High Fructose Corn Syrup And Obesity Essay Conclusion

ABSTRACT

High-fructose corn syrup (HFCS) is a fructose-glucose liquid sweetener alternative to sucrose (common table sugar) first introduced to the food and beverage industry in the s. It is not meaningfully different in composition or metabolism from other fructose-glucose sweeteners like sucrose, honey, and fruit juice concentrates. HFCS was widely embraced by food formulators, and its use grew between the mids and mids, principally as a replacement for sucrose. This was primarily because of its sweetness comparable with that of sucrose, improved stability and functionality, and ease of use. Although HFCS use today is nearly equivalent to sucrose use in the United States, we live in a decidedly sucrose-sweetened world: >90% of the nutritive sweetener used worldwide is sucrose. Here I review the history, composition, availability, and characteristics of HFCS in a factual manner to clarify common misunderstandings that have been a source of confusion to health professionals and the general public alike. In particular, I evaluate the strength of the popular hypothesis that HFCS is uniquely responsible for obesity. Although examples of pure fructose causing metabolic upset at high concentrations abound, especially when fed as the sole carbohydrate source, there is no evidence that the common fructose-glucose sweeteners do the same. Thus, studies using extreme carbohydrate diets may be useful for probing biochemical pathways, but they have no relevance to the human diet or to current consumption. I conclude that the HFCS-obesity hypothesis is supported neither in the United States nor worldwide.

INTRODUCTION

High-fructose corn syrup (HFCS) is a liquid sweetener alternative to sucrose (table sugar) used in many foods and beverages. Early developmental work was carried out in the s and s, with shipments of the first commercial HFCS product to the food industry occurring in the late s. Phenomenal growth over the ensuing 35 or more years made HFCS one of the most successful food ingredients in modern history (1).

HFCS was used in relative obscurity for many years. After all, its compositional similarity to sucrose suggested that it would be metabolized in a like manner. Its safety was never seriously doubted because expert scientific panels in every decade since the s drew the same conclusion: sucrose, fructose, glucose, and, latterly, HFCS did not pose a significant health risk, with the single exception of promoting dental caries (2–5).

Although there was considerable speculation in the s that fructose was responsible for several metabolic anomalies (6–8), convincing proof that this was a significant health risk was never forthcoming. It came as a great surprise to many when, seemingly overnight, HFCS was transformed from a mundane ingredient into the principal focus of scientists, journalists, and consumers concerned about the growing incidence of obesity in the United States and around the world. This article will probe the basis and implications for the current hypothesis that HFCS is somehow uniquely responsible for rising obesity rates and will challenge the science purported to demonstrate a unique role for HFCS in promoting obesity.

BRIEF HISTORY OF HIGH-FRUCTOSE CORN SYRUP

Sucrose from sugar cane or sugar beets has been a part of the human diet for centuries; sucrose from fruit or honey has been a part of the human diet for millennia. Sucrose continues to be the benchmark against which other sweeteners are measured. However, sucrose has posed significant technological problems in certain applications: it hydrolyzes in acidic systems (9), changing the sweetness and flavor characteristics of the product, and it is a granular ingredient that must be dissolved in water before use in many applications. Furthermore, sugar cane was traditionally grown in equatorial regions, some known equally well for both political and climatic instability. The availability and price of sugar fluctuated wildly in response to upsets in either one.

HFCS immediately proved itself an attractive alternative to sucrose in liquid applications because it is stable in acidic foods and beverages. Because it is a syrup, HFCS can be pumped from delivery vehicles to storage and mixing tanks, requiring only simple dilution before use. As an ingredient derived from corn—a dependable, renewable, and abundant agricultural raw material of the US Midwest—HFCS has remained immune from the price and availability extremes of sucrose. It was principally for these reasons that HFCS was so readily accepted by the food industry and enjoyed such spectacular growth.

THE HYPOTHESIS

In Bray et al (10) published the hypothesis that HFCS is a direct causative factor for obesity. They based their hypothesis on a temporal relation between HFCS use and obesity rates between and

Although the HFCS-obesity hypothesis may have been initially developed, as Popkin recently claimed, to simply “spur science” (11), it quickly took on a life of its own. This once mundane ingredient became vilified in scientific circles and then in the public arena when the hypothesis was translated as fact through leading nutrition journals, weekly and specialty magazines, national and local newspapers, and an endless number of television news programs.

