Metabolic syndrome signs in Wistar rats submitted to different high-fructose

ingestion protocols

Rodrigo Ferreira de Moura1, Carla Ribeiro1, Juliana Aparecida de Oliveira2, Eliane Stevanato2 and

Maria Alice Rostom de Mello1*
1Physical Education Department, São Paulo State University (UNESP), Avenida 24-A, 1515 Bela Vista, 13506-900 Rio Claro,

SP, Brazil
2Physical Education Department, University of Taubaté (UNITAU), Rua Terras de Cambra 27, 04383-145 São Paulo, SP, Brazil

(Received 7 January 2008 – Revised 17 July 2008 – Accepted 18 July 2008 – First published online 14 November 2008)

In search of an adequate model for the human metabolic syndrome, the metabolic characteristics of Wistar rats were analysed after being submitted

to different protocols of high fructose ingestion. First, two adult rat groups (aged 90 d) were studied: a control group (C1; n 6) received regular

rodent chow (Labina, Purina) and a fructose group (F1; n 6) was fed on regular rodent chow. Fructose was administered as a 10% solution in

drinking water. Second, two adult rat groups (aged 90 d) were evaluated: a control group (C2; n 6) was fed on a balanced diet (AIN-93G) and

a fructose group (F2; n 6) was fed on a purified 60% fructose diet. Finally, two young rat groups (aged 28 d) were analysed: a control group

(C3; n 6) was fed on the AIN-93G diet and a fructose group (F3; n 6) was fed on a 60% fructose diet. After 4–8 weeks, the animals were eval-

uated. Glucose tolerance, peripheral insulin sensitivity, blood lipid profile and body fat were analysed. In the fructose groups F2 and F3 glucose

tolerance and insulin sensitivity were lower, while triacylglycerolaemia was higher than the respective controls C2 and C3 (P,0·05). Blood total

cholesterol, HDL and LDL as well as body fat showed change only in the second protocol. In conclusion, high fructose intake is more effective at

producing the signs of the metabolic syndrome in adult than in young Wistar rats. Additionally, diet seems to be a more effective way of fructose

administration than drinking water.

Fructose: Metabolic syndrome: Insulin sensitivity: Body fat

Clinically, the metabolic syndrome involves a cluster of dis-
turbances in which glucose intolerance represents an important
symptom. Metabolic syndrome diagnosis implies in positive
results to at least three metabolic alterations including insulin
resistance, hypertension, obesity, endothelial dysfunction and
blood lipid profile alterations(1,2). These multiple risk factors
accelerate the incidence of CVD in a cooperative way(1–4).
Obesity prevalence has quadrupled in the past 25 years in

the USA; 16% of children and 30% of adults are now affected
and many of these obese individuals suffer from the metabolic
syndrome(5). Projections estimate that, in the year 2010, there
will exist 50–75 million individuals with manifestation of this
syndrome in this country alone(6).
The increased fructose consumption in contemporaneous

Western society has been associated with the high prevalence
of non-alcoholic fatty liver disease (NAFLD)(7), obesity, type
2 diabetes andmetabolic syndrome so far(8,9). In fact, laboratory
animals fed on fructose-rich diets show glucose intolerance,
insulin resistance, hyperinsulinaemia and dyslipidaemia(10).
A high flux of fructose to the liver perturbs glucose metabolism
and glucose uptake pathways, and leads to a significantly
enhanced rate of lipogenesis and TAG synthesis, driven by the

high flux of glycerol and acyl portions of TAG molecules from
fructose catabolism(11–13). These metabolic disturbances
maybe underlie the induction of insulin resistance, commonly
observed with high fructose feeding in both human subjects
and animal models(14). Since fructose-fed rats reveal signs of
the metabolic syndrome, they are used as an experimental
model of the human condition(15).

The metabolic alterations observed in fructose-fed rats are
quite divergent among the studies, probably due to study
design. Differences between studies include: the strain of
rat used, such as Wistar(16,17) and Sprague–Dawley(18,19);
the amount and route of fructose administration – diet
(60%)(16,19), oral administration (8 g/kg)(17) or drinking water

(10%)(19); the age of the animals at the beginning of the exper-

iment – young(16,17) or adults(19). Also, the period of fructose
administration applied has been non-standard: from 4(17), 6(18)

or 8 weeks(19) or during several months(18). Natural variation
of the control diet is another potential problem of animal studies.
It can be a particular problemwith non-purified diets, but the use
of synthetic diets is largely described in the literature(20). There-
fore, different experimental designs for fructose administration
in rats induce variable degrees of physiological responses.

