High-fructose corn syrup, energy intake, and appetite regulation
Kathleen J Melanson, Theodore J Angelopoulos, Von Nguyen, Linda Zukley, Joshua Lowndes, and James M Rippe
ABSTRACT
High-fructose corn syrup (HFCS) has been implicated in excess
weight gain through mechanisms seen in some acute feeding studies
and by virtue of its abundance in the food supply during years of
increasing obesity. Compared with pure glucose, fructose is thought
to be associated with insufficient secretion of insulin and leptin and
suppression of ghrelin. However, when HFCS is compared with
sucrose, the more commonly consumed sweetener, such differences
are not apparent, and appetite and energy intake do not differ in the
short-term. Longer-term studies on connections between HFCS, potential
mechanisms, and body weight have not been conducted. The
main objective of this review was to examine collective data on
associations between consumption of HFCS and energy balance,
with particular focus on energy intake and its regulation. Am J
Clin Nutr 2008;88(suppl):1738S– 44S.
INTRODUCTION
The effect of caloric sweeteners on body weight remains unclear
(1–5). Some studies show inverse relations between intake
of sugars and body weight (6–8), whereas others show positive
correlations (9 –11). Different outcomes may arise from differences
in study designs, subjects, liquid versus solid sources of
sweeteners, types of sugars studied, and other factors (12). The
World Health Organization (13), the US Dietary Guidelines
(14), and the American Dietetic Association (15) all recommend
moderating intakes of total added sugars. However, questions
have arisen as to whether certain types of sugars should be limited
more than others.
In particular, some experts have implicated high-fructose corn
syrup (HFCS) as a possible contributing factor to energy overconsumption,
weight gain, and, thus, the rise in the prevalence of
obesity over the past decades (9, 16, 17). The purpose of this
review was to examine current scientific evidence on HFCS and
energy intake regulation in humans to discern whether there may
be something inherent about this sweetener that would warrant
moderation beyond that of other sweeteners to curb obesity. This
review is not intended to refute recommendations by the World
Health Organization, the US Dietary Guidelines, or the American
Dietetic Association regarding moderation of total added
sugars in the diet.
HFCS is produced from the isomerization of some of the
glucose in corn syrup to fructose. HFCS-55, consisting of 55%
fructose and 42% glucose, is used in many sweetened beverages,
whereas HFCS-42 (42% fructose; 53% glucose) is used to
sweeten other products (eg, confections). Before the mid-1960s,
sucrose (50% glucose and 50% fructose) was the predominant
sweetener, but food industry developments in the following decades
led to increased production ofHFCSto replace much of the
sucrose (12, 18, 19). HFCS is now estimated to be a major source
of fructose in theUSdiet (3). Although fructose is present in fruit,
honey, and some other carbohydrate sources, the quantities consumed
from these sources are not as large as is found in foods and
beverages sweetened by HFCS.
RELEVANT MECHANISMS OF SUGARS IN THE
REGULATION OF APPETITE AND BODY WEIGHT
Postprandial glycemia influences appetite responses to nutrient
ingestion either directly or indirectly (20). The glycemic
index (GI) values reported for fructose, glucose, and sucrose are
considerably different: 192, 993, and 685, respectively
(21). The GI of HFCS has not been published, but the GI of cola
sweetened with HFCS is 63 5 (21), a figure close to that of
sucrose, which might be expected because of the similarities
between the sweeteners. Past data have indicated that fructose is
more satiating than glucose (22–26). This may have been due, in
part, to its low GI; low-GI foods have been associated with
greater satiety than high-GI foods (20). Low-GI foods may prolong
satiety between meals, whereas high-GI foods may signal
immediate satiety (1). Fructose is passively absorbed further
down the small intestine than is glucose (27), which may allow
prolonged exposure to gastrointestinal satiety signals than higher
GI sugars (28). It also imparts high postprandial thermogenic
responses and hepatic oxidation (29 –33), which may be associated
with satiety (34 –36).
