when ob/ob mice were fed HFD for 6 weeks, their
body temperature drop triggered by 24 hours
of fasting was reduced to 2.3° ± 1.3°C (n = 6, P <
0.01) (Fig. 2B). Thus, although both the HFD
and ob/ob mice are obese and are widely used
for studies of insulin resistance, the fasting response in HFD-fed wild-type animals differs
from the fasting response in ob/ob mice. Together, these data lend credence to a model in
which leptin signaling participates in fasting-induced temperature declines in a manner blunted
by HFD exposure.
To test whether uridine participates in thermoregulation during fasting and refeeding, we
analyzed plasma uridine levels in HFD-fed ob/ob
and wild-type mice. We detected higher levels
of plasma uridine in ob/ob mice than in wild-type mice; conversely, obese HFD-fed wild-type
mice harbored plasma uridine levels comparable to those in lean chow-fed wild-type mice
(Fig. 2C). Fasting further increased plasma uridine levels in ob/ob mice in the first 4 hours after
food removal, but fasting had no effect on plasma uridine levels in HFD-fed wild-type mice
(Fig. 2C). Upon refeeding, ob/ob mice exhibited
a rapid decline in plasma uridine levels, whereas
no significant changes were observed in obese
HFD-fed wild-type mice (Fig. 2C). These data
reveal a strong correlation between plasma uridine levels and thermoregulation and further
highlight the distinct effects of HFD and leptin-deficiency on body temperature that is mediated through plasma uridine.
Uridine-triggered temperature declines in rodents rely on the activity of uridine phosphorylase (8), the enzyme responsible for initiation
of uridine catabolism. We hypothesized that
increases in plasma uridine levels during fasting
mediate the temperature drop by increasing uridine availability for degradation. To test this, we
injected ob/ob mice with N-(phosphonacetyl)-L-
aspartate (PALA). This compound is an inhibitor of aspartate transcarbamylase (14), which is
the rate-limiting enzyme for uridine biosynthesis
(15) and is part of the trifunctional protein Cad
(carbamoyl phosphate synthetase 2, aspartate
transcarbamylase, and dihydroorotase). In this
context, PALA prevented both the drop in body
temperature in ob/ob mice (Fig. 2D) and the elevation of plasma uridine after 24-hour fasting.
These findings support a model in which plasma
uridine levels govern core body temperature.
Uridine links thermoregulation
with leptin
Temperature exchange with the environment
depends on the difference in temperature be-
tween the subject and surrounding environment
and relies on three mechanisms: conduction,
convection, and radiation. To examine whether
the acute temperature drop triggered by uri-
dine is mediated by temperature exchange with
the environment, we housed mice in a near-
thermoneutral environment (29°C), 7°C above
the ambient room temperature used for the
studies depicted in Fig. 2A. Wild-type mice in-
jected with PBS showed a slight increase in
body temperature after they were moved to 29°C
(37.5° ± 0.24°C, 38.3° ± 0.2°C, and 38.1° ± 0.2°
C at 0, 15, and 30 min, respectively; n = 6)
(Fig. 3A). When mice were injected with uri-
dine and subsequently transferred to the 29°C
incubator, the temperature drop seen at ambient
room temperature (Fig. 2A) was no longer ob-
served; rather, the mice displayed a body temper-
ature only slightly lower than that observed with
the PBS injection under the same conditions
Deng et al., Science 355, eaaf5375 (2017) 17 March 2017 2 of 9
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 WTand 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.
