p107 is crucial to the switch in adipose lineage commitment: a missing link in the PRDM16 pathwa

This study shows that p107 is at the crux in determining adipose lineage commitment. It was completely absent in BAT and only expressed in the stem cell compartment of WAT depots. Moreover, contrary to PRDM16, a major brown adipocyte determination factor, p107 was significantly decreased in subcutaneous compared to infra-abdominal WAT reservoirs. In vivo activation of brown adipocyte formation within subcutaneous WAT by beta3-adrenergic agonist treatment, further significantly decreased levels of p107. Importantly, the absence or the depletion of p107 results in the formation of brown adipocytes in p107 genetically deleted primary mesodermal stem cells and p107 knockdown mesenchymal stem cell lines, respectively. The establishment of brown adipocytes was dependant on the knockdown of p107 during growth or a very early time point during differentiation, suggesting a function in brown adipose lineage commitment rather than the differentiation pathway.;Consistent with the hypothesis that PRDM16 is a brown adipocyte determination factor, PRDM16 over expressing cell lines had significantly reduced levels of p107 concomitant with expression of brown adipocyte markers after differentiation. The control of p107 function by PRDM16 was confirmed by expression assays using a 900 bp p107 promoter fused to the luciferase gene. Notably, the importance of p107 to the PRDM16 brown determination pathway is highlighted by MSC cell lines overexpressing PRDM16 transduced with overexpressing p107 retrovirus. In this case, though the cells undergo adipocyte differentiation, they are blocked from brown adipocyte formation with sustained p107 expression.