Exp. Anim. 59(5), 623–630, 2010
The Influence of Dietary Restriction on the
Development of Diabetes and Pancreatitis
in Female WBN/Kob-Fatty Rats
Toshio AKIMOTO1), Misao TERADA1), Akira SHIMIZU2),
Nobuhiko SAWAI 3), and Hitoshi OZAWA3)
1)Division of Laboratory Animal Science, 2)Department of Analytic Human Pathology, and
3)Department of Anatomy and Neurobiology, Nippon Medical School,
1–1–5 Sendagi, Bunkyo ku, Tokyo 113-8602, Japan
Abstract: Original WBN/Kob male rats commonly develop chronic pancreatitis by the age
of 3 months, while diabetes mellitus occurs at 9 months. In contrast, female rats of this strain
do not show pancreatitis or diabetes. The WBN/Kob-fatty rat is a homozygous (fa/fa) congenic
strain for the fa allele of the leptin receptor gene (Lepr). In WBN/Kob-fatty rats, both females
and males provide a model of non-insulin-dependent diabetes with obesity. The leptin receptor
fatty gene (Leprfa) induces obesity and hyperphagia. In the present study, we examined the
effect of dietary restriction on pancreatitis and diabetes in female WBN/Kob-fatty rats. Five
female fatty rats comprised a restricted feeding group with paired-feeding from 3 to 13 weeks
of age, and five female lean rats comprised a control group with paired-feeding. At 13 weeks
of age, two of the five female fatty rats of the control group developed diabetes mellitus, while
no female fatty rats of the restricted feeding group developed diabetes mellitus. At this stage,
pathological changes of the pancreas were observed in female fatty rats. All female fatty
rats showed severe interlobular, intra-lobular and intra-islet fibrosis. In female fatty rats of
the restricted feeding group, pathological changes of the pancreas were milder those of the
free-feeding fatty group. Although dietary restriction could not completely prevent pancreatitis
in female fatty rats, the development of diabetes was inhibited by its reduction of the severity
Key words: diabetes, leptin receptor, obesity, pancreatitis, WBN/Kob rat
(Received 2 April 2010 / Accepted 30 June 2010)
Address corresponding: T. Akimoto, Division of Laboratory Animal Science, Nippon Medical School, 1–1–5 Sendagi, Bunkyo ku, Tokyo 113-8602,
The WBN/Kob-fatty rat is a homozygous (fa/fa) con-
genic strain for the fa allele of the leptin receptor gene
(Lepr). The leptin receptor fatty gene (Leprfa) is a reces-
sive mutation that leads to leptin receptor deficiency, and
homozygous animals (fa/fa) show obesity, hyperphagia,
insulin resistance, hyperinsulinemia, and glucose intol-
erance [5, 15, 23, 27, 28, 31]. Zucker diabetic fatty rats
are homozygous for the fa allele of the leptin receptor
gene and develop type 2 diabetes with obesity. Type 2
diabetes is a metabolic syndrome caused by an imbalance
between insulin secretion by β-cells and the insulin sen-
sitivity of peripheral tissues. There are many animal
T. AKIMOTO, ET AL.
models in which diabetes mellitus develops spontane-
ously, and its onset is usually secondary to hypoinsuline-
mia. In various strains of rat, obesity and insulin resis-
tance secondary to leptin receptor deficiency induce
diabetes [7, 11, 17, 19]. Original WBN/Kob male rats
spontaneously develop diabetes, although its onset is
secondary to chronic pan-pancreatitis [2, 13, 20, 22, 24,
29]. In contrast, female rats of this strain do not show
pancreatitis or diabetes. Male rats of this strain com-
monly develop chronic pancreatitis by the age of 3
months [2, 13, 20, 22], while diabetes mellitus (charac-
terized by hyperglycemia, hypoinsulinemia, and glyco-
suria) occurs at 9 months of age [20, 22, 29]. In WBN/
Kob-fatty rats, both females and males provide a model
of non-insulin-dependent diabetes with obesity .
WBN/Kob-fatty rats commonly develop pancreatitis and
show reduced glucose tolerance at the age of 7–9 weeks.
WBN/Kob-fatty rats develop diabetes mellitus by the
age of 3–4 months .
