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Cell Rep. 2012 Oct 25;2(4):976-90. doi: 10.1016/j.celrep.2012.08.038. Epub 2012 Oct 11.

Consecutive positive feedback loops create a bistable switch that controls preadipocyte-to-adipocyte conversion.

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  • 1Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.

Abstract

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/EBPβ levels above a critical threshold, triggering three consecutive positive feedback loops: from PPARγ to C/EBPα, then to C/EBPβ, 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.

PMID:
23063366
PMCID:
PMC4959269
DOI:
10.1016/j.celrep.2012.08.038
[PubMed - indexed for MEDLINE]
Free PMC Article
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