Maternal dietary free or bound fructose diversely influence developmental programming of lipogenesis
Yuruk and Nergiz-Unal Lipids in Health and Disease
Maternal dietary free or bound fructose diversely influence developmental programming of lipogenesis
Armagan Aytug Yuruk 0
Reyhan Nergiz-Unal 0
0 Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University , 06100 Ankara , Turkey
Background: Maternal dietary choices throughout preconception, pregnancy, and lactation irreversibly affect the development of fetal tissues and organs, known as fetal programming. Recommendations tend to emphasize reducing added sugars. However, the impact of maternal dietary free or bound fructose in added sugars on developmental programming of lipogenesis is unknown. Methods: Virgin Sprague-Dawley rats were randomly divided into five groups. Rats were given feed and plain water (control) or water containing maltodextrin (vehicle), fructose, high-fructose corn syrup (HFCS) containing 55% fructose, sucrose (20% w/v) for 12 weeks before mating and throughout the pregnancy and lactation periods. Body weight, water, and feed intake were measured throughout the study. At the end of the lactation period, blood was drawn to determine the fasting levels of glucose, insulin, triglycerides, and non-esterified fatty acids (NEFA) in blood. Triglycerides and acetyl Co-A Carboxylase-1 (ACC1) levels in livers were analyzed, and insulin resistance was calculated. Results: The energy intake of dams in the HFCS group was higher than in the fructose group, while weight gain was less in the HFCS group than in the fructose group. HFCS resulted in greater insulin resistance in dams, whereas free fructose had a robust effect on the fetal programming of insulin resistance. Free fructose and HFCS in the maternal diet increased blood and liver triglycerides and NEFA content in pups. Furthermore, fructose and HFCS exposure increased phosphorylated ACC1 as compared to maltodextrin and control, indicating greater fatty acid synthesis in pups and dams. Conclusion: Different types of added sugar in the maternal diet have different metabolic effects on the developmental programming of lipogenesis. Consequently, high fructose intake via processed foods may increase the risk for chronic diseases, and free fructose might contribute to developmental programming of chronic diseases more than bound fructose.
Fetal programming; Fructose; Insulin; Non-esterified fatty acids; Triglyceride
High levels of intake of added sugar has been connected
to many chronic diseases i.e. obesity [
], type II diabetes mellitus [
] and fatty liver diseases [
]. Recent work
indicates that adult chronic diseases might be correlated with
prenatal and maternal nutrition [
]. Exposure to a
maternal diet with high levels of added sugar may increase
the risk of adult obesity and insulin resistance of pups [
Independent of the amount consumed, the type of
added sugar (sucrose, syrups etc.) might have a
significant impact on the metabolic outcome. High intake of
simple sugars might increase de novo lipogenesis,
influence triglyceride production, and decrease fatty acid
]. Fructose, a main component of added sugar,
contributes more to lipid biosynthesis as compared to
]. In fructose metabolism, fructose bypasses
the step requiring phosphofructokinase and does not
stimulate insulin secretion as much as glucose; thus,
high amounts of fructose contribute to de novo
]. In lipogenesis, fatty acid synthesis includes the
rate-limiting step catalyzed by Acetyl-CoA carboxylase
(ACC1), which is controlled by insulin [
However, the mechanisms underlying types of dietary added
sugar types and lipogenesis is still unknown.
Elevated consumption of HFCS and the increasing
prevalence of type II diabetes mellitus (T2DM) and
obesity led to speculation that the free fructose in HFCS
may contribute more to chronic diseases than bound
fructose found in sucrose [
]. Although there are
similar amounts of fructose in HFCS-55 (HFCS
consisting 55% fructose) and sucrose, there are still questions
as to whether HFCS contributes more to the progression
of metabolic abnormalities, such as T2DM or
cardiovascular disease (CVD) [
]. Additionally, added sugars
do not include naturally occurring sugars, such as
fructose in fruits and lactose in milk. A limited number of
studies have indicated that HFCS may have more
negative metabolic effects than natural fructose consumed in
fruit and honey [
]. This might be due to the
natural antioxidants, vitamins, minerals, and fiber
consumed with natural D-fructose in foods.
Added sugars and syrups are those that do not
naturally occur in the food, but are added during processing
or preparation [
]. The major sources of dietary added
sugars are beverages, cakes, desserts, and candies
(except sugar free food and drinks) [
]. Globally, the
most commonly used added sugars are sucrose,
glucose/fructose syrups (HFCS-55), and crystal dextrose
]. Worldwide recommendations for added sugar
intake are less than 5–10% of daily total energy [
such as in Turkey .
