1 Gladstone Institute of Cardiovascular Disease, San Francisco 94103; and 2 Cardiovascular Research Institute and 3 Department of Medicine, University of California, San Francisco, California 94143
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ABSTRACT |
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Mice lacking
acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a
key enzyme in triglyceride synthesis, have increased energy expenditure and therefore are resistant to obesity. Because ambient temperature can significantly affect energy expenditure in mice, we
undertook these studies to determine the effects of different ambient
temperatures on energy expenditure, food intake, and thermoregulation in DGAT1-deficient [Dgat1(/
)] mice.
Dgat1(
/
) mice had increased energy expenditure
irrespective of changes in the ambient temperature. Although core
temperature was normal, surface temperature was increased in
Dgat1(
/
) mice, most likely reflecting an active mechanism to dissipate heat from increased thermogenesis.
Dgat1(
/
) mice had increased food intake at baseline, and
this hyperphagia became more pronounced upon exposure to cold. When
fasted in a cold environment, Dgat1(
/
) mice developed
hypothermia, which was associated with hypoglycemia. These results
suggest that the hyperphagia in Dgat1(
/
) mice is a
secondary mechanism that compensates for the increased utilization of
fuel substrates. Our findings offer insights into the mechanisms of
hyperphagia and increased energy expenditure in a murine model of
obesity resistance.
fasting; glycogen; hypoglycemia; thermoregulation; triglyceride synthesis; uncoupling protein 1; acyl-CoA:diacylglycerol acyltransferase 1
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INTRODUCTION |
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BECAUSE OBESITY RESULTS from an imbalance between energy intake and expenditure (reviewed in Ref. 3), an improved understanding of the mechanisms that underlie increased energy expenditure may be useful in devising strategies to treat obesity. Much of what has been learned about energy expenditure in recent years has resulted from studies in genetically modified rodents. Several murine models of increased energy expenditure and obesity resistance have been reported (reviewed in Refs. 4 and 16). In addition to revealing the biological functions of the inactivated or overexpressed genes, these models may be used to identify new pharmacological targets for the treatment of obesity in humans.
One such model of increased energy expenditure and obesity
resistance is mice that lack acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1). DGAT1 is one of two known enzymes that catalyze the final step
in mammalian triglyceride synthesis (1, 2).
DGAT1-deficient [Dgat1(/
)] mice have reduced adiposity
and are resistant to diet-induced obesity (17). Energy
expenditure on either a chow or a high-fat diet, as measured by
indirect calorimetry, is ~15% higher than in wild-type
[Dgat1(+/+)] mice (17). Part of this increase
may be because of increased leptin sensitivity in
Dgat1(
/
) mice (6). In addition,
Dgat1(
/
) mice fed a high-fat diet have a twofold
increase in locomotor activity (17).
Several aspects of the DGAT1-deficiency phenotype intrigued us.
For example, despite their increased sensitivity to leptin, Dgat1(/
) mice eat more than Dgat1(+/+) mice
(6, 5). In addition, Dgat1(
/
) mice have
abnormal fur lipid composition, which results in impaired water
repulsion and prolonged hypothermia after immersion in water
(7). Because fur lipids may have an important role
in insulating rodents from a cold environment (19), we considered that altered fur lipid composition in
Dgat1(
/
) mice could result in increased heat loss
and contribute to their increased energy expenditure. To investigate
these questions, we studied the effects of different ambient
temperatures on energy expenditure, food intake, and thermoregulation
in Dgat1(
/
) mice. Our results suggest a model in which
DGAT1 deficiency constitutively activates thermogenesis regardless of
changes in the ambient temperature. This increase in thermogenesis, in
turn, results in enhanced heat loss to the environment and compensatory hyperphagia.
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MATERIALS AND METHODS |
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Mice.
Dgat1(/
) mice (98% C57BL/6 and 2% 129/SvJae
background) were generated previously (17).