More recently, fructose’s unique metabolism, mainly through
energy balance regulatory hormones, has been suggested as a
possible mechanism to explain temporal trends in HFCS consumption
and obesity (16). Fructose, unlike glucose, does not
stimulate insulin secretion from pancreatic -cells (25). Insulin
1 From Rippe Lifestyle Institute, Shrewsbury, MA, and Celebration
Health, FL (TJA, VN, LZ, and JMR); the Center for Lifestyle Medicine,
University of Central Florida, Orlando, FL (TJA, JL, and JMR); and the
Department of Nutrition&Food Sciences, University of Rhode Island, Kingston,
RI (KJM).
2 Presented at the American Society for Nutrition Public Information
Committee symposium “High-Fructose Corn Syrup (HFCS): Everything
You Wanted to Know, but Were Afraid to Ask,” held at Experimental Biology
2007 in Washington, DC, 30 April 2007.
3 Supported by PepsiCo North America.
4 Address reprint requests to TJ Angelopoulos, Rippe Lifestyle Institute,
21 North Quinsigamond Avenue, Shrewsbury, MA 01545. E-mail:
tangelop@mail.ucf.edu.
doi: 10.3945/ajcn.2008.25825E.
1738S Am J Clin Nutr 2008;88(suppl):1738S– 44S. Printed in USA. © 2008 American Society for Nutrition
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may be a key element in the chain of events that leads to increased
satiety with the ingestion of most carbohydrates (37). As a result
of high blood glucose, increased circulating insulin can amplify
satiety through actions within the central nervous system (37–
41) or by stimulating leptin secretion (42). Whereas insulin is
secreted in acute response to meals, leptin stimulation is delayed
for several hours (43, 44).
Insulin-mediated glucose uptake and metabolism in adipose
tissues play a key regulatory role in leptin concentrations (41,
45). Leptin, the diurnal patterns of which have been shown to be
regulated by insulin (46), is recognized as a medium- to longterm
regulator of energy balance through its effects on reducing
energy intake and stimulating energy expenditure (47). Leptin
acts via the hypothalamus, blocking the drive to eat caused by
energy expenditure from basal metabolism (47) and potentially
inhibiting the effects of the orexigenic hormone ghrelin (48 –50).
It has been suggested that in the case of fructose, which does not
stimulate insulin secretion, this chain of satiety-producing events
does not occur (16).
Data suggest that the satiating effects of carbohydrates may be
mediated through changes in blood glucose, insulin, and carbohydrate
utilization (20, 51–57). Secretion of leptin and suppression
of ghrelin offer additional potential mechanistic explanations
for the satiating effects of carbohydrates (58–60). For
example, consumption of high-carbohydrate, low-fat meals results
in higher 24-h circulating leptin concentrations in normalweight
women compared with low-carbohydrate, high-fat meals
(61). A 12-wk weight reduction study in obese persons showed
that a high-carbohydrate (65%), low-fat (15%) diet did not result
in the expected weight-loss-induced increases in ghrelin or appetite.
This suggests that isocaloric substitution of dietary carbohydrate
for fat may lower ghrelin and, thus, hunger (62). Such
data may also indicate a role of carbohydrate in ghrelin suppression.
Studies show that both oral and intravenous glucose administration
lower plasma ghrelin (63, 64). However, fructose
consumption does not result in such increases in insulin and
leptin secretion or in ghrelin suppression (65). Melanson et al
(66) showed that although pure fructose does not increase plasma
glucose or insulin,HFCSresults in increased plasma glucose and
insulin, most likely as a result of the glucose moiety.Asdiscussed
below, HFCS and sucrose consumption also produce similar
leptin responses and ghrelin suppression (66), as has been seen in
other studies in which mixed carbohydrates were fed (67).
Intravenous infusion of glucose does not decrease food intake
or visual analogue scale appetite ratings, whereas glucose administered
orally or by tube leads to decreased hunger (28).
These findings suggest that gastrointestinal factors may mediate
carbohydrate-induced satiety. Furthermore, glucose decreases
ghrelin secretion and leads to increased glucagon-like peptide-1
(GLP-1) secretion, more so than fructose (68). GLP-1, which is
inversely related to ghrelin (69), has an inhibitory effect on food
intake through increased satiety (70, 71) and satiation (72).