Consequently, dietary recommendations tend to
emphasize reducing added sugars. However, whether the
different types of added sugar have a similar metabolic
impact on the developmental programming of
lipogenesis has not yet been studied. Thus, the aim of this study
was to investigate the effect of chronic maternal
consumption of bound versus free fructose in three different
types of added sugars (fructose, sucrose, and HFCS-55)
on lipogenesis-related markers such as feed intake; body
weight; circulating levels of glucose, insulin, triglycerides,
and non-esterified fatty acids (NEFA); liver triglycerides;
liver ACC1; and insulin resistance/sensitivity in dams
and their pups.
Animals, experimental design and dietary exposures
All animals received ethical and humane care within the
provisions of the “National Ministry of Food, Agriculture,
and Livestock Regulations on the Protection and Welfare
of Animals Used for Experimental and Other Scientific
Purposes” and Institutional Guidelines. Experiments were
approved by the Animal Ethics Committee of Hacettepe
University, Ankara, Turkey (IRB Number: 2012/57–04).
Power analysis was performed to calculate the required
number of rats (n = 7) per group to determine dietary
effects of added sugar on lipogenesis. To stabilize the milk
yield for pups after birth, 7 offsprings from each dam was
enrolled to the study regardless of gender.
Pathogen-free, 3-week-old, virgin Sprague-Dawley
female rats (n = 35) were obtained from the Hacettepe
University Experimental Animals Research and Breeding
Unit (Ankara, Turkey). To facilitate food and water
intake and to promote minimal sedentary movement
patterns, the rats were maintained individually in
transparent polycarbonate cages at 20–22 °C (12 h light/
dark cycle; 45% relative humidity) throughout the study.
All rats had ad libitum access to standard laboratory rat
chow (Nukleon Laboratory Systems Inc., Ankara,
Turkey) and water throughout the washout and
As summarized in Fig. 1, rats were divided into five
groups after the washout period. The feed (by weight)
consisted of 13% fat obtained from corn oil, 60%
carbohydrates from corn starch and dextrose, and 24%
protein (casein) with an energy content of 4.2 kcal/g
(gross energy). The three groups were administered
fructose (containing 100% free fructose), high fructose
corn syrup (containing 55% free fructose; HFCS-55), or
sucrose (containing 50% bound fructose) added to
water for a final concentration of 0.2 g/mL (20% w/v)
(0.8 kcal/mL). The control group had plain water, and
the fourth group was the energy control (vehicle) and
had an iso-caloric drink consisting of maltodextrin
(0.2 g/mL (20% w/v)). The various combinations of
water and added sugar were prepared fresh at the
animal facility using autoclaved tap water. The energy and
macronutrient composition of the diets per 100 g feed
and 100 mL water is shown in Table 1. The energy
content of the control diet was 415 kcal/100 g (only from
feed), while the energy content for other four groups
were 495 kcal/100 g (415 kcal from feed and 80 kcal
from water). The administered protein and fat content
were the same in all five groups (Table 1). The intake of
feed and water was estimated by daily weighing of
unconsumed feed and water. Body weights were measured
three times per week.
After a 12-week dietary manipulation period, the
17week-old, virgin female rats (dams) were paired with a
Sprague-Dawley male rat and mating was confirmed by
the appearance of a semen plug. All animals became
pregnant; two rats failed to carry the pregnancy to the
third week of gestation. The dietary manipulation
continued in the same way during the pregnancy (3 weeks)
and lactation (3 weeks) periods. Two rats were excluded
from the study due to cannibalism during the lactation
Collection of blood and tissues
Rats were fed until weaning (at the end of third week of
birth) to determine the effects of maternal nutrition on
pups. Also, pups were not fed with any type of feed
(except breast milk) to eliminate any dietary effect other
than maternal nutrition. At the end of the lactation
period, 23-week-old dams and 3-week-old pups were
deprived from feed and water for 5 h to obtain fasting
blood profiles. They were anesthetized by subcutaneous
injection of ketamine (0.1 mg/g body weight) and
xylazine (0.02 mg/g body weight); blood and tissue samples
(liver) were subsequently isolated and the animals were
immediately euthanized by diaphragm puncture [
Blood was drawn from the vena cava into trisodium