*Corresponding author: Dr Maria Alice Rostom de Mello, fax þ55 19 3526 4320, email mellomar@rc.unesp.br

Abbreviations: C1, experiment 1 control group; C2, experiment 2 control group; C3, experiment 3 control group; F1, experiment 1 fructose group; F2, experiment 2

frustose group; F3, experiment 3 fructose group; NAFLD, non-alcoholic fatty liver disease.

British Journal of Nutrition (2009), 101, 1178–1184 doi:10.1017/S0007114508066774
q The Authors 2008

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



In the search of an adequate experimental model to simulate
the human metabolic syndrome, the present study was designed
to analyse the metabolic characteristics of Wistar rats submitted
to high fructose ingestion by different protocols.

Methods

Animal care and experimental design

Male Wistar rats were obtained from the São Paulo State Uni-
versity (UNESP Central Bioterium, Botucatu Campus, SP,
Brazil). The rats were kept in a room with the temperature
set to 25 ^ 1 8C and with a photoperiod of 12 h–12 h at the
Physical Education Department Biodynamic laboratory of
UNESP (Rio Claro campus, São Paulo, Brazil). Free access
to water and food was provided. All experiments were per-
formed in accordance with the European Convention for the
Protection of Vertebrate Animals used for Experimental and
other Scientific Purposes (Council of Europe no. 123, Stras-
bourg 1985).

The animals were separated at random and the studies were
carried out in three separated series of experiments. In the
first, two groups of adult rats were studied: the control
group (C1; n 6) received regular rodent chow (57·3% carbo-
hydrate, 41·2% as starch, Labina; Purina, São Paulo, Brazil)
and the fructose group (F1; n 6) was fed on a regular rodent
chow and 10% of drinking water was composed of fructose
solution. Both groups started the experiment aged 90 d and
the follow-up was done for 8 weeks.

In the second experiment, two groups of adult rats were also
evaluated: the control group (C2; n 6) was fed on a purified
balanced diet (AIN-93G)(21) and a fructose group (F2; n 6)
was fed on a purified 60% fructose diet (Table 1). Both
groups started the experiment at age 90 d and the follow-up
was done for 4 weeks.

Two groups of young rats were analysed in the third exper-
iment: the control group (C3; n 6) was fed on a balanced AIN-
93G diet and the fructose group (F3; n 6) was fed on a 60%
fructose diet. Both groups started the experiment at age 28 d
and the follow-up was done for 8 weeks.

All animals were weighed and measured (nose to anus
length) once per week. At the end of the experimental
period, the Lee index was calculated(22) (by dividing the
cubic root of the final body weight (g) by the final body
length (cm) and multiplying by 1000). This index for rats is
equivalent to the human BMI.

The vessels containing the diets and the bottle of water were
refilled each 2 d. Once per week, the differences between the
full vessels or full bottles and the content 24 h later were con-
sidered as the amount consumed and were registered. The
average amount of fructose ingested was calculated as 60%
of diet (experiments 2 and 3) or 10% of the water ingested
during the whole period (experiment 1).

Oral glucose tolerance test

At the end of each experiment, the rats were fasted for 15 h.
Glucose was administered into the stomach of the rats through
a gastric catheter at the final dose of 2·0 g/kg body weight.
Blood samples for serum glucose determination were obtained
from a cut at the tip tail at 0, 30, 60 and 120min. Serum glu-
cose determination was made by the glucose oxidase method
(Laborlab Kit; Guarulhos, SP, Brazil)(23). The glycaemic
response during the oral glucose tolerance test was
evaluated by the total area under the serum glucose curve
using the trapezoidal method(24).

Subcutaneous insulin tolerance test

At the end of all experimental series, subcutaneous insulin tol-
erance tests were performed for peripheral insulin sensitivity
evaluation. The insulin tolerance tests consisted of a bolus
injection of regular insulin at the dorsal region (30mU/g
body weight). Blood samples were obtained from a cut at
the tip tail at 0, 30, 60 and 120min for serum glucose deter-
mination by the glucose oxidase method (Laborlab Kit)(23).
A constant for serum glucose disappearance (Kitt) was calcu-
lated from the formula 0·693/t1/2. The serum glucose t1/2 was
calculated from the slope of the least square analysis of serum

glucose concentration from 0–30min after insulin injection,

when serum glucose concentration decreased linearly(25).