In attempting to make sense of the HFCS-obesity hypothesis, it is fair to expect several inherent assumptions to hold true before it can be accepted as fact:

  • HFCS and sucrose must be significantly different,

  • HFCS must be uniquely obesity-promoting,

  • HFCS must be predictive of US obesity,

  • HFCS must be predictive of global obesity, and

  • Eliminating HFCS from the food supply must significantly reduce obesity.

Here I examine each assumption to see whether it holds true.

HIGH-FRUCTOSE CORN SYRUP AND SUCROSE ARE NOT SIGNIFICANTLY DIFFERENT

Composition

Confusion about the composition of HFCS abounds in the literature. The carbohydrate compositions of the most common nutritive sweeteners are listed in Table 1. The 2 most important HFCS products of commerce contain 42% fructose (HFCS) and 55% fructose (HFCS). The remaining carbohydrates in HFCS are free glucose and minor amounts of bound glucose, predominantly maltose (di-glucose) and maltotriose (tri-glucose). Mention of HFCS with higher fructose content (ie, HFCS or HFCS) is occasionally seen in the literature, but these products are highly specialized and are manufactured infrequently and in insignificant amounts.

TABLE 1

Carbohydrate composition of common nutritive sweeteners1

Component HFCS HFCS Corn syrup Fructose Sucrose Invert sugar2Honey 
Fructose 42 55  50 45 49 
Glucose 53 42   50 45 43 
Others 5333 10455
Moisture 29 23 20 25 18 
Component HFCS HFCS Corn syrup Fructose Sucrose Invert sugar2Honey 
Fructose 42 55  50 45 49 
Glucose 53 42   50 45 43 
Others 5333 10455
Moisture 29 23 20 25 18 

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Gross et al (16) and others have confused HFCS with common corn syrup, but as shown in Table 1, they are clearly distinct products. Corn syrup is actually a family of ingredients made up only of glucose—either free or bonded to itself in chains of various lengths up to ≈10, depending on the specific corn syrup product.

HFCS is also frequently confused with pure fructose, probably because of its name. “High-fructose corn syrup” is, in retrospect, an unfortunate choice of name, because it conjures up images of a product with very high fructose content. The original intent of the name was simply to distinguish it from ordinary, glucose-containing corn syrup. Pure crystalline fructose has been available to the food industry since the late s, but is still used in relatively minor amounts. The obvious differences between HFCS and pure fructose are aptly demonstrated in Table 1: the latter contains no glucose and is a low-moisture crystalline material. It must be emphasized that from a composition standpoint, pure fructose is a poor model for HFCS.

The glucose-to-fructose ratio in HFCS is nearly ; similar to the ratio in sucrose, invert sugar, and honey. A similar ratio is also found in many fruits and fruit juices. The only practical distinction in composition between sucrose and other fructose-containing sweeteners is the presence of a bond linking fructose and glucose (sucrose chemical name: β-d-fructofuranosyl-α-d-glucopyranoside; 17). The glucose and fructose in HFCS, invert sugar, honey, and fruit is principally monosaccharide (free, unbonded). Thus, when HFCS historically replaced sucrose in formulations, no increase in dietary fructose occurred.

Invert sugar is the name given to sucrose in which the bond linking fructose and glucose has been hydrolyzed. This may be accomplished either with acid or enzyme (invertase). Acid-catalyzed inversion of sucrose is accelerated by increased temperature and reduced pH and takes place within time spans as short as minutes to as long as months (9). Because carbonated beverages are low in pH (colas are near pH ) and are stored in warehouses at ambient temperature—sometimes for weeks before they reach supermarket shelves—considerable inversion can take place before the product reaches the consumer. It is a sweet irony that purists who must have their sucrose-sweetened sodas end up drinking a sweetener composition more similar to HFCS and have been doing so since the first cola was formulated in the s.

Availability

The HFCS-obesity hypothesis of Bray et al relies heavily on the positive association between increasing HFCS use and obesity rates in the United States (10). However, Bray et al treated this association in isolation, offering no perspective on trends in total caloric intake or added sweeteners use in comparison with use of other dietary macronutrients. Loss-adjusted food availability data from the US Department of Agriculture Economic Research Service to provide that missing perspective are compared in Figures 1 and 2 (18). Availability data attempt to provide a more realistic estimate of the amount of food actually available for consumption by subtracting losses in manufacturing, transportation, food preparation, spoilage, and table wastage from food production figures.

FIGURE 1.

Per capita daily caloric intake (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18).

FIGURE 1.

Per capita daily caloric intake (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18).

FIGURE 2.

Change in percentage of daily caloric intake of nutrient groups (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18). Numbers in parentheses indicate percentage change over the time period relative to change in total calories.