FRUCTOSE, ENERGY INTAKE, AND ENERGY
BALANCE REGULATION
Discrepancies exist between the effects of pure glucose and
pure fructose on satiety and energy intake. Some studies show
that a glucose preload decreases hunger and inhibits future food
intake more than does fructose (73, 74). Others show that fructose
inhibits food intake more than does glucose (22–26). Still yet
other studies have found no significant differences between the
sugars (33, 68, 75–77).Astudy in 14 healthy men compared 75-g
loads of an 80% fructose, 20% glucose mixture (glucose was
added to reduce fructose malabsorption), glucose, sucrose and
polycose (a branched polymer of glucose often used as a bulking
agent), and a sucralose (a calorie-free sweetener) control (78).No
significant differences were found in subjective appetite ratings.
Ad libitum energy intake at 1 h was suppressed by glucose relative
to the sucralose control. Blood glucose correlated with
satiety ratings in this study. Intake after the fructose-glucose
mixture did not differ significantly from any of the other conditions,
including the sucralose condition. Energy intake compensation
at the meal 1 h after fructose-glucose consumption was
only 11.5% compared with 36–48% from the other beverages.
Although this was not statistically significant, it suggests incomplete
energy intake compensation.
Inconsistencies in the scientific literature about fructose and
energy intake may be related to subjects or the experimental
design, eg, the time at which satiety was measured, the amount of
carbohydrate given, whether the carbohydrate was as an isolated
monosaccharide or was part of a meal, and the route of administration.
Lack of difference in energy intake is particularly consistent
when fructose is consumed in combination with other
carbohydrates (33, 65, 78), which is the case for HFCS and
sucrose (Table 1). This may be because other carbohydrates
influence the speed or completeness of fructose absorption (27)
or because energy balance regulatory signals are influenced by
the combination of the carbohydrates (66).
Longer-term studies designed specifically to test the effects of
pure fructose on energy intake and body weight are extremely
limited. An early study in which 14 men with type 2 diabetes
supplemented a high-carbohydrate diet with 40–50 g of fructose
for 24 wk showed significant weight gain (85). Because total
energy intake increased with the fructose supplementation, it is
difficult to discern whether the weight gain was specifically
related to the fructose. Furthermore, because this study was conducted
in persons with diabetes, and there was no control group,
applicability to the general population is questionable.
More recently, an outpatient trial was conducted in 7 healthyweight
young males who underwent a 2-wk isocaloric diet that
was then supplemented with 1.5 g fructose per kg body wt daily
for 4 wk. With each of 3 daily meals, volunteers consumed a
20%-fructose solution. This supplementation resulted in a prescribed
excess daily energy intake of 18% from fructose (86).
Although total energy intake was not measured, body weight did
not change over the 4 wk, suggesting a neutral energy balance
despite the added fructose. This could have been due to energy
intake compensation or to increased energy expenditure (EE),
although 5-h EE, as measured by ventilated hood indirect calorimetry,
did not differ significantly throughout the intervention.
However, limitations of this study included a lack of a control
group, a small sample size, and a short duration.
In terms of fructose and hormonal regulators of energy, fructose
tends to blunt insulin responses compared with glucose;
these findings are very consistent (33, 65, 68, 77). Although
lower GLP-1 responses to fructose have been reported (68), this
is not always the case (26, 65, 77).Arandomized controlled study
in 12 healthy-weight women compared fructose and glucose
served in beverages with meals as 30% of total energy intake
during two 2-d laboratory visits. On the first day, when the test
beverages were included, total energy intake was controlled and
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subjective appetite was rated. On the second day, the test beverages
were not served, and food intake was ad libitum. Results
showed that with this large fructose dose, circulating insulin and
leptin were lower and postprandial ghrelin suppression was attenuated
compared with glucose (65).
After breakfasts served with fructose beverages, ghrelin decreased
by 50 pg/mL compared with 100 pg/mL after glucose.