Blood chemistry and body fat

Because of multiple aspects involving insulin sensitivity
evaluation, the fasting insulin concentration was also assessed.

All animals were killed by decapitation and trunk blood was
collected for serum TAG, total cholesterol, HDL-cholesterol,
LDL-cholesterol and glucose determinations by colorimetric
procedures(26). Retroperitoneal, mesenteric (visceral) and sub-
cutaneous posterior fat depots were excised and weighed
according to Cinti(27). Liver total lipid concentration(26) was
also determined.

Statistics

In each experiment, the values of weight and body length
throughout the period of dietary intake were analysed by
two-way ANOVA. All the other results were analysed statisti-
cally by the unpaired Student’s t test. A level of 5% was taken
for statistical significance.

Results

The weight and body-length values in the first experiment are
shown in Fig. 1. No difference was revealed.

Table 1. Composition of the balanced and fructose-rich diets

Ingredient (g/kg) AIN-93G Fructose diet

Casein 202 202
Maize starch 397 –
Dextrinised maize starch 130·5 –
Sucrose 100 27·5
Fructose – 600
L-Cysteine 3 3
Soyabeans 70 70
Mineral mix (AIN-93G)* 35 35
Vitamin mix (AIN-93)* 10 10
Fibre 50 50
Choline chlorhydrate 2·5 2·5

* See Reeves et al.(21).

Metabolic syndrome signs in Wistar rats 1179

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



Data from the first series are displayed in Table 2. No
metabolic difference was observed between control (C1) and
fructose-fed (F1) rats in any of the parameters evaluated.
The average amount of fructose ingested corresponded to
1·74 g/100 g body weight per d.
No differences were observed in weight or body-length

values in the second experiment (Fig. 2).
The data of the second experiment are shown in Table 3.

The fructose group (F2) presented higher values for the
area under the serum glucose curve during glucose tolerance
tests when compared with the control group (C2). Rats of the
F2 group developed insulin resistance when compared with
the C2 group, indicated by a lower constant for serum glu-
cose disappearance (Kitt) value and a higher fasting insulin
concentration. No difference was observed in the basal
serum glucose values between the two groups. Serum total
cholesterol, HDL, LDL and TAG were higher in the F2
group than in the C2 group. In this experiment higher retro-
peritoneal, mesenteric and subcutaneous fat depot weights
were observed in the F2 group in comparison with the C2
group. The concentration of liver total lipids was also
higher in the F2 group compared with the C2 group. No

difference was found between the groups in the results
related to the Lee index. The average amount of fructose
ingested in this second experiment was 2·70 g/100 g body
weight per d.

No difference was observed in weight or body-length values
in the third experiment (Fig. 3).

Table 4 shows data from the third series of experiments.
The area under the serum glucose curve during glucose tole-
rance tests and TAG concentration were higher for the F3
group when compared with the C3 group. No differences
were observed between the groups in insulin resistance,
serum total cholesterol, basal glucose, HDL, LDL, retroperito-
neal, mesenteric and subcutaneous fat depot weights and the
Lee index. In this third experiment, the average amount of
fructose ingested was 3·75 g/100 g body weight per d.

Discussion

There has been clinical and epidemiological evidence
suggesting a progressive association of metabolic syndrome
development and high fructose consumption(28). Indeed, a
marked increase in obesity and metabolic syndrome

Fig. 1. Weight (a) and length (b) of fructose-fed (– –) and control (–X–) animals in the first experiment (P . 0·05).