FIGURE 2.

Change in percentage of daily caloric intake of nutrient groups (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18). Numbers in parentheses indicate percentage change over the time period relative to change in total calories.

Plotted in Figure 1 are per capita daily calories over the y period from to , the most recent data available. As has been widely reported, per capita daily calorie intake increased 24% over that time period.

Trends in caloric intake of major dietary nutrients over the same period are illustrated in Figure 2 to determine whether added sugars increased disproportionately, which is something they surely would have had to do to uniquely impact obesity. In fact, use of added sugars as a fraction of daily calorie intake actually decreased slightly, along with vegetables, dairy, and meat, eggs, and nuts. It is significant that added fat was up 5%, because evidence is growing that added fat is more strongly associated with obesity than are added sugars (19).

It is widely believed that HFCS eclipsed sucrose long ago as the primary nutritive sweetener in the US diet and that fructose concentrations have risen disproportionately as a result, but this is just not so. Per capita daily calories from cane and beet sugar, HFCS, honey, and their total are plotted over the past 35 y in Figure 3. The following points are important to note:

  • There was essentially a one-for-one replacement of sucrose with HFCS from to ;

  • Since , sucrose use and HFCS use have been roughly equivalent, a significant fact that has escaped too many writers on the subject;

  • Fructose contributes ≈– kcal/d (sucrose and HFCS are each half fructose), ≈7–8% of the current kcal/d per capita total calorie intake reported in Figure 1;

  • Honey use is slight in comparison with the other 2 and has remained largely unchanged; and

  • Although availability of sugars was up over this period, which confirms the data shown in Figure 2, use of added sweeteners as a percent of total calories has declined in recent years.

FIGURE 3.

Per capita daily caloric intake of fructose-containing sweeteners (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18).

FIGURE 3.

Per capita daily caloric intake of fructose-containing sweeteners (US Department of Agriculture Economic Research Service loss-adjusted availability), – (18).

Two additional facts are worthy of note here: 1) although commercially available, pure crystalline fructose remains a specialty sweetener used in very limited quantities, and 2) the ratio of fructose-to-glucose from added sugars is ≈, and this value has likely remained unchanged since sucrose use became widespread a century ago (20).

Sweetness

A common misconception about HFCS is that it is sweeter than sucrose and that this increased sweetness contributed to the obesity crisis by encouraging excessive caloric food and beverage consumption (10). HFCS is not sweeter than sucrose. The sweetness of several common nutritive sugars in crystalline and liquid or syrup form is compared in Table 2.

TABLE 2

Sweetness comparison for selected nutritive sweeteners1

Sugars Sweetness intensity (crystalline)2Relative sweetness (10% syrup)3Absolute sweetness (syrups)4
Fructose   — 
Sucrose    
HFCS — 99 97 
Glucose 74–82 65 — 
Sugars Sweetness intensity (crystalline)2Relative sweetness (10% syrup)3Absolute sweetness (syrups)4
Fructose   — 
Sucrose    
HFCS — 99 97 
Glucose 74–82 65 — 

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Sweetness intensities of crystalline compounds were reported in pioneering work by Schallenberger and Acree in (21). They determined that fructose in the crystalline, β-d-fructopyranose anomeric form has ≈ times the sweetness of crystalline sucrose; the relative sweetness of crystalline glucose is lower at – Note that the sweetness of HFCS cannot be determined in crystalline form because HFCS does not crystallize. It is this marked difference in sweetness between fructose and sucrose in crystalline samples that is often confused and inappropriately attributed to HFCS, a blend of equal amounts of glucose and fructose in liquid or syrup form.

Once in solution, β-d-fructopyranose undergoes rapid mutarotation to give a mixture of several tautomers with lower and differing sweetness intensities (23, 22). White and Parke (13) reported the sweetness values of liquid and syrup samples relative to the sucrose standard as established by trained, expert food industry taste panels. In syrup form at 10% solids (the approximate sweetener concentration in most carbonated beverages), HFCS and sucrose yield the same relative sweetness. Under the same experimental conditions, HFCS is less sweet than sucrose, with a value of ≈

In Schiffman et al (22) reported the absolute sweetness of syrups at various concentrations and temperatures. The HFCS absolute sweetness value reported in Table 2 was calculated by regressing Schiffman's data for fructose and glucose to 10% solids and then substituting the resulting values into the known compositions of HFCS and sucrose. Using sucrose once again as the standard by setting its sweetness equal to , a sweetness value of 97 was calculated for HFCS, providing independent validation for the value reported by White and Parke. Schiffman's work also confirmed the earlier work of Hyvonen et al (24) and White (25) that temperature has little effect on sweetness intensity.

