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Food and Nutrition Sciences, 2019, 10, 664-677
http://www.scirp.org/journal/fns
ISSN Online: 2157-9458
ISSN Print: 2157-944X
DOI:
10.4236/fns.2019.106049 Jun. 26, 2019 664 Food and Nutrition Sciences
High Sugar-Fat Diet Induces
Metabolic-Inflammatory Disorders
Independent of Obesity Development
Jéssica Leite Garcia1*, Fabiane Valentini Francisqueti1, Ana Paula da Costa Rodrigues Ferraz1,
Artur Junio Togneri Ferron1, Mariane Róvero Costa1, Cristina Schmitt Gregolin1,
Dijon Henrique Salomé de Campos1, Klinsmann Carolo dos Santos1, Igor Otávio Minatel1,2,
Camila Renata Corrêa1
1Medical School, São Paulo State University (UNESP), Botucatu, Brazil
2Institute of Bioscience, São Paulo State University (UNESP), Botucatu, Brazil
Abstract
Background:
The modern dietary habit, which is rich in refined carbohy-
drates and saturated fats, increases the risk of chronic diseases due to
the
proinflammatory effect of these nutrients.
Aim:
To evaluate the impact of
high sugar-fat diet in the development of metabolic-
inflammatory disorders
in non-obese animals.
Methods:
Male Wistar rats were dist
ributed into two
groups according to the diet: control and high sugar-
fat for 30 weeks. It was
analyzed: dietary efficiency; chow, water and caloric intake; metabolic and
hormonal profile in plasma and inflammatory cytokines in epididymal adi-
pose tissue. Data were compared by Student’s t test or by Mann-
Whitney U
test with p < 0.05 as significant.
Results:
HSF presented lower chow intake,
higher water consumption and dietary efficiency with no difference in the
caloric intake. The final body weight (FBW) an
d weight gain (WG) were
lower in the HSF group and there was no difference in the adiposity index
(AI). HSF diet-induced hyperglycemia and hyperinsulinemia with no differ-
ence for Homeostatic Model Assessment for Insulin Resistance (HOMA-
IR).
Triglycerides,
uric acid, adiponectin and leptin levels were higher in the HSF
group. The HSF group showed increased interleukin-6 (IL-
6) and tumoral
necrosis factor-alpha (TNF-
α
) levels in epidydimal adipose tissue. The uri-
nary protein-creatinine ratio and albuminuria
were higher in the HSF group.
Conclusion:
HSF diet intake is directly involved in the development of me-
tabolic-inflammatory disorders independent of obesity, dissociating the view
that increased adiposity is the major risk factor for complications commonly
found in obese individuals.
How to cite this paper:
Garcia, J.L., Fran-
cisqueti
, F.V.
, da Costa Rodrigues Ferraz,
A
.P., Ferron, A.J.T., Costa, M.R., Gregolin,
C
.S., de Campos, D.H.S., dos Santos, K.C
.,
Minatel
, I.O. and Corrêa, C.R. (2019)
High
Sugar
-Fat Diet Induces Metabolic-Infla-
mmatory Di
s
orders Independent of Obesity
Develo
pment.
Food and Nutrition Sciences
,
10
, 664-677.
https:
//doi.org/10.4236/fns.2019.106049
Received:
May 17, 2019
Accepted:
June 23, 2019
Published:
June 26, 2019
Copyright © 201
9 by author(s) and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution
International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
J. L. Garcia et al.
DOI:
10.4236/fns.2019.106049 665 Food and Nutrition Sciences
Keywords
High Sugar-Fat Diet, Western Diet, Adipose Tissue, Cytokines,
Metabolic Disorders
1. Introduction
The literature suggests that the metabolic syndrome is consequence of adipose
tissue-generated molecules which initiates a state of low-grade inflammation,
responsible by metabolic, hemodynamic and vascular consequences [1]. In a
condition of positive energetic balance, the caloric excess is stored in adipose
tissue, which also has an endocrine function, secreting different adipokines [2].