In the present study, we examined the inhibitory effect
of dietary restriction on diabetes in female WBN/Kob-
Materials and Methods
WBN/Kob-fatty (fa/fa) and WBN/Kob-lean (+/fa, +/+)
rats were produced by mating heterozygous (+/fa) males
with heterozygous (+/fa) females of the WBN/Kob-
Leprfa strain. WBN/Kob-Leprfa strain was established
by introducing the leptin receptor fatty gene (Leprfa) of
the Zucker fatty rat into the original WBN/Kob rat ge-
nome . Ten female fatty rats and five female lean rats
aged 3 weeks were used. The ten female fatty rats were
subdivided into two groups [fatty and fatty-restricted
(FR)]. FR rats were subjected to restricted feeding with
paired-feeding. Five female lean rats were used as the
control group with paired-feeding. The daily food intake
of female lean rats was measured. On the next day, the
same volume of food consumed by the female lean rats
was fed to the restricted feeding group. The animals
were given a commercial diet (MF, Oriental Yeast Co.,
Tokyo, Japan) and tap water, and were housed in an air-
conditioned room (24 ± 2°C, 50–60% relative humidity,
and lights on for 14 h per day from 6:00 to 20:00).
Female fatty rats and female lean rats were checked
for rectal temperature and glycosuria using a Tes-Tape
(Shionogi & Co., Tokyo, Japan), and blood glucose lev-
els were measured using a portable glucose meter (As-
censia Breeze, Bayer-Sankyo, Osaka, Japan). Detection
of glycosuria was used as a diagnosis of diabetes. At 13
weeks of age, animals from the lean, fatty and FR groups
were anesthetized with ether; they were weighed, had
their body lengths measured (from anus to nose), and
were then exsanguinated. Organs, including the gastroc-
nemius muscle, retroperitoneal fat pad, liver, kidney,
adrenal glands, spleen, pancreas, ovary, and uterus were
removed and weighed.
The pancreas was removed, fixed overnight in Bouin's
solution, and embedded in paraffin for histopathological
studies. Serial 4-µm sections were cut and then stained
with hematoxylin-eosin for histological examination.
Data are expressed as the mean ± SD. ANOVA and
the Tukey’s HSD (Honestly Significant Difference) test
were used to analyze differences among groups, and
P<0.05 was considered to be significant.
This study was approved by the Animal Experiments
Ethical Review Committee of Nippon Medical School.
The progress of daily food intake and body weight
during dietary restriction are shown in Fig. 1. From 3
to 7 weeks of age, the daily food intake of FR rats in-
creased, while after 7 weeks the daily food intake re-
mained constant. FR rats had a significantly lower body
weight than to lean female rats from 27 to 59 days
(P<0.05). At 13 weeks of age, the body weights of FR
rats and lean rats were significantly lower than that of
fatty rats (P<0.05) (Fig. 2A). The body length of FR
rats was significantly smaller than that of lean rats, while
the body length of lean rats was significantly smaller
than that of fatty rats (P<0.05) (Fig. 2B). The body mass
index of FR rats was significantly higher than that of
DIETARY RESTRICTION ON FEMAlE WBN/KOB-FATTY RATS
Fig. 1. Progress of daily food intake and body weight during dietary restriction. The columns indicate
daily food intake of female fatty rats in the dietary restriction group. Circles and triangles indicate
body weight of female lean rats and dietary restriction group rats, respectively. Data are expressed
as the mean ± SD. (n=5). Asterisks indicate significant differences (P<0.05) between rats of the
lean group and fatty rats of the dietary restriction group.
lean rats, and significantly lower than that of fatty rats
(P<0.05) (Fig. 2C). The rectal temperature of FR rats
was not significantly lower than that of either lean rats
or fatty rats (Fig. 2D). The blood glucose levels of FR
rats and lean rats were not significantly lower than that
of fatty rats (Fig. 2E). Glycosuria was detected in two
of the five fatty rats (Fig. 2F). The weight of the gas-
trocnemius muscle in FR rats was significantly lower
than those of lean rats and fatty rats (P<0.05) (Fig. 3A).
The total weight of the retroperitoneal fat pad in FR rats
was significantly higher than that of lean rats, and sig-
nificantly lower than that of fatty rats (P<0.05) (Fig. 3B).
The weight of the liver in FR rats and lean rats was
significantly lower than that of fatty rats (P<0.05) (Fig.