These data confirm what the food industry has claimed for more than 20 y: the sweetness intensities of HFCS and sucrose are equivalent. The replacement of sucrose by HFCS did not change the sweetness intensity of foods and beverages, nor did it lead to a “sweetening of America” (26).

Caloric value

HFCS and sucrose are both carbohydrate ingredients that contribute ≈4 kcal/g on a dry solids basis. There can be no argument that long-term overconsumption of foods and beverages containing either one without compensation for energy expenditure may lead to weight gain.

Absorption and metabolism

All fructose-containing nutritive sweeteners appear to share the same intestinal sites for absorption. Honey, fruit sugars, and HFCS reach the small intestines predominantly as monosaccharides. The minor amount of polysaccharide glucose in HFCS is quickly broken down to free glucose by salivary and intestinal amylases. Glucose is absorbed into the portal blood through an active, energy-requiring mechanism mediated by sodium and a specific glucose transport protein. Fructose is absorbed via the sodium independent GLUT-5 transporter (27). Disaccharide sucrose requires hydrolysis before absorption, which is rapidly accomplished by a plentiful sucrase in the brush border.

Much has been made of the metabolic differences between fructose and glucose in the human body: fructose is rapidly taken up by the liver and bypasses a key regulatory step in glycolysis. There are, however, several points of intersection where the metabolism of fructose and glucose interchange. This metabolic flexibility works to man's evolutionary advantage by allowing a variety of food and energy sources to be processed efficiently. It is only when any single nutrient is consumed to excess and overwhelms the body's metabolic capacity that untoward consequences occur.

Fructose malabsorption appears only to be a problem when too little accompanying glucose is present. This was quickly recognized in early sports drinks formulated solely with fructose to enhance performance by exploiting fructose's low glycemic index. Riby et al (28) subsequently showed that the addition of even small amounts of free or polymeric glucose can ameliorate fructose malabsorption and accompanying gastric distress.

The inability of the body to distinguish fructose-containing nutritive sweeteners from one another once they reach the bloodstream is critical to the HFCS discussion, but often overlooked. Sucrose, HFCS, invert sugar, honey, and many fruits and juices deliver the same sugars in the same ratios to the same tissues within the same time frame to the same metabolic pathways. Thus, if one accepts the proposition that a given product will be sweetened with one of the fructose-containing nutritive sweeteners, it makes essentially no metabolic difference which one is used.

HIGH-FRUCTOSE CORN SYRUP IS NOT UNIQUELY OBESITY-PROMOTING

If the HFCS-obesity hypothesis is correct, there should be something quantifiably unique about HFCS that is absent from sucrose. The data presented thus far in support of the hypothesis rely heavily on the metabolic comparison of glucose and fructose. It has been known for many years that fructose fed to experimental animals or human subjects in high concentration (up to 35% of calories) and in the absence of any dietary glucose will produce metabolic anomalies (7, 8). The Fructose Nutrition Review commissioned by the International Life Sciences Institute was highly critical of this line of experimentation (29).

A pure fructose diet is surely a poor model for HFCS, because HFCS has equivalent amounts of glucose. Because no one in the world eats a pure fructose diet, such experimentation must be recognized as highly artificial and highly prejudicial and not at all appropriate to HFCS.

Sucrose is a far more satisfactory model for HFCS. Experiments that test the HFCS-obesity hypothesis in a reasonable way, by comparing it with sucrose, are only now beginning to be published. In a notable current study from , Melanson et al (30) compared the effects of HFCS and sucrose at 30% of calories in 2 randomized 2-d visits in normal-weight women. Concluding that there is nothing uniquely quantifiable about HFCS, they reported no significant difference between the 2 sweeteners in fasting plasma glucose, insulin, leptin, or ghrelin or in energy or micronutrient intake.

Abstract

The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets.

Citation: Meyers AM, Mourra D, Beeler JA () High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity. PLoS ONE 12(12): e woaknb.wz.sk

Editor: Ferenc Gallyas Jr., University of PECS Medical School, HUNGARY

Received: June 27, ; Accepted: December 11, ; Published: December 29,

Copyright: © Meyers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Data are available from: woaknb.wz.sk

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Obesity has increased dramatically in recent decades [1], a phenomenon widely associated with the so-called ‘western diet’: energy-dense, highly palatable foods with high fat and sugar content [2]. More recently, there has been an interest in the possible contribution of high fructose corn syrup (HFCS) to the rise in obesity. Used widely in nearly all commercial foods, from bread to beverages [3], HFCS consumption has risen in parallel with increasing body weights and rates of obesity [4]. While evidence suggests links between increased sugar consumption and the rising prevalence of obesity and metabolic disorder [5–7], the contribution of HFCS per se, because of its higher fructose content, has been controversial with arguments for [4,8–11] and against [12–15] HFCS constituting a specific liability beyond increased sugar consumption generally.