Dgat1(+/+) mice (in C57BL/6 background) were from the
Jackson Laboratory (Bar Harbor, ME). Age-matched 8- to 12-wk-old female
mice were used for experiments unless noted otherwise. Mice were housed
at 20°C in a pathogen-free barrier facility (12:12-h light-dark
cycle) and fed rodent chow (Ralston Purina, St. Louis, MO). For
experiments at 4°C, mice were housed in a walk-in refrigerator for
8 h unless noted otherwise. For experiments at 32°C, an electric
heating pad was placed underneath the mouse cages, and mice were
acclimatized to the new ambient temperature for 24 h before the
start of experiments. For high-fat diet experiments, mice were fed a
Western-style diet containing 21% fat by weight (Harlan Teklad
Laboratory, Madison, WI). The studies were approved by the Committee on
Animal Research of the University of California, San Francisco.
Real-time PCR. Real-time PCR for uncoupling protein 1 (UCP1) was performed as described (7) with primers 5'-CACCTTCCCGCTGGACACT-3' and 5'-GTGATGGTCCCTAGGACACCTTTA-3' and probe 5'-CAAAGTCCGCCTTCAGATCCAAGGTGA-3'.
Temperature measurements. Body temperatures were measured with a digital thermometer (model 4600; Yellow Springs Instruments, Yellow Springs, OH). Surface temperatures were measured by placing the probe in the interscapular region for 30 s. Core temperatures were measured rectally.
Measurement of metabolic parameters. Inguinal, reproductive, mesenteric, and perirenal fat pads were used to determine total fat pad content. Plasma free fatty acid and triglyceride levels were measured as described (17). Plasma glucose concentrations were measured with a glucometer (Accu-chek; Roche Diagnostics, Indianapolis, IN).
For glycogen measurements, tissues were treated with potassium hydroxide, followed by saturated sodium sulfate and ethanol to isolate glycogen granules. The samples were then boiled in hydrochloric acid and neutralized with potassium hydroxide and triethanolamine. Glucose concentrations were measured with a colorimetric kit (Sigma Chemical, St. Louis, MO). The quadriceps muscles from the lower extremities were used for skeletal muscle measurements.Statistical analysis. Data are expressed as means ± SD. Measurements were compared with the two-tailed t-test or Mann-Whitney rank-sum test. For metabolic parameters involving three groups of mice, results were compared with ANOVA, followed by a post hoc Tukey-Kramer test. Correlation was determined by linear regression.
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RESULTS |
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Increased energy expenditure and resistance to
diet-induced obesity in
Dgat1(/
) mice housed at
different ambient temperatures.
To determine whether changes in the ambient temperature affected the
increased energy expenditure in Dgat1(
/
) mice, we
measured their weight loss after an 8-h fast at 4, 20, and 32°C
(thermoneutrality). Because energy intake is eliminated, the
amount of fasting-induced weight loss provides a simple approximation
of energy expenditure. As shown previously (5),
Dgat1(
/
) mice lost more weight than Dgat1(+/+) mice after an 8-h fast at 20°C (Fig.
1). Exposure to 4°C resulted in further
weight loss in both Dgat1(
/
) and Dgat1(+/+) mice, reflecting an increase in energy expenditure because of increased
heat loss in both groups of mice. When housed at 32°C to minimize
heat loss to the environment, the magnitude of fasting-induced weight
loss was reduced in both Dgat1(
/
) and
Dgat1(+/+) mice. However, Dgat1(
/
) mice still
lost more weight than Dgat1(+/+) mice after fasting at
either 4 or 32°C. Dgat1(
/
) mice fed a high-fat diet
also remained resistant to weight gain (Fig.
2A) and had ~50% less
adipose tissue than Dgat1(+/+) mice (Fig. 2B) at
32°C. These results suggest that Dgat1(
/
) mice have
increased energy expenditure across a range of ambient temperatures,
including at thermoneutrality. They provide evidence that the increased energy expenditure in Dgat1(
/
) mice does not simply
result from increased heat loss to the environment. Rather,
thermogenesis appears to be constitutively activated in
Dgat1(
/
) mice regardless of changes in the ambient
temperature.
|
|
Modulation of increased UCP1 expression in
Dgat1(/
) mice by changes in the
ambient temperature.