Table 2. Effects of 8 weeks of fructose feeding as 10 % solution in drinking water in adult male Wistar rats (experiment 1)*

(Mean values and standard deviations of six animals per group)

Group. . . Control (C1) Fructose (F1)

Parameter Mean SD Mean SD

Area under serum glucose curve during GTT (mM £ 120 min) 1084·0 187·3 1124·9 99·6
Kitt (%/min) 0·60 0·27 0·61 0·48
Fasting insulin (mU/ml) 4·09 0·54 4·16 0·63
Serum glucose (mM) 5·7 0·6 5·4 0·7
Serum total cholesterol (mM) 2·19 0·48 2·38 0·44
Serum HDL-cholesterol (mM) 1·64 0·26 1·82 0·16
Serum LDL-cholesterol (mM) 0·49 0·23 0·63 0·37
Serum TAG (mM) 1·90 0·64 1·82 0·67
Retroperitoneal fat depot weight (mg/100 g bw) 533·7 233·2 572·5 155·0
Mesenteric fat depot weight (mg/100 g bw) 651·5 139·9 697·8 167·6
Subcutaneous posterior fat depot weight (mg/100 g bw) 514·4 171·5 521·2 94·1
Liver total lipids (mg/100 mg) 5·35 0·94 5·23 0·57
Lee index 318·6 10·8 316·6 10·0

GTT, glucose tolerance test; Kitt, constant for serum glucose disappearance; bw, body weight.
* See Methods for details of the diets.

R. F. de Moura et al.1180

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



prevalence has been linked to a 30% overall increase in fruc-
tose ingestion in the last 20 years within the USA. It has been
associated with the introduction of high-fructose maize syrup
as a sweetener in soft drinks and other foods(5). In the present
study, we examined the effect of three different protocols of
fructose administration on the metabolic characteristics of
Wistar rats.

In the first protocol, fructose (10%) was administered to
adult (90 d) male Wistar rats in drinking water during 8
weeks. No metabolic differences were observed between
the control and fructose-fed rats. Using the same procedure,
Sanchez-Lozada et al. (19) reported that fructose adminis-
tration was able to induce systemic hypertension, hyperuri-
caemia and hypertriacylglycerolaemia in adult male
Sprague–Dawley rats. Roglans et al. (29) reported hypertria-
cylglycerolaemia and hepatic steatosis in Sprague–Dawley
rats (the authors neither mention the age nor the weight of
the animals at the beginning of the experiment) that had
received fructose (10%) in drinking water for 2 weeks.
Additionally, while adult Sprague–Dawley rats fed fructose

through drinking water developed features of the metabolic
syndrome, adult Wistar rats presented a serum biochemical
profile considered to be healthier for the cardiovascular
system. Thus, the reported differences may be associated
with the rat lineage used. In fact, Wistar rats seem to
be less affected by the deleterious effects of fructose
when administered in drinking water than Sprague–Dawley
ones.

Sanchez-Lozada et al. (19) compared the metabolic effects of
fructose (10%) in drinking water and a high-fructose (60%)
diet in Sprague–Dawley rats. Both procedures induced hyper-
uricaemia and hypertriacylglycerolaemia. However, the 60%
fructose diet resulted in a higher fructose energy intake,
which was directly associated with worsening metabolic syn-
drome parameters. Other studies have also reported hyperinsu-
linaemia, hypertriacylglycerolaemia and glucose intolerance

in Sprague–Dawley rats fed on 60% fructose diets from 4

to 7 weeks(11,12,17,18,30–32). Thus, in the second experiment
series, a fructose diet was administered to adult male Wistar
rats (age 90 d) for 4 weeks.

Fig. 2. Weight (a) and length (b) of fructose-fed (– –) and control (–X–) animals in the second experiment (P . 0·05).

Table 3. Effects of 4 weeks of feeding a 60 % fructose diet in adult male Wistar rats (experiment 2)†

(Mean values and standard deviations of six animals per group)

Group. . . Control (C2) Fructose (F2)

Parameter Mean SD Mean SD

Area under serum glucose curve during GTT (mM £ 120 min) 862·5 80·4 951·4* 106·8
Kitt (%/min) 0·73 0·16 0·47* 0·16
Fasting insulin (mU/ml) 4·04 0·93 4·91* 1·42
Serum glucose (mM) 6·83 0·93 6·33 1·3
Serum total cholesterol (mM) 2·54 0·16 5·82* 1·92
Serum HDL-cholesterol (mM) 0·78 0·17 1·08* 0·16
Serum LDL-cholesterol (mM) 0·51 0·19 0·74* 0·20
Serum TAG (mM) 1·28 0·44 2·55* 0·84
Retroperitoneal fat depot weight (mg/100 g bw) 598·2 173·9 873·9* 347·9
Mesenteric fat depot weight (mg/100 g bw) 659·9 191·2 999·9* 263·8
Subcutaneous posterior fat depot weight (mg/100 g bw) 429·5 197·9 640·4* 203·6
Liver total lipids (mg/100 mg) 5·4 0·3 9·70* 4·0
Lee index 294·3 6·3 296·8 7·8

GTT, glucose tolerance test; Kitt, constant for serum glucose disappearance; bw, body weight.
* Mean value was significantly different from that of the control group (P,0·05; unpaired t test).
† For details of the diets, see Methods.