Although postprandial peaks in the active form of GLP-1
were similar after meals served with fructose-sweetened versus
glucose-sweetened beverages, active GLP-1 remained higher
after lunch and dinner during the fructose trials compared with
the glucose trials. Despite hormonal differences, subjective appetite
and ad libitum energy intake did not differ between fructose
and glucose conditions in this study. However, in the 5
women with high scores for dietary restraint (measured by the
Three-Factor Eating Questionnaire), higher hunger and fat intake
were seen in the fructose condition. Although these women did
not have different hormonal responses, potential susceptibility to
fructose according to subject characteristics should be followed
up in larger groups of persons. This study would need to be
followed up over longer periods to determine whether these
differences in hormonal, but not overall appetitive responses,
persist with time.
HIGH-FRUCTOSE CORN SYRUP, ENERGY INTAKE,
AND BODY WEIGHT: SHORT-TERM STUDIES
The study noted above (65), compared beverages sweetened
with pure fructose and glucose, but as described earlier, HFCS is
more similar to sucrose than it is to fructose. Thus, although the
above study provides evidence that excess fructose consumption
can be detrimental to metabolism, it did not address the issue of
whether the replacement of sucrose in the American diet with
HFCS may be problematic. Therefore, Melanson et al (66) conducted
a similar study design with two 2-d visits in 30 healthyweight
young women to compare hormonal and appetitive responses
to beverages sweetened by HFCS or sucrose. The
beverages were served with 3 meals during the day and provided
30% of energy intake. As with the previous study, energy intake
was controlled on the first day when the test beverages were
served and appetite was rated, and food intake was ad libitum on
the second day of each visit.
TABLE 1
Short-term energy intake regulation studies in which fructose was served in the presence of other carbohydrates or in which high-fructose
corn syrup was served1
Reference Subjects Test sweetener
Comparative
sweetener Time frame VAS EI Metabolic responses
Holt et al, 2000 (79) 11 Lean men Sugared cola Sugar-free cola 1 d NS NS Not measured
Anderson et al, 2002
(78)
14 Healthy-weight
men
80% Fructose,
20% glucose
Glucose,
sucrose,
polycose
60 min NS NS Blood glucose significantly
lower after fructoseglucose
than glucose or
sucrose
Almiron-Roig and
Drewnowski, 2003
(80)
32 Normal-weight
adults
HFCS Orange juice,
1%-fat milk
2 h, 15 min NS NS Not measured
Teff et al, 2004 (65) 12 Normal-weight
women
Fructose beverages
with meals
Glucose
beverages
with meals
2 d NS NS Lower blood glucose,
insulin, and leptin and
less ghrelin suppression
after fructose
Wei and Melanson,
2006 (33)2
12 Obese men Fructose milk
shakes
Glucose milk
shakes
3 h NS NS Lower blood glucose after
fructose; higher EE and
RQ
Perrigue et al, 2006
(81)2
37 Young adults HFCS-55, HFCS-
42
Sucrose, 1%-
fat milk
140 min NS NS Not measured
Melanson et al, 2007
(66)
30 Normal- weight
women
HFCS beverages
with meals
Sucrose
beverages
with meals
2 d NS NS No significant difference in
blood glucose, insulin,
leptin, or ghrelin
suppression
Zuckley et al, 2007
(82)2
29 Obese women HFCS beverages
with meals
Sucrose
beverages
with meals
2 d NS NS No significant difference in
blood glucose, insulin,
leptin, or ghrelin
suppression
Akhavan and Anderson,
2007 (83)
31 Healthy men HFCS Sucrose, varied
fructose:
glucose
75 min (EI @
80 min)
NS NS No significant difference in
blood glucose, uric acid,
insulin, or ghrelin
Soenen and Westerterp-
Plantenga, 2007 (84)
70 Healthy men
and women
HFCS Sucrose (and
milk)
120–140 min NS NS No significant difference in
blood glucose, GLP-1,
insulin, or ghrelin
1 EE, energy expenditure; EI, energy intake at an ab libitum meal after preload consumption; GLP-1, glucagon-like peptide-1; HFCS, high-fructose corn
syrup; NS, not significantly different by statistical analyses; RQ, respiratory quotient; VAS, visual analogue scale ratings of hunger, satiety, and other appetite
variables.
