An adipo-biliary-uridine axis that regulates energy homeostasis

• Published in: Science (American Association for the Advancement of Science) Vol. 355; no. 6330; p. 1173
• Main Authors: Deng, Yingfeng, Wang, Zhao V., Gordillo, Ruth, An, Yu, Zhang, Chen, Liang, Qiren, Yoshino, Jun, Cautivo, Kelly M., De Brabander, Jef, Elmquist, Joel K., Horton, Jay D., Hill, Joseph A., Klein, Samuel, Scherer, Philipp E.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 17.03.2017; The American Association for the Advancement of Science
• Subjects: Adenosine; Adipocytes; Adipocytes - metabolism; Adipose tissue; Animal models; Animal physiology; Animals; Bile; Biosynthesis; Blood Glucose - metabolism; Body temperature; Body Temperature Regulation; Circuits; Clearances; Climate; Deposition; Detoxification; Diabetes mellitus; DNA biosynthesis; Energy; Energy balance; Energy Metabolism; Excretion; Extracellular matrix; Fasting; Fasting - metabolism; Feeding; Feeding behavior; Food intake; Gastrointestinal tract; Glucose; Glucose metabolism; Glycogen; Glycogens; Glycosylation; Hepatobiliary Elimination; Homeostasis; Humans; Insulin; Leptin - metabolism; Lipids; Liver; Male; Mammals; Metabolic disorders; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Obese; Neurological diseases; Nucleic acids; Nucleosides; Nutrient release; Physiology; Plasma; Rats; Rats, Sprague-Dawley; RESEARCH ARTICLE SUMMARY; Rodents; Sensitivity enhancement; Signal Transduction; Synthesis; Temperature control; Thermoregulation; Transcription; Uridine - biosynthesis; Uridine - blood; Xenobiotics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aaf5375

The nucleoside uridine is well known for its role in critical cellular functions such as nucleic acid synthesis. Its role in whole-animal physiology has received comparatively little attention. In mammals, plasma uridine levels are tightly regulated, but the underlying mechanisms are unclear. Studying mouse models, Deng et al. show that plasma uridine levels are controlled by feeding behavior (see the Perspective by Jastroch and Tschöp). Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease. Science , this issue p. aaf5375 ; see also p. 1124 Plasma uridine levels are controlled by feeding behavior, a discovery with possible implications for metabolic disease. Uridine, a pyrimidine nucleoside present at high levels in the plasma of rodents and humans, is critical for RNA synthesis, glycogen deposition, and many other essential cellular processes. It also contributes to systemic metabolism, but the underlying mechanisms remain unclear. We found that plasma uridine levels are regulated by fasting and refeeding in mice, rats, and humans. Fasting increases plasma uridine levels, and this increase relies largely on adipocytes. In contrast, refeeding reduces plasma uridine levels through biliary clearance. Elevation of plasma uridine is required for the drop in body temperature that occurs during fasting. Further, feeding-induced clearance of plasma uridine improves glucose metabolism. We also present findings that implicate leptin signaling in uridine homeostasis and consequent metabolic control and thermoregulation. Our results indicate that plasma uridine governs energy homeostasis and thermoregulation in a mechanism involving adipocyte-dependent uridine biosynthesis and leptin signaling.