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2
Departments of
*
Nutrition and
Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, Tokyo-173–0015, Japan;
**
Department of Clinical Nutrition, Tokyo Kasei University, Tokyo-173–8602, Japan; and
Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka-811–1395, Japan
2To whom correspondence and reprint requests should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • energy expenditure • insulin resistance • diurnal rhythm • insulin-dependent diabetes mellitus • obesity • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The
characteristic features of OLETF rats are late onset hyperglycemia
(
18 wk of age), followed by insulin deficiency at 65 wk
(Kawano et al. 1992
). In an original study by
Kawano et al. (1992)
, rats were divided into three
groups after a glucose tolerance test was conducted. Glucose (2 g/kg)
solution was given orally; blood glucose concentrations were measured
before the test and after 30, 60, 90 and 120 min. Rats with a peak
blood glucose concentration > 16.8 mmol/L and a blood glucose
concentration > 11.2 mmol/L at 120 min were diagnosed with
clinical diabetes mellitus (DM). Rats with either of the two conditions
were diagnosed with impaired glucose tolerance (IGT), and rats with
neither DM nor IGT were considered normal. At 23 wk of age, OLETF rats
of the normal type were not observed; 94.7% had DM and 5.2% had IGT.
On the basis of a previous study (Kawano et al. 1992
),
we considered OLETF rats at 24 wk to have NIDDM.
Obesity is a strong risk factor for diabetes in this strain
(Ishida et al. 1996
). Reduction of body weight by energy
restriction or exercise has been shown to postpone the manifestation of
diabetes (Okauchi et al. 1995
, Shima et al. 1996
). We recently found (Funakoshi et al. 1994
and 1995
) that OLETF rats lack the cholecystokinin (CCK)-A receptor
due to a genetic abnormality. The CCK-A receptor gene of rats is
10 kb in length and consists of five exons interrupted by four
introns (Takata et al. 1995
). Two exons, including the
promoter area, are missing in OLETF rats (Takiguchi et al. 1997
). CCK is one of the most abundant neurotransmitter
peptides in the brain (Dockray 1976
), and two types of
CCK receptors [type A (alimentary) and type B (brain)] have already
been cloned (Wank 1995
). In the brain, CCK-A
receptors are present only in certain regions, including the
hypothalamus (Hill et al. 1987
), and the CCK-A
receptor has been implicated in awareness of satiety (Moran et al. 1986
, Silver et al. 1989
). The disrupted
CCK-A receptor gene was considered to be one of the factors that
induce hyperphagia (Miyasaka et al. 1994
), and
hyperphagia results in obesity and induction of NIDDM.
We previously examined energy balance and the daily profile of energy
expenditure in OLETF and control [Long Evans Tokushima (LETO)] rats
at 8 and 24 wk of age. Although OLETF rats had a greater energy intake,
energy balance per day was not significantly different from that in
LETO rats (Ichikawa et al. 1998
). The diurnal rhythm of
energy expenditure associated with the highest and lowest values for
energy consumption per hour was observed over dark and light periods,
respectively, for both strains at 8 wk of age (Ichikawa et al. 1998
). Two peaks, one between 0500 and 0800 h, the other
between 2000 and 2200 h, were observed. However, these two peaks
had disappeared in OLETF rats at 24 wk of age, the time of
manifestation of NIDDM. In LETO rats, the two peaks of energy
expenditure were apparent at all ages.