Metabolic syndrome signs in Wistar rats 1181

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



Using the fructose-rich diet protocol, we also succeeded in
inducing signs of the metabolic syndrome in fructose-fed
Wistar rats, such as glucose intolerance, insulin resistance
and high serum TAG, total cholesterol and LDL as well as a
high concentration of total liver lipids.
The elevated liver lipid accumulation is the sign of NAFLD

that may contribute to the development of non-alcoholic stea-
tohepatitis(33) in individuals who do not consume significant
amounts of ethanol(34). This result reinforces the assumption
that not only high-fat dietary consumption plays a role in
NAFLD, but also high fructose ingestion. In this way,
Ouyang et al. (35) showed that fructose ingestion in patients
with NAFLD was 2- to 3-fold higher than in control groups.
It has been reported that adult Sprague–Dawley rats given

fructose solution with standard diets gained more weight and
had significantly more fat tissue weight than control rats
given only a standard diet(36). Alterations in body fat were
also observed in the fructose-fed rats of the second exper-
iment, which showed retroperitoneal, mesenteric and subcu-
taneous fat depot weight increase.
Lau et al. (37), in a prospective study with non-diabetic

patients, found no association between the glycaemic

index or glycaemic load of the diet with the probability of

developing insulin resistance. Barbosa et al. (17) compared

the effects of glucose and fructose supplementation (8 g/kg)
in Wistar rats during 3 weeks. The authors reported insulin
resistance and hypertriacylglycerolaemia in response to both
treatments, but the glycaemia was higher in the fructose
group. The fructose glycaemic index is about 3-fold lower
than glucose and therefore the alterations observed may not
be related to this index or even to glycaemic load (glycaemic
index multiplied by amount in grams). In addition, the second
experiment, which revealed more damage to the rats, pre-
sented just an intermediate value of daily fructose ingested
in comparison with the first and third experiments.

The third experiment series was designed to analyse the
metabolic alterations caused in young (28 d) Wistar rats by
administration of a high-fructose diet for 8 weeks. The
young animals fed on the high-fructose diet showed hypertria-
cylglycerolaemia and glucose intolerance in the absence of
alterations in insulin sensitivity, serum total cholesterol,
LDL and HDL concentration as well as mesenteric, retroper-
itoneal and subcutaneous fat depot weights when compared
with the control group. In contrast, insulin sensitivity

Table 4. Effects of 8 weeks of feeding a 60 % fructose diet in young male Wistar rats (experiment 3)†

(Mean values and standard deviations of six animals per group)

Group. . . Control (C3) Fructose (F3)

Parameter Mean SD Mean SD

Area under serum glucose curve during GTT (mM £ 120 min) 1128·1 92·6 1246·8* 69·1
Kitt (%/min) 0·62 0·23 0·65 0·37
Fasting insulin (mU/ml) 4·18 0·55 4·07 0·61
Serum glucose (mM) 7·12 0·83 6·75 0·89
Serum total cholesterol (mM) 2·47 0·58 3·01 0·50
Serum HDL-cholesterol (mM) 0·98 0·27 1·09 0·3
Serum LDL-cholesterol (mM) 0·79 0·33 0·83 0·43
Serum TAG (mM) 0·68 0·19 1·09* 0·25
Retroperitoneal fat depot weight (mg/100 g bw) 713·7 290·4 764·8 228·1
Mesenteric fat depot weight (mg/100 g bw) 762·6 237·7 782·0 143·5
Subcutaneous posterior fat depot weight (mg/100 g bw) 772·0 356·6 696·4 249·5
Liver total lipids (mg/100 mg) 6·48 1·34 6·80 2·55
Lee index 298·8 7·6 307·9 10·7

GTT, glucose tolerance test; Kitt, constant for serum glucose disappearance; bw, body weight.
* Mean value was significantly different from that of the control group (P,0·05; unpaired t test).
† For details of the diets, see Methods.