However, the adipocyte hypertrophy process leads to adipose tissue dysfunction,
characterized by deregulation in the adipokines secretion. Within this context,
there is an increase in the tumoral necrosis factor-alpha (TNF-
α
), interleukin-6
(IL-6), monocyte chemoattractant protein-1 (MCP-1), leptin and resistin levels
and a reduction of adiponectin, a protective and anti-inflammatory agent [3] [4].
This proinflammatory scenario is associated with the development of insulin re-
sistance, type II Diabetes Mellitus, cardiovascular and kidney diseases [5] [6].
On the other hand, a new perspective has discussed the hypothesis regarding
the diet direct effect on disorders development [7]. The Mediterranean diet re-
commends a sufficient intake of whole grains, vegetables, fruit and fish, olive oil,
and a reduced intake of red meat and high fat dairy products in order to reduce
the risk of diseases [8]. In addition, some nutrients have been reported to reduce
the risk of inflammation, among them complex carbohydrates [9], polyunsatu-
rated fatty acid [10], dietary fiber [11], vitamin E [12] and vitamin C [13]. In
contrast, the modern dietary habit, referred as Western Diet, which is rich in re-
fined carbohydrates, saturated fats, and sweetened beverages [14] could increase
the risk of chronic diseases and mortality, and leads to a life quality impairment
due to the proinflammatory effect of these nutrients [15]. These reports show
that dietary quality may be a key factor for the prevention and/or development
of diseases, becoming an emergent health topic that deserves to be investigated.
The association between obesity and the development of diseases due to the
adipose tissue dysfunction is well characterized [16] [17] [18] [19]. However,
since the rates of chronic diseases are increasing also in non-obese individuals
[20] [21], to clarify the direct effect of nutrients on these illnesses will allow fu-
ture interventions. The aim of this study was to evaluate the impact of high sug-
ar-fat diet in the development of metabolic-inflammatory disorders in non-obese
animals.
2. Methods
2.1. Animals and Experimental Protocol
All the experiments and procedures were approved by the Animal Ethics Com-
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10.4236/fns.2019.106049 666 Food and Nutrition Sciences
mittee from Botucatu Medical School (1233/2017) and performed in accordance
with the National Institute of Health’s Guide for the Care and Use of Laboratory
Animals [22]. Male Wistar rats (±45 days) were randomly distributed into two
experimental groups according to the diet: control (C, n = 8) and high sugar-fat
(HSF, n = 27). The diets and water were offered ad libitum for 30 weeks. The C
diet contained soybean meal, sorghum, soybean peel, dextrin, soy oil, vitamins,
and minerals. The HSF diet contained soybean meal, sorghum, soybean peel,
dextrin, sucrose, fructose, lard, vitamins, and minerals, plus 25% sucrose in the
drinking water (Table 1). Both diets were produced according to Francisqueti
et
al.
(2017) [23]. All the animals were kept in a controlled temperature (24˚C ±
2˚C) and relative humidity (55% ± 5%) environment and in 12 h light-dark
cycle.
2.2. Groups Characterization and Composition
At the end of the experiment, a cut-off criterion based on the adiposity index
(AI) was established for the group characterization [24] [25]. AI represents the
fat percentage, which is the most appropriate variable to classify the presence or
Table 1. Diet composition and nutritional values.
Components C HSF
Soybean meal (g/kg) 335 340
Sorghum (g/kg) 278 80
Soy hulls (g/kg) 188 116
Dextrin (g/kg) 146 20
Sucrose (g/kg) - 80
Fructose (g/kg) - 180
Soybean oil (g/kg) 14 -
Lard (g/kg) - 154
Minerals (g/kg) 25 25
Salt (g/kg) 4 8
Nutritional values
Protein (% of ingredients) 20.0 18.0
Carbohydrate (% of ingredients) 60.0 53.5
Fat (% of ingredients) 4.00 16.5
% of unsatured 69.0 47.0
% of saturated 31.0 53.0
% Energy from protein 22.9 16.6
% Energy from carbohydrate 66.8 49.2
% Energy from fat 10.4 34.2
Energy (kcal/g) 3.59 4.35
C: Control; HSF: High sugar-fat. Values do not consider water plus sucrose.
