Quantitative Metabolic Analysis of Brown Adipose Tissue, Skeletal Muscle, and Liver During Cold and Diet Induced Thermogenesis

Abstract

Non-shivering thermogenesis by brown adipose tissue (BAT) is an adaptive mechanism for maintaining body temperature in cold environments, critical in rodents and human infants, and has substantial influence on adult human metabolism. Stimulating BAT therapeutically is also being investigated as a strategy against metabolic diseases because of its ability to function as a catabolic sink, through the thermogenic protein, uncoupling protein 1 (UCP1). Thus, understanding how BAT uses nutrients to fuel its demanding metabolism has both basic and translational implications. Here we developed an arteriovenous (AV) metabolomics technique which we used to quantify metabolite exchange between BAT and skeletal muscle during cold exposure in fed male mice, identifying unexpected metabolite utilization between organs. Of note, glucose and lactate provide ~85% of carbon during chronic cold exposure and that cold and CL316,243 initiate divergent fuel utilization profiles. We identified a novel role for glutamine synthesis during thermogenesis to avoid ammonia buildup and promote fuel oxidation. We then set out to investigate a lesser studied thermogenic process termed diet-induced thermogenesis (DIT), which is initiated through prolonged consumption of high-fat diets (HFD). Here, we found that UCP1KO male mice develop liver fibrosis after HFD feeding but female mice do not. We also found that DIT transcriptionally diverges from cold-induced thermogenesis, however, DIT metabolically prefers glucose as a major fuel source accounting for ~53% of carbon consumption. Together these data present a comprehensive landscape of BAT fuel utilization during cold- and diet-induced thermogenesis providing a framework to guide further translational studies.