p107 Determines a Metabolic Checkpoint Required for Adipocyte Lineage Fates.

Abstract

We show that the transcriptional corepressor p107 orchestrates a metabolic checkpoint that determines adipocyte lineage fates for non-committed progenitors. p107 accomplishes this when stem cell commitment would normally occur in growth arrested cells. p107-deficient embryonic progenitors are characterized by a metabolic state resembling aerobic glycolysis that is necessary for their pro-thermogenic fate. Indeed, during growth arrest they have a reduced capacity for NADH partitioning between the cytoplasm and mitochondria. Intriguingly, this occurred despite an increase in the capacity for mitochondrial oxidation of non-glucose substrates. The significance of metabolic reprogramming is underscored by the disruption of glycolytic capacities in p107-depleted progenitors that reverted their fates from pro-thermogenic to white adipocytes. Moreover, the manipulation of glycolytic capacity on nonspecified embryonic and adult progenitors forced their beige fat commitment. These innovative findings introduce a new approach to increase pro-thermogenic adipocytes based on simply promoting aerobic glycolysis to manipulate nonspecified progenitor fate decisions. Stem Cells 2017;35:1378-1391.