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
  • 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.

  • Fig. 1 Plasma uridine dynamics during fasting and refeeding.

    (A) Plasma uridine levels in male C57BL/6 mice in a fasting/refeeding study (n = 7). (B) Plasma uridine levels in male Sprague-Dawley rats in a fasting/refeeding study (n = 7). (C and D) Plasma uridine and uric acid levels in healthy women after subjects were fasted for ~12 hours overnight, and at regular intervals after they consumed a breakfast meal at 7 a.m. (47). Plasma uridine and uric acid levels after overnight fasting were considered as basal for each subject for statistical analysis (n = 6). Data were analyzed with paired t test. ***P < 0.001, ****P < 0.0001; ns, not significant. Error bars denote SEM.

  • Fig. 2 Plasma uridine dynamics correlates with body temperature fluctuation.

    (A) Body temperature was monitored in male C57BL/6 mice after intraperitoneal injection of PBS or uridine (1 g/kg) (n = 6 per group). (B) Body temperature was monitored in a fasting/refeeding study using male wild-type (WT), ob/ob, and 6 weeks HFD-fed animals (n = 6 per group). (C) Male WT and ob/ob mice fed on chow or HFD (10 weeks) were monitored for plasma uridine levels during a fasting/refeeding study (n = 6 per group). (D) PALA prevented the drop of body temperature by fasting in ob/ob mice (n = 7 per group). Statistical analysis was performed for each condition using time 0 or the fed state of that group as base line if not specified. Data in (A) to (C) were analyzed with paired t test, and data in (D) were analyzed with two-tailed Student t test. *P < 0.05, **P < 0.01. Error bars denote SEM.

  • Fig. 3 Thermoregulation effects of uridine.

    (A) Male C57BL/6 mice were injected intraperitoneally (i.p.) with PBS or uridine (1 g/kg) at room temperature (22° to 25°C), then transferred to a chamber at 29°C, and monitored for their body temperature (n = 6 per group). (B to D) Injection of uridine (i.p., 1 g/kg) reduced the rates of O2 consumption and CO2 production, but increased RER of male C57BL/6 mice in an indirect calorimetry study (n = 5 per group). The arrows indicate the changes due to cage opening. Values of VO2 and VCO2 were plotted relative to the baseline measurements. (E) Body temperature was monitored in male WT and ob/ob mice after uridine i.p. injection (1 g/kg) at the indicated time point. The HFD group consisted of male WT mice fed with HFD for 15 weeks (n = 5 per group). (F) Plasma leptin levels in WT mice (HFD for 15 weeks) were measured before and after uridine i.p. injection (1 g/kg) (n = 6 per group). (G) Plasma leptin levels in WT and ob+/− mice were measured before and 15 min after uridine i.p. injection (1 g/kg) (n = 6 per group). Statistical analysis was performed for different treatments or genotypes at indicated time points if not specified. Data were analyzed with two-tailed Student t test. *P < 0.05, **P < 0.01. Error bars denote SEM.

  • Fig. 4 Biliary release of uridine.

    (A) Uridine concentrations in plasma and bile from 24 hour–fasted male C57BL/6 mice (n = 6). (B) Uridine concentration in bile from male and female C57BL/6 mice (n = 6 to 10 for each time point). (C) Biliary uridine levels in 24 hour–fasted male C57BL/6 mice fed with chow or HFD for 15 weeks (n = 6 per group). (D) Biliary uridine levels in 24 hour–fasted male WT and ob/ob mice fed with chow or HFD for 15 weeks (n = 6 per group). (E) Male C57BL/6 mice were administered with [5-3H]uridine by tail vein injection or oral gavage (gav). Plasma from tail tip and bile from gallbladder were harvested at indicated time points (n = 4 per time point). (F) Male C57BL/6 mice were administered with [3H]uridine by oral gavage. Plasma from tail tip and portal vein and bile from gallbladder were harvested 2 min after gavage (n = 6). Data were analyzed with two-tailed Student t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Error bars denote SEM.

  • Fig. 5 Uridine effects on glucose metabolism.

    (A and B) Plasma glucose levels from male WT mice (HFD for 25 weeks) or ob/ob mice were measured in oral glucose tolerance tests with glucose or glucose-uridine solution (n = 6 per group). (C and D) Plasma glucose levels from male WT mice (HFD for 25 weeks) or ob/ob mice were measured in oral glucose tolerance tests with PBS or uridine intraperitoneal injection 15 min before glucose gavage (n = 6 per group). (E) Plasma glucose levels from male C57BL/6 mice (18 months old) were measured in oral glucose tolerance tests with glucose or glucose-uridine solution (n = 6 per group). (F) Plasma glucose levels from male C57BL/6 mice (18 months old) were measured in oral glucose tolerance tests with PBS or uridine intraperitoneal injection 15 min before glucose gavage separately (n = 6 per group). (G and H) Plasma glucose levels and body weight were measured in male C57BL/6 mice (HFD for 30 days) before and after i.p. injection with PALA or vehicle (Veh) (n = 5 per group). Statistical analysis was performed for different treatments at indicated time points if not specified. Data were analyzed with two-tailed Student t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Error bars denote SEM.

  • Fig. 6 Thermoregulation effects of enteral administration of uridine.

    (A) Body temperature of male WT (chow or HFD for 10 weeks) and age-matched ob/ob mice was monitored before and after oral administration of uridine (1 g/kg, n = 6 per group). (B and C) Body temperature of male WT (HFD for 10 weeks) or age-matched ob/ob mice was monitored before and after oral administration of glucose or glucose-uridine solution (n = 6 per group). Data were analyzed by two-way ANOVA and no significant difference was detected between each group. Error bars denote SEM.

  • Fig. 7 Adipocytes are critical for plasma uridine supply.

    (A) Plasma uridine levels in male WT and FAT-ATTAC mice in a fasting/refeeding study (n = 6 per group). (B) Relative plasma uridine levels in male WT and Agpat2 KO mice in a fasting/refeeding study (n = 4 per group). (C) qPCR quantification of genes involved in pyrimidine biosynthesis in liver from male C57BL/6 mice (n = 5 per group). (D) qPCR quantification of Cad in liver, epididymal fat (eWAT), subcutaneous fat (sWAT), and brown fat (BAT) from male C57BL/6 mice (n = 5 per group). (E) Uridine contents in subcutaneous adipose tissue biopsies from metabolically healthy subjects were reduced 5 hours after breakfast (n = 6). (F to I) Male C57BL/6 mice were treated with streptozotocin (STZ) or vehicle (CTL) and monitored for plasma glucose levels and body weight up to 7 weeks. The uridine concentrations in plasma, bile, and tissues were measured from mice fasted for 24 hours (n = 5 or 6 per group). Statistical analysis was performed for each group or treatment using the fed state or CTL treatment of that group as baseline if not specified. Data were analyzed with two-tailed Student t test. *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote SEM.

Supplementary Materials

  • An adipo-biliary-uridine axis that regulates energy homeostasis

    Yingfeng Deng, Zhao V. Wang, Ruth Gordillo, Yu An, Chen Zhang, Qiren Liang, Jun Yoshino, Kelly M. Cautivo, Jef De Brabander, Joel K. Elmquist, Jay D. Horton, Joseph A. Hill, Samuel Klein, Philipp E. Scherer

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Tables S1 and S2

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