Research Article

An adipo-biliary-uridine axis that regulates energy homeostasis

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Science  17 Mar 2017:
Vol. 355, Issue 6330, eaaf5375
DOI: 10.1126/science.aaf5375

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Uridine's rise and fall: Food for thought

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

Structured Abstract

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.

A regulatory model of energy homeostasis during fasting/refeeding.

The 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. Biliary excretion is the primary mechanism for plasma uridine clearance. Because nutrient intake triggers bile release, plasma uridine levels are elevated during fasting and drop rapidly in the postprandial state. The fasting-associated increase of plasma uridine elicits a hypothalamic response culminating in body temperature lowering, whereas bile-mediated uridine release promotes a decline of plasma uridine and enhances insulin sensitivity.

Abstract

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.

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