2 Abstract.
1740S MELANSON ET AL
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Blood glucose, insulin, leptin, and ghrelin did not differ significantly
between the 2 sweeteners. HFCS- and sucrosesweetened
beverages produced similar ghrelin suppression after
each meal of200 pg/mL after both sucrose and HFCS trials. As
was seen in the fructose-glucose study described above (65), no
significant differences were seen between HFCS and sucrose in
ad libitum energy or macronutrient intakes. Appetite ratings
were also similar (the one exception was a slightly greater desire
to eat after sucrose consumption). Lack of differences between
HFCS and sucrose in energy intake and appetite ratings are not
surprising because of similar responses in plasma glucose, insulin,
leptin, and ghrelin (66), all of which have been postulated as
biomarkers of energy intake regulation (36).
Zuckley et al (82) recently repeated the same study design to
compare hormonal and appetitive responses to HFCS and sucrose
in obese and overweight women. As with the previous
study, preliminary findings showed that these responses toHFCS
and sucrose do not differ significantly in persons carrying excess
body weight. Similar blood glucose and hormones, as well as
appetite ratings and ad libitum energy intake, were seen with
consumption of HFCS and sucrose. Such results should be explored
in other populations, eg, obese men and older, and
younger persons. Additionally, total dietary HFCS should be
differentiated from beverage sources of HFCS, and outcomes
beyond these 3 hormones and appetite should be measured.
Two recent publications, each reporting 2 short-term experiments,
have corroborated data showing a lack of differential
hormonal and appetite responses to HFCS and sucrose (83, 84).
In a total of 31 healthy subjects across 2 experiments, no differences
between the sweeteners were seen in acute (75–80 min)
responses of appetite, blood glucose, uric acid, insulin, and ghrelin
(n 7 for these 3 last variables) (83). Preloads of HFCS,
sucrose, or milk produced similar 2-h responses of glucose, insulin,
GLP-1, ghrelin, rated appetite, and energy intake compensation
in a total of 70 healthy men and women across 2 experiments
(84).
Appetite responses to beverages sweetened by HFCS have
been compared with a variety of other beverages. For example, in
a study of 14 men and 18 women who served as their own
controls, isovolumetric 248-kcal drinks were served with a slice
of toast, and an ad libitum lunch was served 2 h and 15 min later
(80). The drinks were tested in random order on separate days,
including HFCS-sweetened cola, orange juice, and 1%-fat milk.
These were compared with isovolumetric carbonated water. Although
the 3 energy-containing beverages suppressed subjective
hunger ratings, desire to eat, and ad libitum intake more than did
water, they did not differ significantly from each other.
Similar results were seen in a preliminary study that compared
cola sweetened with sucrose, HFCS-55, HFCS-42, or aspartame;
1%-fat milk; and a no-beverage control in 37 adults in a randomized
paired design (87). Hunger and satiety ratings did not differ
significantly among the beverage treatments. Relative to the 2
no-energy treatments, energy intake compensation was similar
among the 4 energy-containing drinks at the meal 140 min later.
These 2 studies examined typical HFCS loads and found similar
appetite responses compared with isocaloric beverages. Therefore,
it is possible that the fructose content of typical HFCS loads
may be below the fructose threshold required to alter metabolism,
or that the presence of other carbohydrate sources might
prevent metabolic alterations. These possibilities warrant further
investigation.
Eleven healthy young males participated in a randomized
study to compare appetite after consumption of isovolumetric
preloads of sugar-rich cola, sugar-free cola, and mineral water on
separate days (79). The sweetener of the sugar-rich cola was not
clarified in this study, but because it took place in Australia, it is
possible that the sweetener was sucrose rather than HFCS. However,
the results showed that satiety immediately after the preloads
was more dependent on volume than on energy content or
sweetness. Lunch intake after the preloads suggested insufficient
energy intake compensation for the energy in the sugar-rich cola,
although this was not statistically significant. Total energy intake
over the full day did not differ among the preloads, which suggests
that, with time, energy intake evened out.