HFCS, containing 55% fructose, 42% glucose, and 3% other saccharides, is primarily used in liquid products [3]. Fructose, including HFCS with its higher fructose content, is more lipogenic compared to other sugars [11,16] and is metabolized differently [17]. Where glucose can enter the cells through GLUT4 (various tissues), GLUT3 (neurons), GLUT2 (homeostasis though uptake in intestine), and GLUT1 (astrocytes and insulin-independent), fructose primarily uses GLUT5, which is not found in pancreatic beta cells, is specific for fructose, and not responsive to insulin [18]. GLUT2 also transports fructose non-selectively, though this low-affinity transporter is involved in transport primarily in the liver, intestine and kidneys [19].

While evidence suggests that fructose [7,11,20,21], and possibly HFCS [22,23] can contribute to the development of metabolic disorder, whether it contributes to weight gain is controversial. Some studies have reported weight gain with fructose or HFCS consumption [23,24] while others have not [21,25,26]. Furthermore, obesity has been associated with altered dopamine (DA) signaling in both human [27–29] and animal studies [30–32]. Reduced dopamine signaling has been suggested to promote compulsive overeating, likening obesity to a dopamine-mediated addiction to food [33,34]. When alterations in dopamine function are observed under high fat diet (HFD), it is difficult to disentangle the potential contribution of increased weight, altered macromolecule composition of the diet per se, and effects secondary of metabolic disorder, including altered insulin and leptin signaling and resistance. Here, we examine whether prolonged consumption of HFCS alters dopamine signaling in the dorsal striatum, a region implicated in reinforcement learning, habit and motivated behaviors, including critical for regulating feeding [35–37].

Materials and methods

Animals

Male and female C57BL/6 mice (3–4 months at start of feeding protocol) were used for all experiments. Housing for mice was maintained in a hour light-dark cycle. All experiments performed during light cycle. All mice were group housed in cages containing 2–4 mice per cage. Mice were not singly housed to avoid inducing stress that could affect both feeding behaviors and dopamine function. All animal experiments were approved by the Queens College Institutional Animal Care and Use Committee in accordance with National Institutes of Health guidelines for the responsible use of animals in research.

Diet protocol

Mice were placed into either a control group (n = 20) receiving chow diet and water or a high fructose corn syrup (HFCS-chow) group (n = 25) receiving chow diet and a 10% solution of HFCS (55% fructose, 42% glucose, 3% other saccharides, Best Flavors, CA) in their drinking water. Body weight was measured weekly. Water/HFCS was changed and measured twice weekly, total consumption was divided by number of mice in the cage to estimate individual consumption. Sufficient HFCS was available such that it was not a limited, competitive resource. HFCS was kept refrigerated during storage. Food was changed twice weekly, but consumption among group housed mice could not reliably be measured. Though single housing facilitates accurate individual measurement of consumption, it also induces stress, which could alter consumption, metabolism and induce stress-related changes in dopamine and insulin function.

Glucose challenge

Prior to glucose challenge (at week 15), mice were food and water deprived for 6 hours. Blood glucose was measured with a glucometer (One Touch Ultra 2, Johnson & Johnson) using tail blood. After measuring baseline fasting glucose, dextrose (1 g/kg) was administered via intraperitoneal (i.p.) injection and blood glucose measured at 15, 30, 60, 90, and minutes following injection.