In rodents, thermogenesis is primarily mediated by UCP1, a brown
adipocyte protein that disrupts the mitochondrial proton gradient,
resulting in the generation of heat instead of ATP (8; also reviewed in
Ref. 13). We have shown that UCP1 expression is increased
in Dgat1(
/
) mice (5, 6). Consistent with these findings, UCP1 expression was twofold higher in
Dgat1(
/
) mice than in Dgat1(+/+) mice at
20°C (Fig. 3). At 32°C, UCP1
expression was decreased in both Dgat1(
/
) and
Dgat1(+/+) mice, although it remained significantly higher
in Dgat1(
/
) mice. At 4°C, UCP1 expression was
increased in both Dgat1(
/
) and Dgat1(+/+)
mice. However, because the magnitude of increase was greater in
Dgat1(+/+) mice, UCP1 expression levels were now similar in
Dgat1(
/
) and Dgat1(+/+) mice. These results
suggest that thermogenesis, as reflected by UCP1 expression, is
increased in Dgat1(
/
) mice at 20 and 32°C. The
difference is not observed at 4°C, perhaps because UCP1 is expressed
maximally in both Dgat1(
/
) and Dgat1(+/+) mice.
|
Increased surface body temperatures in
Dgat1(/
) mice.
To determine the effects of increased energy expenditure on
thermoregulation in Dgat1(
/
) mice, we measured the core
and surface body temperatures of Dgat1(
/
) and
Dgat1(+/+) mice. Consistent with previous findings
(7), Dgat1(
/
) and Dgat1(+/+)
mice had similar core temperatures at both 20 and 4°C (Fig.
4A). However, Dgat1(
/
) mice had higher surface temperatures than
Dgat1(+/+) mice. To determine whether this difference
resulted from active heat dissipation or impaired insulation, we placed
Dgat1(
/
) and Dgat1(+/+) carcasses at 4°C
and found that they had similar rates of decrease in core temperature
(Fig. 4B). These findings suggest that the increased surface
temperature in Dgat1(
/
) mice results from an active
process to dissipate heat rather than from impaired insulation
resulting from altered fur lipid composition.
|
Modulation of hyperphagia in
Dgat1(/
) mice by changes in the
ambient temperature.
We have shown that Dgat1(
/
) mice eat more than
Dgat1(+/+) mice at room temperature (5, 6). To
determine whether changes in the ambient temperature modulate food
intake in Dgat1(
/
) mice, we measured the daily food
consumption of Dgat1(
/
) and Dgat1(+/+) mice
housed at different temperatures. At 20°C, Dgat1(
/
) mice ate ~15% more than Dgat1(+/+) mice (Fig.
5). Both Dgat1(
/
) and
Dgat1(+/+) mice ate more in response to cold exposure, but the increase was greater in Dgat1(
/
) mice. As a result,
Dgat1(
/
) mice ate ~30% more than
Dgat1(+/+) mice at 4°C. When housed at 32°C, both
Dgat1(
/
) and Dgat1(+/+) mice reduced their
food intake, and the difference between Dgat1(
/
) and
Dgat1(+/+) mice was minimal. Thus the increased food intake
in Dgat1(
/
) mice was most pronounced at cold
temperatures.
|
Hypothermia in Dgat1(/
)
mice fasted at 4°C.
To further explore the effects of ambient temperature on energy
expenditure and food intake, we fasted Dgat1(
/
) mice at 4°C for 8 h and measured their core temperatures.
Dgat1(
/
) mice maintained relatively normal core
temperatures when fed ad libitum but developed significant hypothermia
when fasted (Fig. 6).