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not of obesity in experimental models. Since the aim of this study was to eva-
luate animals submitted to HSF diet that did not become obese, this variable was
used to exclude obese animals. A 95% confidence interval (CI) was used for the
average of the adiposity index and the separation point (SP) was the midpoint
between the upper limit of the C group and the lower limit of the HSF group (SP
= 4.58). The animals with AI above the SP were excluded. The final composition
of the groups analyzed in this study was the following: group C, n = 7 and group
HSF, n = 8.
2.3. Biological Material and Euthanasia
At the 30th week, preceding euthanasia, 24 hours urine samples were collected
and the total volume of diuresis was measured. Subsequently all the samples
were centrifuged (3000 rpm at 4˚C for 10 minutes; Eppendorf® Centrifuge
5804-R, Hamburg, Germany), aliquoted and stored at −80˚C. At the end of 30
weeks, the animals were fasted for 8 hours and then anesthetized with Xylazine
(1 mg/kg, i.p.) and Ketamine (100 mg/kg, i.p.) (Syntec, Rhobifarma Indústria
Farmacêutica Ltda., Hortolândia, São Paulo, Brazil) and euthanized by decapta-
tion after foot reflex verification. Blood samples were collected in conic plastic
tubes of 15 mL containing the anticoagulant, ethylenediaminetetraacetic acid
(EDTA) in the proportion of 0.1 mL for each 5 mL of blood, followed by centri-
fugation (3000 rpm at 4˚C for 10 minutes, Eppendorf® Centrifuge 5804-R,
Hamburg, Germany) to obtain plasma. The epididymal, retroperitoneal and vis-
ceral fat deposits were dissected and weighed. The epididymal deposit was stored
in sterile cryotubes (Alfa Ltda-EPP, Ipiranga, São Paulo, Brazil). The collected
materials were stored at −80˚C until the analysis.
2.4. Nutritional Status and Body Composition
The nutritional status was evaluated by dietary efficiency, and chow, water and
caloric intake. Food and water intake were daily calculated from the individual
leftovers of each animal. Caloric intake was determined by multiplying the
energy value of each diet (g × Kcal) by the daily food consumption. For the HSF
group, the caloric intake also included the calories from drinking water. In order
to analyze the capacity to convert the ingested energy in body weight, the dietary
efficiency was calculated by dividing the total gain of body weight by the total
energy ingested. Weight gain (WG) was calculated by the final body weight
(FBW) minus the initial body weight (IBW). After the experimental period, the
deposits of retroperitoneal, visceral and epididymal fat were dissected and
weighted and the AI (%) was calculated by summing the weight of the deposits
divided by body weight and multiplied by 100, giving the result in percentage of
fat [26].
2.5. Metabolic and Hormonal Profile
To evaluate the disorders leaded by the diet, it was analyzed the following para-
meters:
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2.5.1. Metabolic
Plasma glucose, triglycerides, uric acid, (BioClin, Quibasa Química Básica Ltda.,
Belo Horizonte, Minas Gerais, Brazil); albuminuria, proteinuria and creatinine
urinary (CELM®, Barueri, São Paulo, Brazil) were measured by colorime-
tric-enzymatic method in automatic enzymatic analyzer system (Chemistry
Analyzer BS-200, MindrayMedical International Limited, Shenzhen, China).
Protein and creatinine urinary were measured to obtain protein/creatinine ratio
[27].
