Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis

Abstract

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source that partially compensates for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.