Fast-scan cyclic voltammetry

Following the glucose challenge at week 15, a subset of HFCS+Chow mice (n = 8) and Chow mice (n = 11) were used for fast-scan cyclic voltammetry (FSCV) and reuptake analysis. Mice were anesthetized with urethane ( g/kg i.p.) and placed into a stereotaxic frame. A carbon-fiber microelectrode (CFMEs, constructed as in [38]) was lowered into the dorsolateral striatum (DLS: AP, + mm; lat, mm; DV, mm, from the cortical surface) and stimulated dopamine release was measured as described previously [38,39]. Briefly, a bipolar stimulating electrode was lowered into the substantia nigra pars compacta (SNC, AP, mm; lat, mm; DV, mm). A chloride-coated silver wire (Ag/AgCl) reference electrode was implanted contralateral to the CFME and secured with a stainless-steel screw and dental cement. A potential applied to the CFME at V was ramped up to V and back, compared to the reference (Ag/AgCl) electrode, with a scan rate of V/s held at V between scans. CFMEs were cycled at 60 Hz for 15 minutes and then returned to 10 Hz for ten minutes to stabilize background current. Experimental measurements were made at a scan rate of 10Hz. During stimulation protocols, for each 15s recording, background was digitally subtracted by averaging the background current obtained from ten scans selected from prior to stimulation onset [38]. To optimize dopamine signals, both the CFMEs and stimulating electrodes were systemically lowered in .1 mm increments. At each increment, a train of current (24 pulses, 4 ms per pulse, 60 Hz, μA) were used to evoke a reproducible dopamine release. After optimization, dopamine was evoked using 5 pulses of stimulation administered at 5, 20, and 60 Hz, with 2 minutes between stimulations. A cyclic voltammogram electrochemically identified dopamine with a peak oxidation at .6 V and a reduction peak at .2 V. Following recording, recording site was marked with trypan blue (80 nL) and histology performed to determine placement of working electrodes. The CFMEs were calibrated following the experiment using a micro flow cell and 1 μM dopamine solution.

Dopamine reuptake

Demon Voltammetry Analysis Software was used to model dopamine reuptake kinetics ([40]; Wake Forest University, Winston-Salem NC). The decay constant tau was used as a measure of dopamine reuptake and area under the curve (AUC) was used as a measure of overall DA signaling. Tau was calculated from an exponential curve fit and is highly correlated with changes in Km (r = ), suggesting tau is an accurate measure of DA clearance [40]. The area under the curve was calculated using trapezoid method.

Statistical analysis

Mixed ANOVAs were used to test for statistical significance for both the glucose challenge (group x sex x timepoint) and FSCV (group x sex x frequency) data. For FSCV data, post-hoc tests were used to determine significant group differences at individual frequencies tested, with Bonferroni correction for multiple comparisons. All statistical analyses were performed using R statistical software (aov, R version (); The R Foundation for Statistical Computing, woaknb.wz.sk).

Results

High fructose corn syrup did not increase body weight

Mice in the HFCS-chow condition consumed significantly more liquid (F(1,11) = , p < ) compared to controls. HFCS-chow mice consumed an average of mL/day per mouse of HFCS solution compared to mL/day of water consumption in chow mice, contributing approximately 4 kcal to each mouse's daily caloric intake. The HFCS-chow fed mice did not gain more weight compared to chow controls (Fig 1A, F(1,41) = , p = ). There were no significant sex by group differences (F(1,41) = , p = ) so the male and female data were combined.

Fig 1. Body weight and glucose challenge.

(A) Average weekly body weight across 15 weeks of experiment. (B) Glucose challenge (1 g/kg dextrose) at week (C) Area under the curve for the glucose challenge. N = 20 (chow), 25 (HFCS-chow); ANOVA (panels A/B, repeated measures: group * sex * measurement timepoint; panel C: group * sex), * < , ** < , *** < , error bars S.E.M.

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HFCS-chow induced glucose dysregulation

Glucose levels were tested at week There was no difference in fasting glucose between groups (F(1,41) = , p = ), but the HFCS-chow group exhibited a higher peak glucose and reduced clearance compared to chow controls (Fig 1B, F(1,41) = , p < ), again with no group by sex differences observed (F(1,41) = , p = ). The mean area under the curve (AUC) for each group is shown in Fig 2C (F(1,41) = , p < ). Though sex differences were not statistically significant, the effects of HFCS on glucose handling appeared more pronounced in males. As our study may be underpowered to reliably detect sex differences, the AUC means for the glucose challenge is shown broken down by diet and sex in Table 1.

Fig 2. HFCS attenuates evoked dopamine release in the dorsolateral striatum.

(A) Average color plots for Chow and HFCS+Chow at 60 Hz, 5 pulses. (B) Average dopamine release by group across frequencies, showing: top, raw data (HFCS, red; Chow, blue); bottom, HFCS group (red) normalized to controls (normalized controls, gray trace). (C) Average voltammograms for Chow (blue) and HFCS+Chow (red) across frequencies. (D) Average peak DA concentration across frequencies. (E) Average tau (decay rate) for Chow (blue) and HFCS-Chow (red) at 60Hz, 24 pulses. (F) Average AUC for Chow (blue) and HFCS-chow (red) at 60Hz, 24 pulses (G) Percent decrease normalized to Chow (gray) across frequencies (red). N = 11/8, Chow, HFCS+Chow, respectively. ANOVA (panels D/G, repeated measures, group * sex * frequency; panels E/F, group * sex), * p < , error bars S.E.M.