citrate (12.9 mM). The plasma samples were snap-frozen
in liquid nitrogen and stored at −80 °C for further
analysis. Livers were isolated from adherent tissue, rinsed
with ice-cold saline to remove remaining blood, and
snap-frozen in liquid nitrogen for further analysis [
Measurement of glucose, insulin, free fatty acids and triglycerides
The levels of fasting glucose (Cayman Chemical
Company, USA), insulin (Bertin Pharma, CNIM
Company, Montigny-le-Bretonneux, France), NEFA
(Cayman Chemical Company, USA), and triglycerides
(Cayman Chemical Company, USA) were measured with
enzymatic colorimetric commercial tests, following the
manufacturers’ instructions by using an Absorbance
Microplate Reader (ChromMate 4300, Awareness
Technology Inc., USA). To measure the lipid content in the
livers, liver lobes were homogenized with ice-cold saline
by a microhomogenizator (T25 İka Labortechnik,
Germany). Triglycerides in homogenized livers were
measured by an enzymatic colorimetric method, normalized
for protein content, and determined with the BioRad DC
protein kit (BioRad Laboratories Inc., USA) [
Estimation of insulin resistance/sensitivity
Homeostasis model assessment of insulin resistance
(HOMA-IR = (fasting insulin (μU/mL) x fasting glucose
(mmol/L)) / 22.5) and quantitative insulin sensitivity
check index (QUICKI = 1/[log(fasting insulin (μU/mL) +
log (fasting glucose (mg/dL))]) was calculated from
fasting blood insulin and glucose levels [
Measurement of ACC1 in the livers with western blotting
ACC1 and the phosphorylated form of ACC1 (p-ACC1)
were measured by Western blot analysis of homogenized
liver tissues. Liver tissues were lysed with ice-cold
NP40-based lysis buffer (pH 7.45) in the presence of
protease and phosphatase inhibitors [
]. Protein in lysates
was quantified with the BioRad DC protein kit (BioRad
Laboratories Inc., USA). Samples with equal protein
amounts were separated on 10% SDS-PAGE gels, and
transferred to blotting membranes by semi-dry transfer.
Membranes were immunoblotted with a primary
antiACC1 rabbit mAb (1:1000) and secondary HRP-coupled
goat anti-rabbit peroxidase conjugate Ab (1:20,000),
using an ECL system (Thermo Fisher). Blots were
reprobed with rabbit β-actin mAb (1:1000) to confirm
the visible band. Analysis of antibody staining was
performed by densitometry [
Results were expressed as mean ± standard error mean
(SEM). Differences of diet on maternal and fetal outcomes
were assessed using a non-parametric Mann-Whitney U
test. Statistical significance was set at p < 0.05, and data
Added sugar (g/day)
Added sugar (kcal/day)
Fat (kcal/day) 6.2 ± 0.3 6.8 ± 0.3
HFCS: High Fructose Corn Syrup; M: Mean; SEM: Standard Error of Mean
*p < 0.05 compared to control, #p < 0.05 compared to maltodextrin
Diet groups (M ± SEM)
48.5 ± 2.0
6.9 ± 0.3
27.7 ± 1.1
3.2 ± 0.1
12.9 ± 0.5
0.7 ± 0.0
99.7 ± 4.1
19.3 ± 0.8
77.1 ± 3.3
11.7 ± 0.6
46.9 ± 2.5
3.5 ± 0.2
14.1 ± 0.6
0.8 ± 0.0
analysis was performed with the statistical Package for
Social Sciences (SPSS version 22.0, Chicago, IL, USA).
Dietary free or bound fructose effect maternal feed and drink intake, and body weight changes of dams and pups
The rats were administered either plain water (control)
or water with the polysaccharide maltodextrin (vehicle),
or the same amount of added sugar types i.e. sucrose,
fructose, and HFCS with a concentration of 20% (w/v),
as shown in Table 2. Energy, carbohydrate, protein, fat,
fiber, and micronutrient contents were similar in all four
diets, except the regular control diet. The control group
received feed and plain water (30.6 ± 1.3 kcal/day).
Dietary groups received feed and sweetened water with
added sugars (20%, w/v) including sucrose, fructose, or
HFCS (97.6 ± 1.7, 81.9 ± 4.4, and 108.3 ± 3.8 kcal/day,
respectively). As an energy control (vehicle) for added
sugar in water, the complex carbohydrate maltodextrin
was used (80.2 ± 3.4 kcal/g) (Table 2). Total energy
and carbohydrate intake of HFCS, sucrose, and
fructose groups were higher than those in the control
group (p < 0.05). The HFCS and sucrose groups
consumed more of the water with added sugar than the
maltodextrin group (p < 0.05), while there was no
significant difference in the water intake of the fructose
and maltodextrin groups. Because of the differences
in feed intake, the overall fat and protein intake of
the HFCS group were the highest, and the sucrose
group consumed more fat and protein than the
control and maltodextrin groups (p < 0.05).