Dgat1(
/
) mice also had slightly lower core temperatures
than Dgat1(+/+) mice after fasting for 8 h at 20°C
(36.5 ± 0.2 vs. 37.1 ± 0.3°C, n = 5, P < 0.05). These findings indicate that food intake is essential for Dgat1(
/
) mice to maintain a normal body
temperature during exposure to cold.
|
|
Decreased plasma glucose levels in
Dgat1(/
) mice fasted at 4°C.
In contrast to the results for plasma lipids, plasma glucose levels
were significantly lower in Dgat1(
/
) mice than in
Dgat1(+/+) mice after fasting (Table 1). Calorie-restricted
Dgat1(+/+) mice also had decreased plasma glucose levels. In
addition, the severity of hypothermia in Dgat1(
/
) mice
correlated with the degree of hypoglycemia (Fig.
7). These findings suggest that the
depletion of glucose may contribute to the hypothermia in
Dgat1(
/
) mice fasted at 4°C.
|
Reduction of fasting-induced hypothermia in
Dgat1 (/
) mice after
oral feeding of glucose.
To further explore the relationship between plasma glucose levels and
thermoregulation, we fasted Dgat1(
/
) mice at 4°C for 4 h and fed them either 0.2 kcal glucose or 0.2 kcal corn oil. Oral feeding of glucose restored normal plasma glucose levels and
prevented the development of profound hypothermia in
Dgat1(
/
) mice after an additional 4 h of
fasting (Fig. 8). Oral feeding of corn
oil also increased plasma glucose levels and reduced the severity
of hypothermia in Dgat1(
/
) mice, although not to the same extent as glucose feeding.
|
Decreased glycogen content in
Dgat1(/
) mice.
Because glycogenolysis plays an important role in maintaining
euglycemia during fasting states, we hypothesized that
Dgat1(
/
) mice have decreased tissue glycogen content. In
fed mice housed at room temperature, liver glycogen content trended
lower in Dgat1(
/
) mice than in Dgat1(+/+)
mice (Fig. 9), although the difference was not significant (P = 0.06). However, skeletal
muscle glycogen content was significantly reduced in fed
Dgat1(
/
) mice. After 4 h of fasting at 4°C, liver
glycogen content was decreased in both Dgat1(
/
) and
Dgat1(+/+) mice but was ~50% lower in
Dgat1(
/
) mice. Similar findings were observed in the
skeletal muscle.
|
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DISCUSSION |
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In this study, we show that Dgat1(/
) mice had
increased energy expenditure irrespective of changes in the ambient
temperature. We also show that surface body temperature was increased
in Dgat1(
/
) mice, possibly reflecting an active
mechanism to dissipate heat from increased thermogenesis. Upon exposure
to cold, Dgat1(
/
) mice had more pronounced hyperphagia,
most likely to compensate for increased utilization of fuel substrates
for thermogenesis. This increased utilization may explain why
Dgat1(
/
) mice became hypoglycemic and hypothermic more
quickly than Dgat1(+/+) mice when fasted in a cold environment.
Energy expenditure of small mammals (such as mice) differs considerably
from that of large mammals (such as humans). For example, because of
their high surface area-to-volume ratio, mice can lose a substantial
amount of heat to the environment, and this heat loss can play an
important role in determining their rate of energy expenditure
(reviewed in Ref. 16). Our results, however, suggest that
increased heat loss to the environment is not a primary mechanism for
the increased energy expenditure in Dgat1(/
) mice.
Instead, we speculate that the increased heat loss reflects an active, compensatory process (e.g., increased vasodilatation in the skin) to
prevent hyperthermia in a state of increased thermogenesis. The
mechanism for this constitutive activation of thermogenesis in
Dgat1(
/
) mice may relate to their increased sensitivity
to leptin, an adipocyte-derived hormone that enhances UCP1 expression (8; also reviewed in Refs. 11 and 13).