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HFCS attenuates evoked dopamine release in the dorsolateral striatum

To assess whether HFCS induces impairments in evoked DA release, FSCV was used to measure evoked DA release in the dorsolateral striatum (DLS). A stimulation train of 5 pulses was administered to the substantia nigra pars compacta in descending order at 60, 20, and 5 Hz, with 2 minutes intervals between scans at different frequencies. Evoked peak dopamine release was significantly lower in HFCS-chow mice compared to chow controls (Fig 2A–2D, F(1,15) = , p < ), with reduced responsiveness to increasing frequency compared to controls (group x frequency, F(1,15) = , p < ); that is, the percent decrease in evoked release in HFCS-chow mice relative to controls is greater at higher frequencies (Fig 2G, F(1,15) = , p < ). Post-hoc tests to assess group differences at each frequency tested indicated significant effects of HFCS at 60 and 20 (p < , , respectively), but not at 5 Hz (p = ), suggesting that higher frequency dopamine cell activity, associated with phasic dopamine cell activity, may be more affected than lower frequency, tonic activity.

In the presence of attenuated evoked DA release, prolonged DA clearance may act as a compensatory mechanism to increase DA signaling [41]. Reduced DAT expression and function are often observed in rodent DIO model, both with and without concomitant reductions in released dopamine [42]. We observe no decrease in clearance assessed by tau (time to half peak, Fig 2E, F(1,15) = , p = ). To assess total DA signaling we calculated the area under the curve for DA traces. Consistent with reduced peak release, HFCS-Chow show significantly reduced AUC, suggesting a decrease in total dopamine signaling in HFCS-Chow mice relative to chow controls (Fig 2F, F(1,15) = , p = ). Although obesogenic diets have been shown to reduce DAT surface expression/function in the mesolimbic pathway [31,32,43–45], reduced DAT has not been consistently reported in the absence of weight gain [45].

Dopamine was electrochemically identified through its voltammogram signature (Fig 2C) and recoding sites were histologically verified (Fig 3). There were no significant sex or group x sex differences in evoked DA release (sex, F(1,15) = , p = ; interaction, F(1,15) = , p = ), AUC (Fig 2F, F(1,15) = , P = ) and uptake kinetics (F(1,15) = , p = ), thus sexes were combined for analysis and figures.

Fig 3. Recording sites for fast scan cyclic voltammetry recording.

Blue circles are recording sites for Chow and red circles are recording sites of HFCS+Chow. Chow, n = 11; HFCS-Chow = 8.

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Discussion

Evidence suggest that increased consumption of fructose, possibly via HFCS, can induce metabolic dysregulation [7,11,20–23], though whether this is associated with weight gain has been controversial. Here we demonstrate that mice maintained on standard chow with ad libitum access to HFCS exhibit altered glucose regulation compared to chow controls in the absence of any significant weight gain. These data indicate that HFCS-induced metabolic dysregulation can arise independently of obesity associated with increased fat consumption. The HFCS induced glucose dysregulation observed here is consistent with previous studies of fructose and HFCS [17,20,21,23]. Several studies have observed metabolic abnormalities with fructose or HFCS in the absence of weight gain. For example, Blakely et al demonstrated that a diet of 15% d-fructose did not significantly alter body weight or food intake, but elevated fasting insulin [46]. Similarly, a study by Huang et al [21] showed that both the HFD and high fructose increased fasting insulin, though only mice on HFD exhibited obesity.

Here we use both males and females, providing evidence in rodents that the effects of HFCS on metabolism and dopamine can be observed in both sexes. Though we observe some indication that the metabolic effects may be more pronounced in males than females (Table 1), these differences were not statistically significant, likely due to a lack of power as our study was not designed specifically to assess sex differences. The human literature on sex differences in fructose-related metabolic effects is complex and varies depending upon the measure (e.g. [47]). With respect to glucose regulation specifically, earlier findings suggested that men were selectively susceptible to fructose-induced glucose dysregulation [48]; however, subsequent studies have found contrary results and suggest that sex differences in response to fructose may be age-dependent [49]. As metabolic studies can be conducted in humans, the primary importance in observing HFCS effects in both sexes here is to lend support to the appropriateness of the rodent model than to make inferences from rodents about sex differences in humans.