Maternal feed intake, consumption of the water with
added sugar, and body weight changes are presented in
Fig. 2. Body weight, and feed and water intake of the
animals in all of the groups were similar at the baseline
measured during the washout period (2 weeks) prior to
the 18-week dietary period (Fig. 2a). The mean body
weights (60.4 ± 4.6 g) as well as the feed and water
123.0 ± 2.3*#
23.4 ± 0.4*#
93.5 ± 1.7*#
13.5 ± 0.5*#
54.1 ± 1.9*#
4.6 ± 0.2*#
18.4 ± 0.7*#
1.0 ± 0.0*#
8.9 ± 0.3*#
102.9 ± 6.1*
19.6 ± 1.0*
78.5 ± 4.1*
11.5 ± 0.5*
46.1 ± 1.8*
3.8 ± 0.3
15.2 ± 1.2
0.8 ± 0.1
7.3 ± 0.6
135.6 ± 5.4*#
26.0 ± 0.9*#
103.9 ± 3.5*#
15.4 ± 0.4*#
61.7 ± 1.8*#
4.9 ± 0.3*#
19.7 ± 1.2*#
1.1 ± 0.1*#
9.5 ± 0.6*#
intake of the dams at the start of the experiment did
not vary significantly (Fig. 2a-c) (p > 0.05). During the
18-week dietary period, body weight changes, and
feed and water intake were elevated differently in
each group (Fig. 2a-d). Weight gain, and feed and
water intake differences began preconception and
continued through the gestation and lactation periods.
Terminal body weights of dams in the HFCS group
(293.7 ± 9.9 g) were the highest, followed by the
fructose group (289 ± 6.4 g), and the sucrose group
(282.0 ± 13.9 g), as compared to the maltodextrin group
(258.3 ± 17.4 g) and the control group (252.9 ± 11 g)
(Fig. 2a) (p < 0.05). In agreement with this, the daily
feed intakes were the highest in the HFCS group, and
the second highest in the fructose group (Fig. 2b).
Although the average daily energy intake in all dietary
periods was the highest in the HFCS group, the body
weight gain of the fructose group was not significantly
less than in the HFCS group (p > 0.05).
All animals became pregnant and two rats failed to
carry pregnancy to the third week of gestation. The litter
size at birth did not vary significantly between the
groups, but there was an effect of diet exposure for dams
on the overall litter size. Body weights of the pups at
baseline were approximately 6.3 ± 0.3 g (p < 0.05), and after
weaning the body weights of the pups in the HFCS group
(37.0 ± 2.2 g) were the highest, followed by the fructose
group (35.7 ± 2.4 g), and the sucrose group (31.6 ± 2.4 g),
as compared to the maltodextrin (28.1 ± 2.2 g) and control
groups (25.4 ± 1.8 g) (Fig. 2d) (p < 0.05).
Dietary free or bound fructose influence maternal and fetal glucose metabolism and insulin resistance
After the 18-week dietary period, blood plasmas
from all rats (dams and pups) were analyzed for
fasting glucose and fasting insulin levels (Fig. 3a, b).
The blood glucose levels of dams in the fructose
(397.5 ± 91.5 mg/dL), HFCS (316.6 ± 111.4 mg/dL),
and sucrose (158.1 ± 7.5 mg/dL) groups were higher
compared to the maltodextrin (130.4 ± 20.3 mg/dL)
and control (85.2 ± 7.7 mg/dL) groups (p < 0.05). In
parallel, the blood glucose levels of the pups were
higher in the fructose (532.79 ± 32.1 mg/dL) and
HFCS (279.4 ± 70.1 mg/dL) groups, as compared to
the maltodextrin (149.5 ± 17.7 mg/dL) and control
(103.6 ± 6.2 mg/dL) groups (p < 0.05). However,
sucrose (153.9 ± 16.9 mg/dL) intake in pups did not
significantly affect the fasting blood glucose level as
compared to maltodextrin (p > 0.05) (Fig. 3a). The
fasting serum insulin levels of dams in the HFCS
(3.9 ± 0.7 ng/mL), sucrose (3.74 ± 0.2 ng/mL), and
fructose (2.3 ± 0.3 ng/mL) groups were higher
compared to the maltodextrin (2.2 ± 0.2 ng/mL) and
control (0.8 ± 0.1 ng/mL) groups (p < 0.05). In pups,
the blood insulin levels observed in the fructose
(3.24 ± 0.7 ng/mL) and HFCS (1.55 ± 0.2 ng/mL)
groups were elevated as compared to the maltodextrin
(1.33 ± 0.2 ng/mL) and control (0.45 ± 0.1 ng/mL) groups
(p < 0.05). However, sucrose (1.42 ± 0.2 ng/mL) intake in
pups did not significantly affect fasting blood insulin
levels, as compared to maltodextrin (p > 0.05) (Fig. 3b).