Our findings also shed light on the observation of increased food
intake in Dgat1(/
) mice (5, 6). The
hyperphagia in Dgat1(
/
) mice was minimal at
thermoneutrality and accentuated by exposure to cold. This suggests
that the hyperphagia in Dgat1(
/
) mice reflects a
compensatory process for an increased demand on fuel substrates. These
results help to explain why Dgat1(
/
) mice eat more
despite an increased sensitivity to leptin (6), which
decreases food intake (reviewed in Ref. 11). Apparently, the need to replenish fuel substrates is a more powerful appetite stimulus in Dgat1(
/
) mice than the inhibitory effects of
increased leptin sensitivity on food intake.
Our results indicate that glucose plays an important role in
maintaining normal energy homeostasis in cold-exposed
Dgat1(/
) mice. The severity of hypothermia in fasted
mice correlated with plasma glucose concentrations rather than with
plasma lipid concentrations. Moreover, oral feeding of glucose restored
normal plasma levels and prevented the development of profound
hypothermia in Dgat1(
/
) mice. Oral feeding of
triglycerides (corn oil) with a comparable caloric content had a less
significant effect in ameliorating the hypoglycemia and hypothermia in
Dgat1(
/
) mice, most likely because only a relatively
small portion of the corn oil can be converted directly into glucose
(via glycerol and gluconeogenesis). These results provide evidence that
the depletion of glucose, and not calories in general, triggers the
drop in body temperature in Dgat1(
/
) mice.
Our findings are consistent with the clinical observation that
hypoglycemia is a predisposing factor for hypothermia in humans (15). At least two possible mechanisms may account for the
hypoglycemia-induced hypothermia in Dgat1(/
) mice. One
possibility is that hypoglycemia per se induces hypothermia, perhaps
through a mechanism involving the central nervous system. Another
possibility may relate to the adage "fat burns in the flame of
carbohydrates" (18). In the setting of hypoglycemia,
fatty acids may not be fully oxidized, because oxaloacetate, a major
component of the citric acid cycle, is shunted to gluconeogenesis. As a
result, acetyl-CoA derived from the breakdown of fatty acids cannot
enter the citric acid cycle by binding with oxaloacetate. In this
scenario, cellular energy metabolism is impaired, even if lipid
substrates are still readily available.
Interestingly, perilipin-deficient mice, another murine model of
increased energy expenditure, obesity resistance, and hyperphagia, also
develop profound hypothermia when fasted in a cold environment (14). It would be of interest to determine whether
increased depletion of fuel substrates also accounts for the
fasting-induced hypothermia in perilipin-deficient mice. It would also
be of interest to examine whether other murine models of increased
energy expenditure and hyperphagia, such as mice lacking protein kinase
A-RII (9) or protein tyrosine phosphatase-1B (10,
12), have a similar mechanism for their increased food consumption.
In summary, our findings offer insights into the mechanisms of
hyperphagia and increased energy expenditure in a murine model of
obesity resistance. We show that the increased energy expenditure in
Dgat1(/
) mice is not dependent on changes in the ambient temperature. Instead, Dgat1(
/
) mice appear to have a
constitutive activation of thermogenesis, which results in increased
heat dissipation to the environment. This is associated with a
dependency upon exogenous fuel sources to maintain normal body
temperature during exposure to cold. Similar mechanisms may be active
in other murine models of obesity resistance and increased energy expenditure.
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ACKNOWLEDGEMENTS |
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We thank R. Streeper for advice on glycogen measurement and helpful discussions, S. Ordway and G. Howard for editorial assistance, R. Bituin for real-time PCR studies, and K. Mulligan and M. Schambelan for comments on the manuscript.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants K08-DK-61363 (to H. Chen) and R01-DK-56084 (to R. Farese, Jr.) and the J. David Gladstone Institutes.
Address for reprint requests and other correspondence: R. V. Farese, Jr., Gladstone Institute of Cardiovascular Disease, P. O. Box 419100, San Francisco, CA 94141-9100 (E-mail: bfarese{at}gladstone.ucsf.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
September 3, 2002;10.1152/ajpendo.00248.2002
Received 6 June 2002; accepted in final form 10 September 2002.
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