Inhibition of nucleotide biosynthesis disrupts lipid accumulation and adipogenesis

Energy balance and nutrient availability are key determinants of cellular decisions to remain quiescent, proliferate, or differentiate into a mature cell. After assessing its environmental state, the cell must rewire its metabolism to tabolites regulate cell fate decisions is poorly understood. We used adipogenesis as our model system to ascertain the role of metabolism in differentiation. We isolated adipose tissue stromal vascular fraction cells and profiled metabolites before and after adipogenic differentiation to identify metabolic signatures associated with these distinct cellular states. We found that differentiation alters nucleotide accumulation. Furthermore, inhibition of nucleotide biosynthesis prevented lipid storage within adipocytes and downregulated the expression of lipogenic factors. In contrast to proliferating cells, in which mechanistic target of rapamycin complex 1 is activated by purine accumulation, mechanistic target of rapamycin complex 1 signaling was unaffected by purine levels in differentiating adipocytes. Rather, our data indicated that purines regulate transcriptional activators of adipogenesis, peroxisome proliferator-activated receptor gamma and CCAAT/enhancerbinding protein alpha, to promote differentiation. Although de novo nucleotide biosynthesis has mainly been studied in proliferation, our study points to its requirement in adipocyte differentiation.

Automated summary

Energy balance and nutrient availability play important roles in cellular decisions of quiescence, proliferation, and differentiation. However, how metabolic rewiring and nucleotide metabolism regulate cell fate decisions remains unclear. Using adipogenesis as a model, this study identified metabolic signatures associated with differentiation and revealed the requirement of nucleotide biosynthesis for adipocyte differentiation. Moreover, purines were found to regulate transcriptional activators of adipogenesis to promote differentiation, independent of mechanistic target of rapamycin complex 1 signaling.