To estimate the effect of dietary free or bound fructose
on insulin sensitivity and insulin resistance, HOMA-IR
and QUICKI were calculated from fasting blood glucose
and insulin levels (Fig. 3c, d). The HOMA-IR of the
dams were higher in the HFCS (63.18 ± 36.18), fructose
(50.47 ± 21.25), and sucrose (26.39 ± 7.14) groups as
compared to the maltodextrin (7.78 ± 4.77) and control
(2.36 ± 1.01) groups (Fig. 3c) (p < 0.05). The HOMA-IR
values of the pups were the highest in the fructose (79.94
± 31.34) group, followed by the HFCS (15.04 ± 7.58),
maltodextrin (8.15 ± 4.10), sucrose (6.82 ± 3.60) and
control (1.54 ± 0.82) group (p < 0.05). Conversely, the insulin
resistance in the sucrose group of pups was not
significantly different from the maltodextrin group (p > 0.05)
(Fig. 3c). Furthermore, the insulin sensitivity scores of the
dams estimated by QUICKI were comparable in the
fructose (3.09 ± 0.14), HFCS (2.88 ± 0.14), maltodextrin (2.76
± 0.07), control (2.73 ± 0.08), and sucrose (2.70 ± 0.03)
groups (Fig. 3d) (p > 0.05). Similarly, the QUICKI values of
the pups were comparable in the fructose (3.28 ± 0.03),
control (3.12 ± 0.20), HFCS (3.08 ± 0.14), maltodextrin
(2.88 ± 0.01), and sucrose (2.83 ± 0.07) groups (Fig. 3d)
(p > 0.05).
Dietary free or bound fructose Alter maternal and fetal circulating free fatty acids, triglycerides and fatty acid synthesis
Blood plasma and livers from all of the rats were
analyzed for circulating triglycerides, NEFA, liver
triglycerides, and a liver fatty acid synthesis rate limiting enzyme
(ACC1) after dietary exposure for 20 weeks, including
the preconception, gestation, and lactation periods. The
effect of dietary free or bound fructose on these
biomarkers of de novo lipogenesis are shown in Fig. 4.
Blood triglyceride content was the highest in dams
and pups in the fructose group (24.9 ± 3.8; 42.8 ±
6.8 mg/dL), followed by the HFCS group (22.4 ± 3.4;
36.1 ± 8.2 mg/dL) and the sucrose group (20.0 ± 1.4;
24.4 ± 2.1 mg/dL), as compared to the maltodextrin
(18.7 ± 2.2; 20.5 ± 2.9 mg/dL) and control groups (16.1
± 1.5; 17.1 ± 1.7 mg/dL) (p < 0.05). However, the blood
triglyceride content in dams from the sucrose group
was not significantly different from that in the
maltodextrin group (p > 0.05) (Fig. 4a). Blood NEFA levels
were higher in dams and pups of the HFCS (0.9 ± 0.2;
1.1 ± 0.3 mM), fructose (0.7 ± 0.1; 0.9 ± 0.1 mM), and
sucrose (0.5 ± 0.1; 0.8 ± 0.1 mM) groups as compared to
the maltodextrin (0.4 ± 0.04; 0.6 ± 0.03 mM) and control
groups (0.4 ± 0.1; 0.7 ± 0.1 mM) (Fig. 4b) (p < 0.05).
The total triglyceride content per gram of liver tissue
were the highest in the dams and pups from the fructose
group (16.2 ± 5.3; 8.3 ± 1.6 mg/g), followed by the HFCS
group (14.7 ± 1.2; 5.8 ± 0.9 mg/g) and the sucrose group
(11.8 ± 0.7; 1.2 ± 0.5 mg/g), as compared to the
maltodextrin (9.4 ± 1.6; 0.5 ± 0.1 mg/g) and control (8.8 ± 0.9;
0.4 ± 0.1 mg/g) groups (Fig. 4c) (p < 0.05). To measure
the rate of fatty acid synthesis, the regulator enzyme
ACC1 was detected by western blot in livers. Liver
samples were analyzed for ACC1 and p-ACC1 in
homogenized tissue samples (Fig. 4d). Fructose and HFCS
exposure resulted in thicker p-ACC1 bands on western
blot membranes as compared to the maltodextrin and
control groups, indicating a more active fatty acid
Studies showed that fructose taken from natural sources
such as honey and fruits had more positive and less
negative effects on weight loss, waist hip ratio and
] compared to industrial
fructose. Honey and fruits contain fructose as well as
fiber and antioxidants such as vitamin C, resveratrol and
flavonols. Thus, unlike added sugars fruits and honey
can be evaluated as healthy fructose sources despite the
relatively high fructose content [
added fructose should be considered different from
natural fructose. Because many studies reported that; added
fructose intake might be related to elevated plasma
triglyceride levels [
], hypertension , increased
body weight [
], increased plasma insulin and glucose
] and hepatic insulin resistance .
