Brown adipose tissue sustains thermogenesis through metabolic flexibility in glucose utilization

Brown adipose tissue (BAT) is a cold-activated organ that uncouples mitochondrial respiration from ATP synthesis to produce heat. Activated BAT can consume an extreme amount of glucose, per gram of tissue, in both mice and humans. However, the contexts, mechanisms and necessity for BAT glucose utilization remain surprisingly undefined in vivo. Here we show that while BAT thermogenesis is maintained across diverse dietary contexts, its glucose utilization is particularly responsive to diet. Importantly, we find cold-induced BAT glucose uptake and thermogenesis to be independent of the previously proposed critical transporter, GLUT1. Instead, inducible GLUT4 loss eliminates cold-induced glucose uptake and compromises BAT thermogenesis only when dietary lipids are low during cold stress. We furthermore illustrate the unexpected capacity for brown adipocytes to sustain ATP levels without glycolysis, even during substantial mitochondrial uncoupling, when alternative nutrients are abundant. Collectively, our work demonstrates that BAT sustains thermogenesis through marked metabolic flexibility across nutrient contexts. BAT thermogenesis is sustained by metabolic flexibility, with GLUT4-dependent glucose utilization becoming critical selectively during cold exposure when dietary lipids are limited.