Fig. 3. Weight (a) and length (b) of fructose-fed (– –) and control (–X–) animals in the third experiment (P . 0·05).

R. F. de Moura et al.1182

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



impairment has been described in 5-week-old Wistar–Hann-
over rats, after 28 d of high-fructose diet ingestion associated
with hypertriacylglycerolaemia and unchanged body-weight
gain, basal serum glucose and serum total cholesterol(38).

Interestingly, the third experiment showed that the average
amount of daily fructose ingestion was almost 40% higher
than in the second experiment, but did not induce a complete
metabolic syndrome picture in these animals. A reasonable
hypothesis could be the influence of protective mechanisms
linked to youth in Wistar rats. However, further investigation
will be necessary.

It is important to note that the AIN-93G provided in both
series of experiments is recommended for the growth phase
and is composed of 75% more fat and 42·9% more casein
than an adult maintenance diet. However, the C2 rats pre-
sented fat depot values very similar to the C1 rats that ingested
the regular rodent chow.

The dietary ingestion of fructose in humans is basically
associated with soft drinks (whose sugars are composed of
45% of glucose and 55% of fructose), which account for
just 8% of total energy intake(39). However, Montonen
et al. (40) in a cohort-designed study reported that the risk of
type 2 diabetes occurrence is 1·67 higher with this dietary pro-
file. The emerging evidence from recent epidemiological and
biochemical studies clearly suggests that the high fructose
dietary intake has rapidly become an important causative
factor in the development of the metabolic syndrome(8).

Nevertheless, the present study was not designed to investi-
gate fructose dose-response characteristics, as there are differ-
ent metabolic responses to high-fructose diets even within
rodents(17). The importance of the present study resides in
identifying the most adequate protocol to induce the metabolic
syndrome in Wistar rats. According to the present findings,
feeding adult rats (90 d) on a purified high-fructose (60%)
diet for 4 weeks seems to be an appropriate protocol for this
purpose.

Concerning the limitations of the study, the lack of baseline
values for the biochemical variables implies that already exist-
ent differences could have been missed. However, the ran-
domisation process to compose the groups diminishes this
possibility.

The absence of energy expenditure or physical activity
measures does not exclude the possibility that the differences
in the fat depots are related to lower physical or metabolic
activity. Nonetheless, based on the randomisation assumption
it would imply that the fructose diet plays a role in spon-
taneous physical activity. Additional studies may answer this
question.

In conclusion, the results in the three series of experiments
reveal that high fructose intake is more effective to produce
signs of the metabolic syndrome in adult than in young
Wistar rats, despite a shorter feeding period. Also, diet
seems to provide a better effective route for fructose adminis-
tration than drinking water.

Acknowledgements

The authors thank Clarice Y. Sibuya, Eduardo Custódio and
José Roberto R. Silva for technical assistance. This research
was supported by Brazilian foundations FAPESP (process:

07/54 098-0 and 05/57 741-6) and CNPQ (process: 30 027/
2004-6). R. F. M was responsible for the statistical analysis
and wrote the manuscript. C. R. was responsible for the bio-
chemical analysis and was co-author of the manuscript. J. A.
O. conducted study 1. E. S. was responsible for designing
and planning study 1. M. A. R. M. designed, planned and
oversaw studies 2 and 3. All the authors read and agreed
with the final format. The study authors have no conflict of
interests.

References

1. Reaven GM (1988) Role of insulin resistance in human disease.

Diabetes 37, 1595–1607.
2. Zecchin HG, Carvalheira JBC & Saad MJA (2004) Mecanismos

moleculares da resistência à insulina na sı́ndrome metabólica

(Molecular mechanisms of insulin resistance in the metabolic

syndrome). Rev Soc Cardiol Est São Paulo 14, 574–589.
3. Fujioka S, Matsuzawa Y, Tokunaga K & Tarui S (1987) Contri-

bution of intra-abdominal fat accumulation to the impairment of

glucose and lipid metabolism in human obesity. Metabolism 36,
54–59.