2.5.2. Hormonal
Insulin, adiponectin (EMD Millipore Corporation, Billerica, MA, USA) and lep-
tin (Crystal Chem, Elk Grove Village, IL, USA) were analyzed in plasma by
ELISA. The readings were performed on Spectra Max 190 microplate reader
(Molecular Devices®, Sunnyvale, CA, USA). The Homeostatic Model Assessment
for Insulin Resistance (HOMA-IR), which allows to evaluate the insulin resis-
tance, was calculated according to the following formula [28]:
fasting insulin (μUI/mL) × fasting glucose (mmol/L)/22.5
2.6. Adipose Tissue Inflammation
The analyzes were performed in the epididymal adipose tissue once it reflects the
visceral adipose tissue behavior [29]. The tissue samples were homogenized in
phosphate-buffered saline (PBS) at 1:10 (sample: buffer) and the supernatant
was used to measure the IL-6 and TNF-
α
cytokines levels by ELISA (EMD Mil-
lipore Corporation, Billerica, MA, USA). Readings were performed on Spectra
Max 190 microplate reader (Molecular Devices®, Sunnyvale, CA, USA). Total
proteins (BioClin, Quibasa Química Básica Ltda., Belo Horizonte, Minas Gerais,
Brazil) were measured in the supernatant by a colorimetric-enzymatic method
and analyzed in automatic enzymatic analyzer system (Chemistry Analyzer
BS-200, MindrayMedical International Limited, Shenzhen, China). The results
are expressed in pg/g of protein.
2.7. Statistical Analysis
Parametric data are presented as means ± standard deviation and compared by
Student’s t test. Non-parametric data are presented as median (interquatile
range) and compared by Mann-Whitney U test. The software used was Sigma
Plot version 12.0 for Windows (Systat Software Inc., San Jose, CA, United
States). A p value < 0.05 was considered as statistically significant.
3. Results
3.1. Nutritional Status and Body Composition
Table 2 shows the nutritional status and body composition of the animals. The
chow intake was lower in HSF group accompanied by higher water intake. There
was no difference in the caloric intake between the groups and the dietary effi-
ciency was decreased in HSF group. The final body weight and weight gain
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Table 2. Nutritional status and body composition.
Parameters C HSF p value
Chow intake (g/day) 24.0 (22.6 - 27.8) 8.52 (7.83 - 9.59) p < 0.001*
Water intake (mL/day) 36.0 ± 5.47 50.0 ± 5.98 p < 0.001*
Calori intake (kcal/day) 88.9 ± 9.51 86.3 ± 7.39 p = 0.691
Dietary efficiency (g/kcal) 0.016 ± 0.00 0.012 ± 0.00 p < 0.001*
IBW (g) 183 ± 13.9 171 ± 9.38 p = 0.084
FBW (g) 492 ± 54 405 ± 30 p = 0.002*
WG (g) 302 ± 53.0 231 ± 37.5 p = 0.010*
TF (g) 21.6 ± 1.85 19.3 ± 2.5 p = 0.095
VAT (g) 4.94 ± 1.06 4.69 ± 0.69 p = 0.596
EAT (g) 8.05 ± 0.91 5.93 ± 1.34 p = 0.006*
RAT (g) 8.58 ± 1.15 8.77 ± 1.39 p = 0.787
AI (%) 4.46 ± 0.36 4.79 ± 0.43 p = 0.142
C: control; HSF: high sugar-fat; IBW: initial body weight; FBW: final body weight; WG: weight gain; TF:
total fat; VAT: visceral adipose tissue; EAT: epididymal adipose tissue; RAT: retroperitoneal adipose tissue;
AI: adiposity index. Data are presented as means ± standard deviation or as median (interquartile range). *
indicates p < 0.05.
were lower in the HSF group and there was no difference in the adiposity index
between the groups.
3.2. Metabolic and Hormonal Profile
The HSF diet induced hyperglycemia and hyperinsulinemia; however, there was
no difference for HOMA-IR between the groups (Figure 1). Triglycerides and
uric acid (Figure 2) were higher in the HSF group as well as adiponectin and
leptin levels (Figure 3).