In this study, we examined differences in carcass composition and in blood concentrations of glucose, in plasma concentrations of insulin, trigryceride and cholesterol in both the OLETF and LETO strains at 8 and 24 wk of age. The profiles of circadian changes in energy expenditure were analyzed by the cosinor method in both strains at 24 wk of age, and eating patterns during light and dark periods were examined. We also induced insulin deficiency [insulin-dependent diabetes mellitus (IDDM)] using STZ injection of LETO rats and compared these rats with insulin-resistant OLETF rats at 24 wk of age.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The protocol was reviewed and approved by the appropriate committee of
the Tokyo Metropolitan Institute of Gerontology. Male OLETF and LETO
(control) rats were obtained at 4 wk of age from Otsuka Research
Institute, Tokushima, Japan, and fed commercial rat food (CE-2, Clea
Japan, Tokyo). Rats were maintained in individual cages in an
air-conditioned room at 21°C with a 12-h light:dark photocycle
(lights on, 0800–2000h) at the Tokyo Metropolitan Institute of
Gerontology. At 8 and again at 24 wk of age, the rats were kept for
3 d in individual metabolic cages for simultaneous measurements of
energy balances (Ichikawa and Fujita 1987
). After the
completion of the study, at 24 wk of age, the rats were anesthetized
with ether, blood was obtained and the carcasses were examined.
Carcass composition.
To compare the age-related changes in carcass composition,
additional OLETF and LETO rats (n = 7/group) were
examined at 8 wk of age. Carcasses were frozen at -30°C. Protein and
energy contents were measured as described previously (Ichikawa and Fujita 1987
); after the completion of metabolic study,
findings were compared with those from 24-wk-old rats.
Metabolic study and determinations.
Oxygen consumption and carbon dioxide production in expired air were
measured continuously with an automatic O2-CO2
analyzer (NEC Medical Systems, model IH26, Tokyo, Japan). Energy
expenditure per hour and per day were calculated. The basal metabolic
rate (BMR) was calculated on the basis of the lowest value of energy
expenditure per hour. The sources of energy used for combustion were
estimated on the basis of the respiratory quotient (RQ) during the
metabolic study (Ichikawa and Fujita 1987
).
Samples of urine and feces were collected. The energy and fat contents of the urine, feces and food during the test period were determined by using the Kjeldahl method with an automatic bomb calorimeter (Shimazu, model CA-4, Kyoto, Japan) and a hot ether extraction apparatus (Laboman Geneco, Ex-Fat, Nihon General, Tokyo, Japan), respectively. From the values obtained, the energy balances and the apparent digestibility of the ingested food were estimated.
Rats were anesthetized with ether between 0900 and 1100 h without
prior food deprivation. Blood samples were drawn from the abdominal
aorta into heparinized syringes. The blood glucose concentrations were
measured immediately by the glucose oxidase method. To measure plasma
triglyceride and cholesterol, the rest of the blood was mixed with EDTA
and centrifuged at 1500 x g for 15 min at 4°C;
the plasma was frozen at -30°C. Plasma cholesterol and triglyceride
were measured by enzymatic analysis (Allain et al. 1974
,
Fossati and Prencipe 1982
). Plasma insulin was measured
by RIA (Funakoshi et al. 1996
) with rat insulin as a
standard.
Induction of IDDM in LETO rats.
To induce IDDM in LETO rats, streptozotocin (STZ; 60 mg/kg in 0.2 mL
citrate buffer; Sigma Chemical, St. Louis, MO) (Yamanouchi et al. 1997
) was injected intraperitoneally at 12 wk of age. The
rats were maintained until 24 wk of age at which time the metabolic
study was conducted.
Statistical analysis.
Values are expressed as means ± SEM. All results,
except those for the daily profiles, were analyzed by one-way ANOVA
with respect to strain or treatment, or two-way ANOVA with respect
to age and strain, followed by Fisher’s Least Significant Difference
means comparison; a P-value < 0.05 was considered
significant. When variances were unequal, the Kruskal-Wallis test
was used instead of one-way ANOVA to analyze some of the results
shown in Table 1
. The daily profiles of energy expenditure were analyzed by the cosinor
method. A 24-h cosine curve was fitted to the data series
(Halberg et al. 1967
, Ichimaru 1993
).