3C). The total weight of the kidney in FR rats was sig-
nificantly lower than that of lean rats, and in lean rats
was significantly lower than that of fatty rats (P<0.05)
(Fig. 3D). The total weight of the adrenal organ in FR
rats was not significantly lower than that of either lean
rats or fatty rats (Fig. 3E). The weight of the spleen in
FR rats was significantly lower than those of lean rats
and fatty rats (P<0.05) (Fig. 3F). The weight of the
pancreas in FR rats was significantly lower than that of
lean rats (P<0.05) (Fig. 3G). The total weight of the
ovary in FR rats was significantly lower than that of
either lean rats or fatty rats (P<0.05) (Fig. 3H). Addi-
tionally, the weight of the uterus in FR rats was signifi-
cantly lower than that of lean rats (P<0.05) (Fig. 3I).
Histological findings of the pancreas are shown in Fig.
4. At 13 weeks of age, three of the five FR rats showed
pathological changes related to mild chronic pancreati-
tis, while all fatty rats showed pathological changes
related to severe chronic pancreatitis. FR rats showed
only focal interstitial edema and fibrosis with mild in-
flammatory cell infiltration in interlobular, intra-lobular
and intra-islet areas (Fig. 4C and 4D). At this stage,
fatty rats showed severe inflammatory cell infiltration
fibrosis, extra hemorrhage and hemosiderin deposition
in interlobular, intra-lobular and intra-islet areas (Fig.
4E and 4F). The pancreata of lean rats, including islets
T. AKIMOTO, ET AL.
and pancreatic acini, were normal (Fig. 4A and 4B). The
degree of pancreatitis for each group was described as
the percentage of lesion area (Fig. 5). The percentage
of area with histopathological abnormalities in FR rats
was significantly lower than that in fatty rats (P<0.05).
FR rats had a significantly lower body weight than
lean rats from 27 to 59 days. At 13 weeks of age, the
body weights and liver weights of FR rats were similar
to those of lean rats. The BMI and weight of the retro-
peritoneal fat pads of FR rats were significantly higher
than those of lean rats and significantly lower than those
of fatty rats. Other organ weights (gastrocnemius mus-
cle, adrenal, spleen, pancreas, ovary, and uterus) and the
body length of FR rats were lower than those of lean rats
and fatty rats. With respect to relative organ weight per
body weight, the gastrocnemius muscle, adrenal glands
and pancreas, ovary and uterus of FR rats were greater
than those of fatty rats (data not shown). Fatty rats had
markedly higher body weights than FR rats. The relative
weight per body weight for other organs showed a ten-
dency to be the same as the organ weight (data not
At 13 weeks of age, the body weight of fatty rats was
greater than that of lean rats allowed the same food con-
sumption (data not shown). The body weights of mature
Zucker fatty rats are greater than those of lean rats when
given the same caloric intake . Therefore, the pe-
riod of paired-feeding employed in this experiment was
maintained up to 13 weeks of age to eliminate any dif-
ferences in body weight between FR rats and lean rats.
Female WBN/Kob-fatty rats were obese and devel-
oped pancreatitis and diabetes . At 13 weeks of age,
two of the five female fatty rats had developed diabetes
mellitus, while no female fatty rats developed diabetes
mellitus in the restricted feeding group. At this stage,
Fig. 2. Body growth parameters and diabetes of the three groups at 13 weeks of age. Body
weight (A); body length (B); body mass index (weight in g)/(height in centimeters)2
(C); rectal temperature (D); blood glucose levels (E); incidence rate of glucosuria
(F). Data are expressed as the mean ± SD. (n=5). Asterisks indicate significant
DIETARY RESTRICTION ON FEMAlE WBN/KOB-FATTY RATS
pathological changes of the pancreas were observed in
all the female fatty rats. All female fatty rats showed
severe interlobular, intra-lobular and intra-islet fibrosis.
In female fatty rats of the restricted feeding group,
pathological changes of the pancreas were milder com-
pared with those of the free-feeding fatty group. Obe-
sity was recently proposed as a risk factor for acute
pancreatitis . Furthermore, several studies have
shown that obesity is strongly associated with the onset
of complications and increased mortality in patients with
acute pancreatitis [8, 18], and a decreased survival rate
has been reported in genetically obese Zucker rats fol-
lowing induction of experimental acute pancreatitis .
These results suggest that obesity could accelerate pan-
creatitis in WBN/Kob-fatty rats. In the present study,
dietary restriction controlled obesity in female WBN/Kob-
fatty rats. Thus, pancreatitis was alleviated by dietary
restrictions applied to female WBN/Kob-fatty rats.