3.3. Adipose Tissue Inflammation
The HSF group showed increased levels of the proinflammatory cytokines, IL-6
and TNF-
α
, in adipose tissue (Figure 4).
3.4. Renal Injury
The urinary protein-creatinine ratio and albuminuria were higher in the HSF
group (Figure 5).
4. Discussion
The aim of this study was to evaluate the impact of high sugar-fat diet in the de-
velopment of metabolic-inflammatory disorders in non-obese animals. The
group submitted to HSF diet presented relevant metabolic, hormonal and in-
flammatory changes usually found in obesity and associated with increased adi-
posity [30]. According to the literature, the major risk factor for the obesity and
obesity-related disorders development is the intake of processed foods rich in
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Figure 1. (a) Glucose; (b) Insulin and (c) HOMA-IR. C (Control); HSF (High Sugar-Fat)
groups; HOMA-IR: Homeostatic Model Assessment for Insulin Resistance. * indicates p
< 0.05.
Figure 2. (a) Triglycerides and (b) Uric acid. C (Control) and HSF (High Sugar-Fat)
groups. * statistical difference to p < 0.05.
Figure 3. (a) Adiponectin and (b) Leptin levels. C (Control); HSF (High Sugar-Fat)
groups. * indicates p < 0.05.
Figure 4. (a) Adipose tissue TNF-
α
and (b) IL-6. TNF-
α
: Tumor necrosis factor alpha;
IL-6: interleukin-6; C (Control); HSF (High Sugar-Fat) groups. * indicates p < 0.05.
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Figure 5. (a) Protein/creatinine ratio; (b) Albuminuria. C (Control) and HSF (High
Sugar-Fat) groups. * indicates p < 0.05.
sugars and fats [5]. However, once in this study the HSF group presented adi-
posity index similar to C group, all the disorders were independent of adiposity
gain.
One of the consequences of the chronic high sugar-fat diet intake is the oc-
currence of insulin resistance, which favors the onset of type II Diabetes Mellitus
[30]. Although HSF group did not present difference in HOMA-IR index, the
animals presented high levels of glucose and insulin compared to C group,
which indicates impairment in carbohydrates metabolism. The sugar intake
leads to an increase in the insulin levels, hormone responsible by the glucose
absorption by tissues [31]. Hyperinsulinemia stimulates and increase the leptin
secretion by the adipose tissue through PI3K/Akt/mTOR pathway [32], leading
to a decrease in the appetite and an increase in the energy expenditure [33]. In
agreement with this finding, the groups presented the same caloric intake; how-
ever, the HSF group showed lower chow intake, dietary efficiency, and body
weight with no increased adiposity index, confirming the leptin effects.
Hypertriglyceridemia and hyperuricemia were also observed in the HSF group
as consequence of the diet. High triglycerides levels can be leaded directly by two
diet components: 1) the lard, which is composed mostly of saturated and mo-
nounsaturated fatty acids [34], whose ingestion is associated with elevated plas-
ma levels of triglycerides [35]; 2) the fructose, a simple carbohydrate found in
sucrose [36] of drinking water and also in the chow. Fructose is absorbed in the
intestine through the portal vein and metabolized in the liver, following different
metabolic pathways to generate energy substrates such as glucose, glycogen, lac-
tate and fatty acids. In opposition to glucose, fructose breakdown is not regu-
lated by the main glycolysis limiting step at the phosphofructokinase level, acting
as a substrate for new hepatic lipogenesis and lipid production, which can also
explain the hypertriglyceridemia [37] [38]. Moreover, uric acid can be originated
from one of the fructose degradation pathways and the excessive intake of this
sugar leads to hyperuricemia [37], considered a biomarker of some cardiovascu-
lar and renal diseases [39] [40].