"Acrophase" represents the time that shows the highest value of the
fitting curve, "Mesor" indicates the time-adjusted mean value
and "Amplitude" is the amplitude of the cosine curve (Fig. 1
). A probability of < 0.01 was considered to signify goodness of
fit.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Body weight was significantly greater in OLETF than in LETO rats at all
points after 5 wk of age (Fig. 2
), and daily energy intake was significantly greater in OLETF rats than
in LETO rats throughout the experiment (Table 1)
. However, energy
intake per unit body weight was not different between strains because
OLETF rats were much heavier than LETO rats (Table 1)
.
|
Absolute contents of fat, water and protein, but not ash, were
significantly higher in OLETF than in LETO rats at 8 wk of age
(Table 2
). However, at 24 wk of age, fat and protein contents were significantly
greater in OLETF than in LETO rats, whereas water content did not
differ between strains. Thus, absolute and relative fat weights were
significantly greater in OLETF than LETO rats at 8 and 24 wk of age.
|
Energy consumption profiles over 24-h test periods in LETO rats at 24
wk of age revealed a circadian rhythm with two peaks, one between 0500
and 0800 h, the other between 2000 and 2200 h (Fig. 3
, upper panel). However, the two peaks were not apparent in
24-wk-old OLETF rats (Fig. 3
, middle panel).
|
. When
we examined circadian changes in total, carbohydrate and fat metabolism
by the cosinor method, we found that total energy metabolism and energy
derived from carbohydrate determined the rhythm. The typical patterns
are shown in Figure 4
. The mesor values of energy expenditure in the LETO and OLETF rats were
8.5 and 9.7 kJ/h, respectively (Fig. 4)
. LETO and OLETF rats showed the
same acrophase (LETO, -0.22 rad; OLETF, -0.22 rad). The acrophase of
carbohydrate metabolism differed between the strains (Fig. 4)
. However,
the profile of energy expenditure derived from fat did not exhibit a
rhythm in either strain (Fig. 4)
.
|
The lowest energy expenditures were observed during the light period
(actually, 1200–1400 h), during which time the rats were usually
sleeping. Therefore, the lowest value was used as the BMR. BMR (kJ/d)
was significantly higher in OLETF than LETO rats; however, when
expressed per unit body, BMR was significantly lower in OLETF than LETO
rats at 24 wk of age (Table 1)
. Total energy expenditure per day did
not differ between strains, whereas that per unit body weight was
significantly lower in OLETF than LETO rats (Table 1)
.
Energy contents of the urine and feces, energy balance and
digestibility did not differ significantly between strains (Table 1)
.
The percentage of energy expenditure derived from fat, when estimated
by the RQ, was significantly greater in OLETF than LETO rats (Table 1)
,
although that derived from carbohydrate did not differ between strains.
The blood glucose concentrations did not differ between the strains at
8 wk of age (LETO and OLETF, 8.50 ± 0.21 and 7.30 ± 0.65
mmol/L, respectively). On the other hand, the blood glucose, plasma
insulin, triglyceride and cholesterol concentrations were significantly
higher in OLETF than in LETO rats at 24 wk of age (Table 3
).
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Despite their high energy intake, STZ-treated LETO rats had lower
body weights and lower energy balance than nontreated LETO and OLETF
rats because of the high energy content in the urine and feces, and
lower BMR relative to body weight (Table 1)
. Blood glucose levels were
significantly higher and the plasma insulin levels were significantly
lower in STZ-treated LETO rats than in normal LETO and OLETF rats
at 24 wk (Table 3)
. The plasma levels of triglyceride and cholesterol
were also higher than normal (LETO) rats at 24 wk of age (Table 3)
.
A peak of energy expenditure during the early part of the dark period
was apparent in STZ-treated LETO rats, although the peak preceding
the light period (between 0500–0800 h) was not present (Fig. 3)
. The
rhythm of total energy expenditure demonstrated a circadian change when
analyzed by the cosinor method [acrophase, 0.86 rad (20:42 h); mesor,
6.6 kJ/h]. The pattern was significantly different from that of the
other two groups (Fig. 4)
. The diurnal rhythm of energy consumption
derived from carbohydrates showed an acrophase of -2.46 rad (14:35 h),
whereas the rhythm derived from fat demonstrated an acrophase of 0.28
rad (22:55 h), as shown in Figures 3
and 4
, respectively.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. This result is
consistent with previous evidence that NIDDM is associated with
hyperinsulinemia and hyperglycemia resulting from an increase in
peripheral insulin resistance, which was manifested in OLETF rats at 24
wk of age (Ishida et al. 1996
, Kawano et al. 1992
). On the other hand, the amount of energy derived from fat
for daily combustion was further increased in STZ-treated LETO
rats (with IDDM), in response to absolute deficiency of insulin.