However, most of these studies are hyper caloric or have high
fructose content (most people cannot get that much
fructose on a standard daily diet).
Since there is clear evidence that exposure to high
dietary sugar during pregnancy is associated with an
increased predisposition to obesity, dietary
recommendations mostly tend to emphasize reducing added sugars
]. However, whether all added sugar types (free or
bound forms) induce a similar metabolic response on
the developmental programming of lipogenesis needs to
be clarified. Therefore, this study investigated the effect
of chronic maternal consumption of bound or unbound
fructose in three different added sugars (fructose,
sucrose, and high-fructose corn syrup containing 55%
fructose) on lipogenesis-related markers.
Effect of dietary free or bound fructose on maternal feed and drink intake, and body weight changes of dams and pups
During all periods of this study, the energy intakes of all
groups were higher as compared to the vehicle and
control groups. The daily feed intake of the HFCS group
was the highest, and the fructose and sucrose groups
consumed more feed than the vehicle and control
groups. As published by others, the taste of HFCS may
induce increased water consumption, resulting in higher
energy intake [
]. On the other hand, excess free
fructose intake may decrease insulin and leptin
secretion, which in turn may result in less postprandial
ghrelin suppression and stimulate more feed intake, as
shown by others [
The body weights in the fructose, HFCS, and sucrose
groups were higher than in the vehicle and control groups,
as indicated by energy intake. In agreement of our results,
some studies have shown that fructose intake increases
the body weight of rats and mice [
11, 44, 45
some studies have reported that HFCS and fructose intake
(%10 w/v) did not affect the body weights of dams [
]. Similar to our results, other studies have
reported that maternal fructose (free or in HFCS) intake
leads to an increase in the body weight of pups [
9, 46, 47
A study showed that maternal fructose exposure
decreased hypothalamic sensitivity to exogenous leptin,
enhanced food intake, and decreased several anorexigenic
]. Another study reported that maternal
fructose intake lead to alterations in leptin and adiponectin
]. However, further studies are needed to clarify
the mechanism underlying the influence of fructose on
the developmental programming of obesity. A
metaanalysis showed that fructose consumption in isocaloric
studies did not change body weight, while hypercaloric
studies showed a significant increase [
metaanalysis reported that 10–20% (w/v) fructose consumption
was associated with elevated body weight in rodents [
As indicated, some studies have reported an increase in
the body weight due to fructose consumption, while other
studies showed a decrease, or no change. These
controversial results of fructose on body weight might be due to
fructose type (bound or free), dose, exposure time, or
subjects of the study (human or rodent).
The energy intake through feed and sweetened
water of dams in the HFCS group was higher than in
the fructose group, but body weight gain was lesser
in the HFCS group than in the fructose group in this
study. Although fructose (100% free fructose) has
almost the same energy content as HFCS-55
(including 55% free fructose) and sucrose (including 50%
bound fructose), more energy intake did not result in
body weight gain in the HFCS and sucrose groups as
compared to the fructose group. This might reveal
the effect of free fructose-induced lipogenesis and
body weight elevation, as compared to bound fructose
Fructose and HFCS intake affect the body weight of
dams in a same way, but in this study only HFCS intake
resulted in elevated body weight of pups during the 3
weeks. In parallel with this data, even a 10% (w/v)
fructose-containing maternal diet caused body weight
increase in pups, as shown recently by others [
results might be related to the HFCS-induced fetal
programming of lipogenesis via hormonal (insulin) or
enzymatic (ACC1) pathways [
Influence of dietary free or bound fructose on maternal and fetal glucose metabolism and insulin resistance
To elucidate the hormonal control of the lipogenesis,
blood glucose, and insulin content, insulin resistance and
insulin sensitivity were analyzed. Blood glucose levels were
the highest in the fructose group, following by the HFCS
and sucrose groups, as compared to the vehicle and
control groups. Thus, maternal fructose consumption resulted
in elevated fasting blood glucose of pups in this study. In
this regard, a meta-analysis reported that 10–21% (w/v)
fructose consumption is associated with elevated blood
glucose and insulin levels [
]. Accordingly, one recent
paper reported that a high fructose diet in rats adversely
affects glucose tolerance and insulin resistance [
fructose intake over a long period might alter the insulin
signaling pathways and cause hyperglycemia and
hyperinsulinemia, as shown by other studies [
Additionally, fructose intake in the maternal diet increased peak
glucose, decreased glucose tolerance , increased serum
insulin levels and altered insulin signal transduction as
compared to glucose, as shown by other studies [
glucose intake via in the form of sucrose or HFCS, triggers
insulin secretion. However, high intake of free fructose
causes an indirect increase of blood insulin. Fructose may
cause an increase in blood NEFA level and liver
triglycerides, which might disturb insulin receptors and signaling,
resulting insulin resistance [
]. The consequences of
fructose consumption on fetal developmental
programming needs to be studied further.