In addition to the metabolic and hormonal changes, the diet was also able to
increase the proinflammatory cytokines levels in the adipose tissue. Adipose tis-
sue inflammation has been suggested to exert a central role in the physiopathol-
ogy of many obesity-related disorders, as insulin resistance and type II Diabetes
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Mellitus [41]. Adipocyte hypertrophy in obesity is an important source for the
development of adipose tissue inflammation [42]. Since the HSF group did not
present difference in adiposity index compared to C group, the inflammation in
adipose tissue can be explained by the high leptin levels, once this hormone can
upregulate the secretion of inflammatory cytokines, such as TNF-
α
and IL-6 [43]
[44]. Moreover, these cytokines induce leptin expression in adipose tissue fa-
voring a proinflammatory scenario [43], in a feedback loop.
Adiponectin level was increased in the HSF group, an unexpected result. The
literature reports a negative correlation between adiponectin levels and the in-
crease in adipose mass [45] [46] [47]. A possible explanation for this result in the
present study was described by Westerink
et al.
, (2014), showing that this adi-
ponectin elevation is an early anti-inflammatory response due to diet quality
[48]. Another explanation for the high adiponectin levels is the impairment in
kidney disease, once this hormone is excreted via kidney filtration [49] and the
HSF animals showed impairment in the renal function.
The renal impairment was characterized in HSF group by the increased pro-
tein/creatinine ratio and albuminuria. Total proteinuria (represented by the
protein/creatinine ratio) and albuminuria are important markers of kidney
damage used as prognostic indicators in patients with chronic kidney disease
[50]. Moreover, albuminuria is likely a reflection of early damage to the glome-
rular vascular endothelium as well as decreased ability of the tubule to reabsorb
urinary albumin [51]. Urinary measurement of total proteinuria includes higher
molecular weight non-albumin urinary proteins as well, which may be tubular as
well as glomerular in origin [52]. The changes in the renal function may be asso-
ciated with the proinflammatory cytokines in adipose tissue, once these cyto-
kines are able to reach the circulation and other organs (as kidneys), leading to a
local inflammation, contributing to renal damage, fibrosis and renal chronic
disease development [53] [54]. Another factor involved in the renal impairment
is the increase of leptin, which induces the synthesis of type 1 collagen in mesan-
gial cells, as well as type 4 collagen in glomerular endothelial cells contributing
to extracellular matrix deposition, glomerulosclerosis, and proteinuria [55] [56]
[57]. High insulin levels, also found in this experiment, interfere with mechan-
isms of renal injury, such as increased sympathetic activity and renal sodium
reabsorption and potentiation of vascular response to angiotensin II and aldos-
terone [58].
5. Conclusions
In summary, the HSF diet leaded to an increase of glucose, triglycerides, insulin,
leptin and uric acid. Moreover, the diet promoted inflammation in adipose tis-
sue and the impairment of renal function. This was a cause-and-effect study, and
it did not evaluate the mechanisms by which the alterations independent of ob-
esity occurred; however this work could support future studies that clarify these
mechanisms and that allow future interventions.
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Based on these results, it is possible to conclude that the HSF diet intake is di-
rectly involved in the development of metabolic-inflammatory disorders inde-
pendent of obesity, dissociating the view that increased adiposity is the major
risk factor for complications commonly found in obese individuals.
Acknowledgements
Unidade de Pesquisa Experimental da Faculdade de Medicina de Botucatu-
UNESP (UNIPEX), unit where the research was developed and the grants
2015/10626-0 and 2018/15294-3, São Paulo Research Foundation (FAPESP). The
authors declare no conflict of interesting.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.
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... 30 At the same time, hyperinsulinemia stimulates and increases the leptin secretion by adipose tissue through the PI3K/Akt/ mTOR pathway, which can explain the increased leptin levels in the ROb animals that did not present increased body fat. 31 The metabolic responses to hyperinsulinemia and hyperleptinemia are well established in the literature. 22,26 Nevertheless, these conditions also promote responses in other target organs, such as the heart. ...
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