4. Kaplan NM (1989) The deadly quartet: upperbody obesity, glu-

cose intolerance, hyperglycemia and hypertension. Arch Intern

Med 149, 1514–1520.
5. Nakagawa T, Tuttle KR, Short RA & Johnson RJ (2005)

Hypothesis: fructose induced hyperuricemia as a causal mech-

anism for the epidemic of the metabolic syndrome. Nat Clin

Pract Nephrol 1, 80–86.
6. Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil

GS & Loskutoff DJ (1999) Tumor necrosis factor a is a key

component in the obesity-linked elevation of plasminogen acti-

vator inhibitor 1. Proc Natl Acad Sci U S A 96, 6902–6907.
7. Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S

& McClain C (2007) Nonalcoholic fatty liver disease: predis-

posing factors and the role of nutrition. J Nutr Biochem 18,
184–195.

8. Gross LE, Li L, Ford ES & Liu S (2004) Increased consumption

of refined carbohydrates and the epidemic of type 2 diabetes in

the United States: an ecologic assessment. Am J Clin Nutr 79,
774–779.

9. Astrup A & Finer N (2000) Redefining type 2 diabetes: ‘diabe-

sity’ or ‘obesity dependent diabetes mellitus’? Obes Rev 1,
57–59.

10. Hwang I-S, Ho H, Hoffman BB & Reaven GM (1987) Fructose-

induced insulin resistance and hypertension in rats. Hyperten-

sion 10, 512–516.
11. Katakam PV, Ujhelyi MR, Hoenig ME & Miller AW (1998)

Endothelial dysfunction precedes hypertension in diet-induced

insulin resistance. Am J Physiol 275, 788–792.
12. Kelley GL, Allan G & Azhar S (2004) High dietary fructose

induces a hepatic stress response resulting in cholesterol and

lipid dysregulation. Endocrinology 145, 548–555.
13. Hallfrisch J (1990) Metabolic effects of dietary fructose. FASEB

J 4, 2652–2660.
14. Basciano H, Federico L & Adeli K (2005) Fructose, insulin

resistance, and metabolic dyslipidemia. Nutr Metab (Lond) 2,
5–18.

15. Okada Y, Yoshino T, Takeuchi A, Endoh M, Ohta H, Jinno Y,

Yokoyama T, Izawa T & Kobayshi E (2000) Effects of the Kþ

channel opener KRN4884 on the cardiovascular metabolic syn-

drome model in rats. J Cardiol Pharmacol 35, 287–293.
16. Joyeux-Faure M, Rossini E, Ribuot C & Faure P (2006) Fruc-

tose-fed rat hearts are protected against ischemia-reperfusion

injury. Exp Biol Med 231, 456–462.

Metabolic syndrome signs in Wistar rats 1183

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n



17. Barbosa CR, Albuquerque EMV, Faria EC, Oliveira HCF &

Castilho LN (2007) Opposite lipemic response of Wistar rats

and C57BL/6 mice to dietary glucose or fructose supplemen-

tation. Braz J Med Biol Res 40, 323–331.
18. Lee YC, Ko YH, Hsu YP & Ho LT (2006) Plasma leptin

response to oral glucose tolerance and fasting/re-feeding tests

in rats with fructose-induced metabolic derangements. Life Sci

78, 1155–1162.
19. Sánchez-Lozada LG, Tapia E, Jiménez A, et al. (2007) Fruc-

tose-induced metabolic syndrome is associated with glomerular

hypertension and renal microvascular damage in rats. Am J Phy-

siol Renal Physiol 292, 423–429.
20. Daly ME, Vale C, Walke M, George K, Albert MM & Mathers

JC (1997) Dietary carbohydrates and insulin sensitivity: a

review of the evidence and clinical implications. Am J Clin

Nutr 66, 1072–1085.
21. Reeves PG, Nielsen HN & Fahey GC (1993) AIN-93

purified diets for laboratory rodents: final report of the Amer-

ican Institute of Nutrition ad hoc writing committee on the

reformulation of the AIN-76A rodent diet. J Nutr 123,
1939–1951.