HIGH-FRUCTOSE CORN SYRUP, ENERGY INTAKE,
AND BODY WEIGHT: LONGER-TERM STUDIES
On the basis of studies focused specifically on fluids, high
consumption of sugar-sweetened beverages, in general, may be
associated with excess body weight (88). Drinking soda sweetened
with HFCS has been associated with increased ad libitum
energy intake and body weight compared with the same amount
of soda sweetened with the noncaloric sweetener aspartame (10).
Studies have also shown increases in energy intake and body
weight over 10 wk when subjects incorporated sucrose, as compared
with nonnutritive sweeteners, into their diets (11). In children,
Ludwig et al (9) found that the overall quantity of sugarsweetened
beverages ingested was predictive of initial and
follow-up body mass index. Prospective epidemiologic data in
adults have associated increases in sugar-sweetened beverages
with weight gain (89). Together, these studies imply that increased
energy intake by sweetened beverages is not compensated
for in subsequent intake, which may lead to overconsumption.
However, these studies do not determine whether HFCS
may be more of a factor in weight gain than other caloric sweeteners,
nor do they specifically address the implications of total
dietaryHFCSfrom all sources on energy intake and body weight.
Overall, longer-term studies have mainly compared HFCS with
noncaloric sweeteners; prospective studies comparing HFCS
with other caloric sweeteners are needed.
Most studies of HFCS, energy intake, and body weight have
specifically focused on beverage consumption rather than total
dietary HFCS. Some research has shown that energy intake compensation
is less precise when caloric beverages are consumed
versus solid food (1, 90, 91). For example, a study that compared
weight gain after 4 wk of consumption of a sweetened soda
versus the same carbohydrate load in the form of jelly beans
found more weight gain after the beverage (91). However, a
recent review (92) provided evidence that questions the plausibly
of claims that liquid energy sources, in particular, may increase
weight gain. For example, because liquid meal replacements can
promote weight loss when used appropriately, appropriate use of
caloric beverages (ie, replacing calories versus adding calories)
may be more of a concern.
CONCLUSIONS
Collectively, scientific evidence suggests that high consumption
of pure fructose may be problematic to energy intake regulation.
However, HFCS is more similar to sucrose than it is to
fructose in terms of its content, appetitive responses, and aspects
HFCS AND ENERGY INTAKE 1741S
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of its metabolism that have been measured to date. Thus, existing
theoretical and empirical evidence suggests that fructoseinduced
problems are not more related to HFCS than sucrose
consumption.
The potential hormonal and physiologic responses to HFCS
have not yet been connected to longer-term appetite or metabolism,
and, thus, to body weight regulation. Longer-term studies
have mainly compared HFCS beverages with noncaloric beverages,
and, therefore, are relevant more to the issue of increased
caloric intake from sweeteners than to the effects of specific
sweeteners relative to each other. Research is needed in this area,
especially considering the significant use of sweeteners in the
United States and other developed countries (3, 12, 18, 19). It is
important to determine whether any sweetener needs to be limited
more than others. Mechanistic approaches, as well as
outcome-oriented approaches focused on energy intake and body
weight, should be included in this research agenda.
As shown in Table 1, insufficient scientific evidence currently
exists to indicate that HFCS disrupts short-term energy balance
signals or increases short-term appetite and energy intake more
than do other tested sweeteners. The metabolic and endocrine
responses that have been measured to date are similar between
HFCS and sucrose, the sweetener HFCS has largely replaced in
the US diet. Additional work should be performed to see whether
these results extend to other metabolic and endocrine responses.
In addition, longer-term investigations of the effect of HFCS on
energy balance regulatory systems are needed to further understand
the role of this sweetener in body weight regulation. (Other
articles in this supplement to the Journal include references
93–96.)
The contributions of the authors were as follows—KM: developed the
article outline, conducted the literature search, devised the table, and wrote
the article; TJA: assisted in developing the article outline and contributed to
the literature search and assisted in the development of the body of the article
and edited all drafts; VN: assisted with editing the final article; LZ: assisted
with editing the final article; JL: contributed to the literature search and edited
several drafts; JMR: helped to edit the final article. JMR has received grant
support and consulting fees from PepsiCo NA. None of the other authors had
any conflicts of interest to declare.
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