Brown adipose tissue activity impacts systemic lactate clearance in male mice

Non-shivering thermogenesis in brown adipose tissue (BAT) is linked to metabolic health. Yet, how its activity states impact on systemic metabolism and in particular on lactate, a highly abundant metabolite increasingly recognized as a critical player in energy metabolism, remains unresolved. The goal of this study was to investigate the impact of BAT activity on lactate metabolism at the whole organism level. To activate or inactivate non-shivering thermogenesis in BAT, we housed C57Bl6/J male mice at 4, 21 and 30°C and then conducted lactate tolerance tests. In mice exposed to cold exposure (4°C), systemic lactate clearance was elevated. In contrast, clearance of systemic lactate was poor in mice housed under thermoneutral conditions (30°C) that inactivate BAT thermogenesis, as well as in mice deficient for the mitochondrial uncoupling protein-1. To better understand lactate metabolic fate during the clearance phase, in vivo stable isotope tracing experiments with labelled ¹³C-lactate and analyses by mass spectrometry were performed. These experiments revealed that lactate contribution to gluconeogenesis was increased under cold exposure while its contribution to the tricarboxylic acid cycle was reduced in BAT under thermoneutrality. Remarkably, we also identified that lactate entered a pyruvate cycling process that was highly active in BAT, and repressed at thermoneutrality. Our study shows that inactivation of non-shivering thermogenesis decreased systemic lactate clearance, concomitantly with changes in metabolic fate of lactate in BAT and in gluconeogenic organs, in male mice. KEY POINTS: Lactate clearance is enhanced upon cold exposure and reduced at thermoneutrality. UCP1-deficient mice exhibit impaired lactate clearance. Oxidative utilization of lactate in brown fat is decreased at thermoneutrality. Prolonged cold exposure increases lactate contribution to gluconeogenesis. Lactate enters a highly active pyruvate cycling process in brown adipose tissue.