An Adipo-Biliary-Uridine Axis That Regulates Energy Homeostasis

INTRODUCTION Uridine is a pyrimidine nucleoside that is critical for cellular function and survival. In addition to its role in RNA and DNA biosynthesis, uridine is required for glycogen deposition, protein and lipid glycosylation, extracellular matrix biosynthesis, and detoxification of xenobiotics. Plasma uridine levels are maintained within a narrow range, and most cells depend on a readily available pool of uridine in plasma to maintain basic cellular functions. Enhanced understanding of the physiological mechanisms controlling biosynthesis and clearance of this metabolite has the potential to shed light on several disease states, including diabetes, cancer, and neurological disorders. RATIONALE Despite its pivotal physiological role, uridine has received limited attention in comparison to other nucleosides such as adenosine. Studying rodent models, we set out to define the mechanisms regulating plasma uridine levels and to dissect the molecular circuitry whereby uridine governs energy homeostasis in normal and obese conditions. RESULTS One of our key findings is that plasma uridine levels are subject to tight regulation during feeding and fasting in both rodents and humans. Plasma uridine levels are elevated during fasting and drop rapidly in the postprandial state. We demonstrate that liver is the predominant biosynthetic organ and contributor to plasma uridine in the fed state, whereas the adipocyte dominates uridine biosynthetic activity in the fasted state. Both glucose and uridine levels must be maintained in the fasted state, not only as basic building blocks for macromolecule biosynthesis, but also as fuels for metabolically active cell types such as neurons. We find that the fasting-induced rise in uridine is tightly linked to a drop in core body temperature driven by a reduction in metabolic rate. The fasting-induced drop in body temperature, although small, is highly reproducible and seen in both rodents and humans. Plasma uridine homeostasis thus links thermoregulation to the fasting/refeeding cycle. Leptin signaling governs uridine-dependent thermoregulation such that leptin deficiency amplifies fasting-induced declines in core temperature. Conversely, prolonged exposure to a high-fat diet blunts the fasting-induced body temperature drop. We clarify the mechanism underlying the rapid reduction of plasma uridine upon refeeding, which involves both reduction of uridine synthesis in adipocytes and enhancement of its clearance through the bile. Uridine from the digestive tract has a different fate than uridine derived biosynthetically from the adipocyte in the fasted state. Adipose tissue–derived uridine increases plasma uridine concentrations, which in turn elicit a hypothalamic response culminating in body temperature lowering. In contrast, gut-derived uridine is never fully released into the circulation, but rather is rapidly resorbed into bile again and effectively reused as part of an enterohepatic recycling process. This minimizes the effects of postprandial uridine absorption, obviating an impact on temperature control in the fed state. CONCLUSION Our results show that plasma uridine concentrations in mammals are regulated by fasting/refeeding. Adipocytes are key contributors to uridine supply during fasting, whereas biliary excretion is the primary mechanism for uridine clearance following food intake. Bile-mediated uridine release promotes body temperature declines during fasting and enhances insulin sensitivity in a leptin-dependent manner. Because nutrient intake triggers bile release, our work identifies a metabolic regulatory model in which feeding behavior directly regulates plasma uridine homeostasis, which then alters energy balance through thermoregulation.