To estimate insulin resistance, the HOMA-IR and
QUICKI indexes were calculated from fasting glucose
and fasting insulin levels. The HOMA-IR of the dams
was the highest in the HFCS and fructose groups, as
compared to the sucrose group in this study. The
HOMA-IR of pups was the highest in the fructose and
HFCS groups, as compared to the sucrose group.
Similarly, Saad et al. reported elevated HOMA-IR scores in a
group of pups exposed to maternal fructose intake [
Also, in another study, perinatal fructose consumption
increased the fasting insulin levels and HOMA-IR scores
of pups [
]. In this study, the HOMA-IR value of the
maltodextrin group was higher than expected. A
previous study found that there were different gastric
emptying rates of different carbohydrates, and more water
soluble carbohydrates, like maltodextrin, might leave the
gastrointestinal tract faster [
], which may explain
this result. However, there was no significant difference
between the different types of added sugars on the
insulin sensitivity of dams and pups. Free fructose caused
insulin resistance, but did not affect insulin sensitivity in
this study. However, a study showed that fructose-fed
animals have a low score in QUICKI as compared to the
control group . Thus, a higher value of HOMA-IR
and a lower value of QUICKI mean higher levels of
insulin or glucose and an increased risk of insulin
HFCS resulted in more insulin resistance in dams, but
free fructose had a more robust effect on the
developmental programming of insulin resistance in pups. The
effect of HFCS may be more due to the free fructose in
HFCS than sucrose. This may be proof that maternal
intake of added sugar might alter the development of
glucose and insulin regulation pathways, β cell function of
the fetus, and may cause predisposition to diabetes. In
parallel with this hypothesized mechanism, other studies
have shown that maternal fructose intake during
pregnancy elevated plasma insulin and glucose levels in pups
]. Maternal hyperglycemia may cause glucose
transition via the placenta, and glucose transition might
cause excess fetal insulin secretion. Alternatively,
maternal hyperinsulinemia might lead to insulin transition to
the fetus, resulting in fetal hyperinsulinemia. Maternal
blood glucose or insulin-induced fetal hyperinsulinemia
might cause hyperplasia or hyperactivity of pancreatic β
cells, leading to glucose tolerance abnormalities or
insulin resistance [
Outcome of dietary free or bound fructose on maternal and fetal circulating free fatty acids, triglycerides and fatty acid synthesis
To examine the hypothesis that fructose-induced
steatosis might disturb insulin receptors and signaling,
maternal and fetal NEFA, triglycerides, and the fatty acid
synthesis regulating ACC1 enzyme were analyzed. In
this study, not only blood, but also liver triglyceride
contents were the highest in the fructose group,
followed by the HFCS group and the sucrose group, as
compared to the maltodextrin and control groups in
dams and pups. Many studies have shown that high
fructose intake might increase blood and liver
triglyceride levels [
46, 52, 65
], hepatic fatty acid synthesis [
and ACC1 enzyme expression [
]. In parallel with
this data, a study showed that HFCS- and
fructosesupplemented water consumption elevated serum
triglyceride levels as compared to sucrose-supplemented
water . Sanchez Lozada et al. showed that both
fructose (30%) and glucose (30%) intake increased
blood triglyceride and cholesterol levels compared to
sucrose (60%) [
]. Similar results were also shown in
humans: Hochuli et al. reported that moderate fructose
(40 g/day fructose for 3 weeks) intake induced de-novo
fatty acid synthesis compared to high sucrose consisting
diet (80 g/day) [
]. Furthermore, in a meta-analysis,
10–21% (w/v) fructose was associated with elevated
blood triglyceride levels [
]. On the other hand, there are
some studies reported conflicting results. These studies
are mostly different from ours in terms of the study
design. For example, compared to our study Toop et al. [
administered less sugar (10% vs 20%) for a shorter
duration (10 weeks vs 21 weeks) to the rats. In a clinical
trial, it was found that a three-day consumption of
fructose (52 g) lowered insulin levels but did not differ
from sucrose intake (65 g) in terms of plasma triglyceride
]. In this study, administered fructose amount
and three-day intervention may not suitable enough to see
overall effects of added sugars on lipid profile. Thus, the
differences in the design of the may cause conflicting
Moreover, free fructose and HFCS had a robust effect
of increasing blood and liver triglyceride and NEFA
contents in pups as compared to dams. This might give a
clue for the developmental/fetal programming of
lipogenesis. Conversely, in some studies, HFCS intake did
not change body weight, triglyceride [
] and apoprotein
] levels as compared to sucrose in adults. Moreover,
while the metabolism of fructose does not stimulate
insulin secretion as much as glucose, high amounts of
fructose may contribute to de novo lipogenesis in liver,
which is the main regulator organ for fructose
]. Not only being free or bound to another
molecule, but also the type of molecule (D or L type
fructose) might be important in metabolic regulation
and integration [
]. However, studies comparing the
metabolism by the type (D or L type) or form (bound,
free) of fructose are limited.
