The highly expressed lipid buffer FABP4 enforces adipocyte cell identity by driving the initial cell differentiation process

How differentiating progenitor cells can attain a distinct differentiated cell-identity is a challenging problem given the promiscuous nature of critical transcription factors and the typically fluctuating signaling environment in which cells exist. Here we test the hypothesis that a unique and robust differentiated cell identity can result from a core component of the differentiated state doubling up such that it has key functions in the differentiated state and also works at low levels as a positive-feedback signaling mediator that drives progenitor cells to differentiate. Using live single-cell fluorescence imaging analysis in the adipocyte differentiation system, we show that FABP4, one of the most abundant core components that buffers lipids in differentiated adipocytes, regulates at low levels expression of PPARG, the master regulator of adipocyte differentiation. Adipocyte progenitor cells transition from a priming phase of differentiation to a second phase during which low levels of FABP4 and PPARG mutually reinforce each other’s expression. In this way both proteins reach a threshold where cells irreversibly commit to the differentiated state. Before and after reaching this threshold, PPARG transcriptionally increases FABP4 expression while fatty-acid loaded FABP4 binds to and increases PPARG activity. Together, our study suggests a control principle for robust cell identity, whereby a core component of the differentiated state also promotes differentiation from its own progenitor state.