Abstract
Formation of beige adipocytes within white adipose tissue enhances energy expenditure, which is a promising strategy to reduce obesity and prevent metabolic symptoms. Vitamin A and its bioactive metabolite, retinoic acid (RA), have regulatory roles in lipid metabolism. Here we report that RA induces white adipose tissue browning via activating vascular endothelial growth factor (VEGF) signaling. RA triggered angiogenesis and elicited de novo generation of platelet-derived growth factor receptor α positive (PDGFRα+) adipose precursor cells via VEGFA/VEGFR2 signaling. In addition, RA promoted beige/brown adipocyte formation from capillary networks in vitro. Using PDGFRα tracking mice, we found that the vascular system acted as an adipogenic repository by containing PDGFRα+ progenitors which differentiated into beige adipocytes under RA or VEGF164 treatments. Conditional knockout of VEGF receptors blocked RA-stimulated white adipose tissue browning. Moreover, the VEGFA and RA activated p38MAPK to enhance the binding of RA receptor to RA response elements of the Prdm16 promoter and upregulated Prdm16 transcription. In conclusion, RA induces white adipose tissue browning by increasing adipose vascularity and promoting beige adipogenesis of PDGFRα+ adipose progenitors.
Highlights
Due to the global obesity epidemic, there is an urgency for an increased understanding of adipose tissue development and its roles in metabolic dysfunction
Inguinal white adipose tissue (WAT)-derived SVCs were cultured on matrigelcoated plates in endothelial basal medium supplemented with dimethyl sulfoxide (DMSO) or Retinoic acid (RA) for 2 days
RA signaling acted as a central regulator of adipose tissue remodeling and adipocyte differentiation that is required for the process of WAT browning
Summary
Due to the global obesity epidemic, there is an urgency for an increased understanding of adipose tissue development and its roles in metabolic dysfunction. The formation of brown adipocytes within white adipose tissue (WAT), termed beige adipogenesis, enhances energy expenditure and provides a new alternative for preventing and reducing obesity and other metabolic symptoms [4]. The process of adipogenesis is spatially and temporally associated with vascular development, high vascularization is observed in mature adipose tissue [5]. The function of this vascularization is not limited to providing oxygen and nutrients, and transporting metabolic products such as transporting growth factors [6] which are critical for adipose tissue expansion and remodeling [7]. Endothelial cells and adipocytes interplay through reciprocal exchange of growth factors, hormones and cytokines [5]
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