Title : New Insights into the Metabolic Functions of Adipose Pyruvate Kinase M2
Pyruvate kinase M2 (PKM2) is primarily a tetrameric enzyme that catalyzes the transfer of a phosphate from phosphoenolpyruvate to ADP, resulting in pyruvate and ATP. PKM2 is abundant during embryogenesis and in specific adult tissues such as adipose and pancreatic islets. New evidence suggests that PKM2 expression in these tissues may have a pivotal role in regulating glycolysis, cell death, and proliferation. However, the metabolic functions of PKM2 in these tissues remain largely unexplored. Our preliminary data shows that shRNA-mediated depletion of PKM2 in white pre-adipocytes promotes the development of a brown fat-like thermogenic program, which translated into increased mitochondria biogenesis and expression of UCP1, BMP7, and PRDM16. Additionally, metabolomic profiling of PKM2 deficiency revealed notable metabolic similarities with bona fide brown adipocytes. Importantly, PKM2 deficiency in white adipocytes increases ATP turnover, and enhances basal and maximal mitochondrial respiration. Notably, transplantation of PKM2-deficient pre-adipocytes into mice gives rise to ectopic fat pads with morphological and biochemical characteristics of brown adipocytes with enhanced glucose uptake in vivo. Collectively, these findings identify PKM2 as a novel component of the molecular circuit that contributes to adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.