetic mechanisms.Support or Funding InformationSupported by NIH 1P20GM104320