Fig. 3. Organ weights of the three groups at 13 weeks of age. Gastrocnemius (A); retroperito-
neal fat pads (B); liver (C); kidney (D); adrenal (E); spleen (F); pancreas (G); ovary (H);
uterus (I). Data are expressed as the mean ± SD. (n=5). Asterisks indicate significant
T. AKIMOTO, ET AL.
In the present study, female WBN/Kob-fatty rats de-
veloped diabetes at three months of age, as observed in
lean male WBN/Kob rats at 9 months of age . Obe-
sity and hyperphagia accelerate and/or promote the de-
velopment of pancreatitis and diabetes in this strain. The
leptin receptor fatty gene (Leprfa) induces insulin resis-
tance and hyperinsulinemia . Hyperinsulinemia in
Zucker fatty rats is not affected by dietary restriction ,
but dietary restriction retards the decrease of serum in-
sulin levels in male SDT-fatty rats, which are derived
from a strain congenic for the leptin receptor fatty gene
. At 12 weeks of age, a dietary restriction group of
male SDT-fatty rats showed hyperinsulinemia. This in-
dicates that dietary restriction dose not affect insulin re-
sistance caused by the leptin receptor fatty gene (Leprfa).
Furthermore, dietary restriction retards increase of blood
glucose levels in male SDT-fatty rats . In female
WBN/Kob-fatty rats, lesions of the pancreas were re-
Fig. 4. Histopathology of the pancreas of the three groups at 13 weeks of age. Female lean rats (a,
b); female fatty-restricted rats (c, d); female fatty rats (e, f). Paraffin sections of pancreata
were prepared and stained with hematoxylin and eosin. Bar= 100 µm. The pancreata of lean
rats, including islets and pancreatic acini, were normal (a, b). FR rats showed only a focal
interstitial edema and fibrosis with mild inflammatory cell infiltration in interlobular, intra-
lobular and intra-islet areas (c, d). Fatty rats showed severe inflammatory cell infiltration fi-
brosis, extra hemorrhage and hemosiderin deposition in interlobular, intra-lobular and intra-
islet areas (e, f).
DIETARY RESTRICTION ON FEMAlE WBN/KOB-FATTY RATS
duced by dietary restriction. These findings suggest that
blood glucose levels and insulin secretion were main-
tained by reduction of pancreatitis in FR rats. Two of
the five fatty rats developed diabetes, while none of the
five FR rats developed diabetes. Although there was no
significant difference between the onset of diabetes in
the two groups, we consider the development of diabetes
in FR rats was inhibited by the reduction in severity of
The growth curve, body weight, body length and organ
weights of FR rats were similar to those of restricted
Zucker fatty rats . Although the adipose deposit
weight of restricted Zucker fatty rats was higher than
that of lean rats, the weights of other organs in restricted
Zucker fatty rats were lower than those of lean rats .
The leptin receptor fatty gene responds to caloric restric-
tion with preservation of fat cell volume. Thus, the in-
hibition of obesity and fat deposition were incomplete
in the FR rats, although the body weight of female WBN/
Kob-fatty rats was controlled by dietary restriction.
Acute pancreatitis leads to increased production of
TNFα  by macrophages and pancreatic acinar cells
, as well as the premature activation of enzymes
within acinar cells and the destruction of pancreatic tis-
sue . In caerulein-induced pancreatitis (CIP), plas-
ma leptin levels are increased and the onset of pancrea-
titis is accompanied by increased pancreatic expression
of the leptin gene . In CIP rats, leptin decreases the
plasma level of TNFα and increases the plasma level of
IL-4, an anti-inflammatory cytokine . Furthermore,
Jaworek et al. suggested that leptin protects the pan-
creas by the inhibiting of pancreatic enzyme secretion
. In the present study, dietary restrictions did not
completely prevent pancreatitis in female WBN/Kob-
fatty rats. These findings suggest that lack of leptin
protection may accelerate the development of pancrea-
titis in WBN/Kob-fatty rats.
In summary, dietary restriction inhibited body weight,
hyperphagia and diabetes. Based on the relationship
between obesity and histological changes of the pan-
creas in female WBN/Kob-fatty rats, it appears that dia-
betes was secondary to severe degeneration of the islets
of langerhans due to diffuse pancreatitis. Thus, diabe-
tes in FR rats was inhibited by the reduction in severity
of pancreatitis. However, inhibition of pancreatitis,
obesity and fat deposition was incomplete in FR rats.
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