22. Bernardis LL & Peterson BD (1968) Correlation between Lee

index and carcass fat content in weaning and adult female rats

with hypothalamic lesions. J Endocrinol 40, 527–528.
23. Latorraca MC, Carneiro EM, Boschero AC & Mello MAR

(1998) Protein deficiency during pregnancy and lactation

impairs glucose-induced insulin secretion but increases the sen-

sitivity to insulin in rats. Br J Nutr 80, 291–297.
24. Mathews JNS, Altaman DG, Campbell MJ & Royston P (1990)

Analysis of serial measurements in medical research. BMJ 27,
230–235.

25. Lundbaek K (1962) Intravenous glucose tolerance test as a tool

in definition and diagnosis of diabetes mellitus. BMJ 2,
1507–1513.

26. Nogueira DM, Strufaldi B, Hirata MH, Abdalla DSP & Hirata

RDC (1990) Sangue – parte I: glicı́dios (Blood – part 1: glycides).

In Métodos de Bioquı́mica Clı́nica (Methods of Clinical Bio-

chemistry), pp. 153–168 [Pancast editor]. São Paulo: Pancast.

27. Cinti S (2005) The adipose organ. Prostaglandins Leukot Essent

Fatty Acids 73, 9–15.
28. Elliott SS, Keim NL, Stern JS, Teff K & Havel PJ (2002) Fruc-

tose, weight gain, and the insulin resistance syndrome. Am J

Clin Nutr 76, 911–922.

29. Roglans N, Vilà L, Farré M, Alegret M, Sánchez RM, Vázquez-

Carrera M & Laguna JC (2007) Impairment of hepatic Stat-3

activation and reduction of PPARa activity in fructose-fed

rats. Hepatology 45, 778–788.
30. Oron-Herman M, Rosenthal T, Mirelman D, Miron T, Rabinkov

A, Wilchek M & Sela B (2005) The effects of S-allylmercapto-

captopril, the synthetic product of allicin and captopril, on car-

diovascular risk factors associated with the metabolic syndrome.

Atherosclerosis 183, 238–243.
31. Sharabi Y, Oron-HermanM,Kamari Y,Avni I, Peleg E, Shabtay Z,

Grossman E& Shamiss A (2007) Effect of PPAR-g agonist on adi-

ponectin levels in the metabolic syndrome: lessons from the high

fructose fed rat model. Am J Hypertens 20, 206–210.
32. Wang X, Hattori Y, Satoh H, Iwata C, Banba N, Monden T,

Konsuke U, Kamikawa Y & Kasai K (2007) Tetrahydrobiop-

terin prevents endothelial dysfunction and restores adiponectin

levels in rats. Eur J Pharmacol 555, 48–53.
33. Pitt HA (2007) Hepato-pancreato-biliary fat: the good, the bad

and the ugly. HPB (Oxford) 9, 92–97.
34. ZivkoviAC,GermamJB&SanyalAJ (2007)Comparative review

of diets for themetabolic syndrome: implications for nonalcoholic

fatty liver disease. Am J Clin Nutr 86, 285–300.
35. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL,

Diehl AM, Johnson RJ & Abdelmalek MF (2008) Fructose

consumption as a risk factor for non-alcoholic fatty liver

disease. J Hepatol 48, 993–999.
36. Kanarek RB & Orthen-Gambill N (1982) Differential effects of

sucrose, fructose and glucose on carbohydrate-induced obesity

in rats. J Nutr 112, 1546–1554.
37. Lau C, Faerch K, Glümer C, Tetens I, Pedersen O, Carstensen

B, Jorgensen T & Borch-Johnsen K (2005) Dietary glycemic

index, glycemic load, fiber, simple sugars, and insulin resist-

ance. Diabetes Care 28, 1397–1403.
38. Bezerra RMN, Ueno M, Silva MS, Tavares DQ, Carvalho CRO,

Saad MJA & Gontijo JAR (2001) A high-fructose diet induces

insulin resistance but not blood pressure changes in normoten-

sive rats. Braz J Med Biol Res 34, 1155–1160.
39. Park YK & Yetley EA (1993) Intakes and food sources of fruc-

tose in the United States. Am J Clin Nutr 58, 737S–747S.
40. Montonen J, Järvinen R, Knekt P, Heliövaara M & Reunanen

(2007) A consumption of sweetened beverages and intakes of

fructose and glucose predict type 2 diabetes occurrence. J Nutr

137, 1447–1454.

R. F. de Moura et al.1184

B
ri
ti
sh

Jo
u
rn
al

o
f
N
u
tr
it
io
n