We observed that blood NEFA content elevated after
HFCS intake in both dams and pups. Correspondingly,
some studies have reported that high fructose intake
increases NEFA and causes dyslipidemia and hepatic lipid
]. Nevertheless, maternal high
fructose intake did not increase the blood NEFA levels of
dams, as compared to glucose, shown by other studies
. Liu et al. reported that high fructose intake
increases both plasma NEFA levels and oxidation,
resulting in stimulation of excess insulin secretion and insulin
]. Additionally, it was shown that acylation
stimulating protein (ASP) might stimulate NEFA
oxidation and lipolysis in adipocytes [
]. Therefore, high
fructose intake might increase de novo lipogenesis and
fatty acid acylation; resulting in high plasma triglyceride
and NEFA levels.
ACC1 plays an essential role in the regulation of fatty
acid synthesis and degradation. This enzyme catalyzes
the rate-limiting step in fatty acid synthesis at the level
of production of malonyl-CoA. Some studies have
shown that high fructose intake might lead to relatively
higher ACC1 and pACC1 expression [
Accordingly, other studies showed that fructose may activate
transcription factors such as sterol regulatory
elementbinding proteins (SREBP-1c and ChREBP), which
control de novo lipogenesis enzymes such as ACC1 and
fatty acid synthase (FAS) [
14, 52, 79
]. In support of this
mechanism, we presented that a higher level of the
activated enzyme p-ACC1 caused more fatty acid synthesis
in the fructose and HFCS groups.
In this study, we showed an adverse effect of free
fructose on body weight, plasma glucose, insulin responses,
and liver lipogenesis parameters, as compared to bound
fructose, in both dams and their pups. Additionally, our
study found that fructose intake with maternal diet
might affect insulin resistance and lipogenesis in the
adult life of the pups. This might be evidence for the
role of free fructose on developmental programming.
However, free fructose in natural foods itself could not
cause negative health effects in small amounts taken via
healthy diet. Fructose dose and exposure time may be
the reason of conflicting results between studies. To
explain the exact mechanisms of metabolic changes,
adipose deposition, adipokines, insulin signal transduction,
and transcriptional factors must be evaluated in future
studies. In conclusion, bound or free high fructose intake
may increase the risk for chronic diseases, especially
obesity and type II diabetes mellitus. Thus, free fructose,
as that found in HFCS, contributes to chronic disease
development more than bound fructose does, similar to
sucrose. Different types of added sugar in the maternal
diet result in different metabolic responses in the
developmental programming of lipogenesis.
Ab: Antibody; ACC: Acetyl Co-A carboxylase; ASP: Acylation stimulating
protein; ChREBP: Carbohydrate-responsive element-binding protein;
CVD: Cardiovascular diseases; ECL: Enhanced chemiluminescence; FAS: Fatty
acid synthase; HFCS: High fructose corn syrup; HOMA-IR: Homeostasis model
assessment of insulin resistance; HRP: Horseradish peroxidase;
mAb: Monoclonal antibody; NEFA: Non-esterified fatty acids; NP-40: Nonidet
P-40; QUICKI: Quantitative insulin sensitivity check index; SDS-PAGE: Sodium
dodecyl sulfate polyacrylamide gel electrophoresis; SEM: Standard error of
mean; SREBP-1c: Sterol regulatory element binding protein-1c; T2DM: Type 2
We thank Betul Kisioglu and Elif Ugur for assistance during the laboratory
analysis, and Yagmur Kaya for assistance inauguration of the animal
This study was supported by Hacettepe University Scientific Research
Projects Coordination Unit (Project Number: 013D03401001), Ankara, Turkey.
Availability of data and materials
The authors could share the data in case needed.
AAY carried out data collection and analysis, and helped draft the
manuscript. RNU designed the study, conducted the data collection and
analysis, and drafted and finalized the manuscript. Both authors read and
approved the final manuscript.
All animals received ethical and humane care within the provisions of the
“National Ministry of Food, Agriculture, and Livestock Regulations on the
Protection and Welfare of Animals Used for Experimental and Other
Scientific Purposes” and Institutional Guidelines. Experiments were approved
by the Animal Ethics Committee of Hacettepe University, Ankara, Turkey
(IRB Number: 2012/57–04).
Consent for publication
The authors declare no consent for publication yet.
The authors declare that they have no competing interests.
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