BMR (kJ/d) was significantly higher in OLETF than in LETO rats at 24 wk
of age. It has been reported that the higher BMR is related to an
increase in fat-free mass (Ravussin et al. 1982
). The increase in BMR (kJ/d) may be due to greater
body protein mass (Table 2)
. On the other hand, BMR per kilogram body
did not differ between strains (Table 1)
. This may be explained by the
accumulation of fat mass in OLETF rats.
When the energy sources were calculated, energy derived from carbohydrate determined the circadian rhythm, but the energy expenditure fueled by fat was not different between strains at 24 wk of age. The percentage of food intake during light and dark periods in OLETF rats at 24 wk of age did not differ from that in LETO rats. Therefore, the reason why the original two peaks were not apparent was unknown, although the eating behavior during the dark period might have changed.
The diurnal rhythm in STZ-treated LETO rats was completely
different from that in healthy LETO rats or OLETF rats with NIDDM.
Total energy metabolism exhibited a diurnal rhythm (Fig. 3)
, but only
one peak was observed, between 1400 and 1800 h. The energy derived
from fat, not from carbohydrate, determined the diurnal rhythm (Fig. 4)
. The acrophase of utilization of carbohydrate as an energy
source occurred earlier than that of utilization of fat in
STZ-treated LETO rats, indicating that the decrease of blood
glucose utilization and compensatory increase of fat utilization
occurred during the dark period. These observations are explained by
the findings that STZ-treated LETO rats showed a greater blood
glucose concentration and less plasma insulin than normal LETO rats;
utilization of carbohydrates for combustion was not effective, due to
absolute insulin deficiency. The eating behavior in this group was not
recorded, but in alloxan- or STZ-induced diabetes, the rats are
hyperphagic, with increased food intake during the light period
(Reuterving and Hagg 1987
).
Recent reports have shown that diabetic animals exhibit abnormalities
in the circadian rhythms of plasma levels of corticosterone, locomotor
activity, and eating and drinking under the light/dark cycle
(Hansen et al. 1996
, Reuterving and Hagg 1987
, Stephan et al. 1972
, Velasco et al. 1988
and 1993
). Moreover, the level of
light-induced Fos expression in the suprachiasmatic nucleus (SCN)
is decreased in diabetic (IDDM) rats (Nagai et al. 1994
and 1996
, Stoynev and Ikonomov 1982
,
Yamanouchi et al. 1997
). The mammalian SCN is the center
of the circadian timing system. CCK-A receptors locate in the
hypothalamus in normal rats (Hill et al. 1987
).
Yamanouchi et al. (1997)
and Shimazoe et al. (1999)
reported a decrease in Fos expression or lowered
entrainment function in the SCN of OLETF rats. However, in examining
the diurnal rhythm of energy expenditure, it is suggested that the
absence of the CCK-A receptor may play only a minor role. Moreover,
the condition of NIDDM in OLETF rats at 24 wk of age produced only a
minor modification of the circadian rhythm of energy metabolism,
whereas the presence of IDDM led to dramatic changes in energy
expenditure rhythm.
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FOOTNOTES |
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3 Abbreviations used: BMR, basal metabolic rate; CCK, cholecystokinin; DM, diabetes mellitus; IDDM, insulin-dependent diabetes mellitus; IGT, impaired glucose tolerance; LETO, Long Evans Tokushima; NIDDM, noninsulin-dependent diabetes mellitus; OLETF, Otsuka Long Evans Tokushima Fatty; RQ, respiratory quotient; SCN, suprachiasmatic nucleus; STZ, streptozotocin.
Manuscript received November 12, 1999. Initial review completed January 19, 2000. Revision accepted June 13, 2000.
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