The mechanism by which HFCS induces metabolic disorder is likely related to fructose metabolism. Fructose bypasses the phosphofructokinase regulatory step in glycolysis, unlike glucose, and has a rapid uptake into the liver [50]. Fructose also has critical effects on lipid metabolism. The cause for hypertriglyceridemia is proposed to be increased hepatic de novo lipogenesis, which leads to hepatic insulin resistance [14,16,51]. This may occur due to increased diacylglycerol, an activator of protein kinase C (PKC) which causes decreased tyrosine phosphorylation of the insulin receptor, increased glucose production, and impaired glucose tolerance [11].

The nigrostriatal and mesolimbic DA pathways are important modulators of feeding behaviors and obesity [36,52–56]. Reduced dopamine function has been consistently associated with obesity, though the exact cause is not clear [57,58]. Three potential causal factors have been identified: diet composition per se (increased fat, independent of caloric intake and body weight), insulin resistance associated with obesity and HFD, and increased body weight and adiposity [42,53]. An increased ratio of fat macromolecules in the diet can induce changes in the DA system independent of total caloric intake or body weight [59]; specifically, a downregulation in D2/D3 receptors has been observed, although evoked DA release has not been tested under these conditions. In the present study, DA attenuation was observed with HFCS added to the diet in the absence of increased fat consumption or increased body weight, indicating that neither is necessary for dietary induced changes in DA function.

Our data shows HFCS induces glucose dysregulation in parallel with reduced evoked DA release. Reduced DAT function in response to HFD is one of the most robust findings in the rodent DIO literature. Rodents with access to HFD at 6 weeks or more have slower DA clearance and reduced surface expression of DAT [31,32,43–45]. This altered DA clearance is likely a consequence of insulin resistance [44]. Insulin resistance disrupts PI3K/Akt signaling, known to regulate DAT [31], causing reduced DAT expression on the plasma membrane [60]. Interestingly, despite reduced evoked dopamine release, we did not observe any evidence of altered reuptake kinetics in mice with access to HFCS and observed reduced total dopamine (AUC), suggesting that HFCS is not downregulating DAT, in contrast to high fat diets. This may suggest a different underlying mechanism or reflect an early stage in progressive diminution of dopamine function where increased DAT appears later as a compensatory mechanism.

Finally, we tested HFCS because it is ubiquitous in Western diets [3,6,61]. Moreover, because of differences in metabolic handling of fructose, there have been suggestions that HFCS per se, versus other sugars, may particularly contribute to increased obesity [4,8–11,24]. A review of this literature is beyond this scope of this discussion; however, accumulating evidence suggests the metabolic effects of HFCS are likely not substantially different from sucrose, at least acutely [12,13,15,25,62]. This does not diminish the significance of the present data, but does suggest the reduced evoked dopamine observed here might not be unique to HFCS. That said, in comparing access to HFCS vs. sucrose, Levy et al [63] suggest that HFCS has a greater effect in altering reward related gene expression compared to sucrose. While many FSCV studies have examined dopamine activation in response to sugar ingestion (e.g., [56,64,65]), here we assess more global changes in dopamine function after extended access to HFCS, analogous to studies of the effect of high fat diet on dopamine physiology. Future studies might include both HFCS and sucrose to assess whether the increased sugar consumption more broadly, in the absence of weight gain or increased fats, can alter dopamine physiology.

Conclusion

We confirm prior studies demonstrating that HFCS can induce metabolic dysregulation and add to accumulating data that this can arise in the absence of obesity. Reduced dopamine is associated with obesity (for review, [57]) and may contribute to compulsive eating [33,34,54,66]. We demonstrate that HFCS can impair dopamine function in the absence of weight gain or increased fat consumption. As reduced dopamine function has been implicated in compulsive behaviors [67,68] and reduced energy expenditure [57,69,70] and insulin dysregulation incurs increased obesity risk [71], changes in glucose regulation and dopamine function induced by HFCS may precede and contribute to obesity in the long-run.

Increased consumption of sugar-sweetened soft drinks has been associated with increased rates of obesity and metabolic disorder, especially in developed countries that consume a ‘Western’ diet when compared to those countries with lower access [9]. Although most softdrinks are sweetened with HFCS [3], whether it is HFCS per se that contributes to this risk has been controversial [12,13,15]. The addition of HFCS to current rodent DIO models may better recapitulate modern, Western diets associated with increased rates of obesity, allowing for better characterization of both dietary-induced obesity and underlying mechanisms.

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