期刊
CELL REPORTS
卷 2, 期 4, 页码 976-990出版社
CELL PRESS
DOI: 10.1016/j.celrep.2012.08.038
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类别
资金
- Stanford University
- Stanford Cardiovascular Institute
- DFG [AH 220/1-1]
Adipogenesis, or the conversion of proliferating preadipocytes into nondividing adipocytes, is an important part of the vertebrate weight-maintenance program. It is not yet understood how and when an irreversible transition occurs into a distinct state capable of accumulating lipid. Here, we use single-cell fluorescence imaging to show that an all-or-none switch is induced before lipid accumulation occurs. Conversion begins by glucocorticoid and cAMP signals raising C/EBP beta levels above a critical threshold, triggering three consecutive positive feedback loops: from PPAR gamma to C/EBP alpha, then to C/EBP beta, and last to the insulin receptor. Experiments and modeling show that these feedbacks create a robust, irreversible transition to a terminally differentiated state by rejecting short- and low-amplitude stimuli. After the differentiation switch is triggered, insulin controls fat accumulation in a graded fashion. Altogether, our study introduces a regulatory motif that locks cells in a differentiated state by engaging a sequence of positive feedback loops.
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