Human fetal mesenchymal stem cells differentiate into brown and white adipocytes, and reveal a role for ERRα in human UCP1 expression

We have investigated the ability of fetal mesenchymal stem cells (fMSCs) to differentiate into brown and white adipocytes and compared the expression of a number of marker genes and key regulatory factors. We have shown that the expression of key adipocyte regulators and markers during differentiation is similar to that in other human and murine adipocyte models, including induction of PPARγ2 and FABP4. Notably we found that the pre-adipocyte marker Pref-1, is induced early in differentiation and then declines markedly as the process continues, suggesting that fMSCs first acquire pre-adipocyte characteristics as they commit to the adipogenic lineage, prior to their differentiation into mature adipocytes. After adipogenic induction, some stem cell isolates differentiated into cells resembling brown adipocytes and others into white. Detailed investigation of one isolate showed that the novel brown fat determining factor PRDM16 is expressed both before and after differentiation. Importantly these cells exhibited elevated basal UCP-1 expression, which was dependent on the activity of the orphan nuclear receptor ERRα, highlighting a novel role for ERRα in human brown fat. Thus fetal MSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. They also offer invaluable insights into the characteristics of human brown fat.