Our laboratory has investigated two hypotheses regarding the effects of fructose consumption: 1) The endocrine effects of fructose consumption favor a positive energy balance, and 2) Fructose consumption promotes the development of an atherogenic lipid profile. In previous short- and long-term studies, we demonstrated that consumption of fructose-sweetened beverages with 3 meals results in lower 24-hour plasma concentrations of glucose, insulin, and leptin in humans compared with consumption of glucose-sweetened beverages. We have also tested whether prolonged consumption of high-fructose diets could lead to increased caloric intake or decreased energy expenditure, thereby contributing to weight gain and obesity. Results from a study conducted in rhesus monkeys produced equivocal results. Carefully controlled and adequately powered long-term studies are needed to address these hypotheses. In both short- and long-term studies we demonstrated that consumption of fructose-sweetened beverages substantially increases postprandial triacylglycerol concentrations compared with glucose-sweetened beverages. In the long-term studies, apolipoproteinB concentrations were also increased in subjects consuming fructose, but not those consuming glucose. Data from a short-term study comparing consumption of beverages sweetened with fructose, glucose, high fructose corn syrup (HFCS) and sucrose, suggest that HFCS and sucrose increase postprandial triacylglycerol to an extent comparable to that induced by 100% fructose alone. Increased consumption of fructose-sweetened beverages along with increased prevalence of obesity, metabolic syndrome, and type 2 diabetes underscore the importance of investigating the metabolic consequences fructose consumption in carefully controlled experiments.

Some investigators have proposed that increased fructose consumption may be related with the current epidemics of obesity and metabolic syndrome.
Consumption of dietary fructose has increased in conjunction with rising intake of fructose-containing sugars, largely in the form of sugar-sweetened beverages. Malik et al conducted a systematic review of the relationship between sugar-sweetened beverage consumption and risk of weight gain and concluded that the evidence indicates that increased consumption of sugar-sweetened beverages is associated with weight gain [5]. We have hypothesized that fructose consumption could promote weight gain because it does not stimulate insulin secretion or leptin production by adipose tissue [2, 3]. Since leptin production is regulated by insulin-mediated glucose metabolism [6–8] and ingestion of fructose does not result in meal-related increases of plasma glucose or insulin concentrations, we hypothesized that meals accompanied with fructose-sweetened beverages would result in reduced circulating leptin concentrations when compared with glucose-sweetened beverages. We compared leptin concentrations over two separate 24-h periods in 12 normal-weight young women who consumed fructose- or glucose-sweetened beverages with meals. Consumption of fructose-sweetened beverages at 30% of energy requirements with 3 meals resulted in lower 24-h circulating glucose, insulin, and leptin concentrations, and resulted in less postprandial suppression of ghrelin after each meal compared with consumption of glucose-sweetened beverages [9]. In a second short-term study comparing fructose- and glucose-sweetened beverages (30% of energy requirements), meal-induced insulin secretion was attenuated and 24-hour circulating leptin profiles were reduced in both overweight/obese men and overweight/obese women [10]. Fructose-sweetened beverage consumption also reduced the percent (proportional) change of leptin concentrations between the morning nadir and the late night peak [9, 10]. Results from a clinical study investigating the weight/body fat loss during an ad libitum low-fat, high carbohydrate diet suggest an association between the amplitude of the diurnal leptin pattern and long-term energy balance [11].
In long-term comparisons of fructose- and glucose-sweetened beverages (25% of energy requirements consumed with meals), fructose consumption resulted in significant reductions in the 24-h areas under the curve (AUC) for glucose, insulin, and leptin [12], whereas consumption of glucose did not. These results indicate that reductions of insulin secretion and attenuated 24-hour leptin profiles observed in the short-term studies are not transient, but are maintained during long-term fructose consumption.
Insulin and leptin function as key endocrine signals to the central nervous system in the long-term regulation of energy balance [13, 14]. Therefore, prolonged consumption of diets high in energy from fructose could lead to increased caloric intake or decreased caloric expenditure, contributing to weight gain and obesity as a result of reduced insulin and leptin signaling in the brain [3]. However, obtaining definitive evidence in support of this hypothesis in human subjects would be extremely difficult. It would require that subjects be provided and restricted to ad libitum consumption of a high fructose or high glucose diet that has been designed to achieve a comparable and controlled macronutrient distribution in all subjects, regardless of quantities consumed. It would also require that the intervention last at least 12 months, since a difference in body weight change as small as 0.5 kg/year between groups would be a clinically relevant finding. The costs, as well at the compliance and retention issues, involved in conducting such a study would likely prove to be prohibitive.
 FRUCTOSE AND ADDED SUGAR CONSUMPTION
If prolonged consumption of 25% of energy from HFCS or sucrose increases postprandial TG, Apo-B, and small dense-LDL to a comparable degree as fructose alone, this finding is likely to have important public health implications. The Institute of Medicine of the National Academies in the 2002 Dietary References Intakes (DRI) concluded that there was insufficient evidence to set an upper intake level for added sugars since there were not specific adverse health outcomes associated with excessive intake [33]. Therefore, they suggested a maximal intake level of 25% of energy intake from added sugars.
The estimated mean intake of added sugars by Americans is 15.8%, however this value is based on consumption data from the 1994–1996 Continuing Survey of Food Intakes by Individuals (CSFII) [34]. Recent data demonstrate that these intake rates may significantly underestimate actual sugar and sugar-sweetened beverage consumption by children and young adults. It was reported that the mean energy intake from sugar-sweetened beverages by 265 college students was 543 kcal/d [35], representing more than 20% of energy in a 2,500 kcal/d diet and over 25% of a 2,000 kcal/d diet. The mean intakes of sugar-sweetened beverages in 172 boys and 211 girls (age 13 years) were 809 ml/d and 674 ml/d, respectively [36]. Assuming a 2,500 kcal/d and 2,000 kcal/d energy intake for the boys and girls, respectively, these adolescents consumed approximately 15% of energy as sugar-sweetened beverages. Mundt et al followed 208 boys and girls (aged 8–19) for an average of 5 years and found that sugar-sweetened beverage consumption increased with age, while physical activity declined [16]. By the final year of the study, both males and females were consuming over 16% of energy as sugar-sweetened beverages. Similar results were reported for 2,371 girls followed from ages 9–15 [17]. Sugar-sweetened beverage consumption increased with age and averaged 14%–16% of total energy intake during the final study year. A recent analysis of energy consumed as beverages in the U.S. population (using 1999–2002 National Health and Nutrition Examination Survey data) [18] reported that the percent of energy consumed from soft drinks, fruit drinks, and juices averaged 18.5% for males and 13.5% for females (11-18 years of age). These data suggests that the proportion of energy intake consumed from sugar-sweetened beverages by adolescents, college students, and adults up to 39 years of age approaches or exceeds 15.8% (the current estimate for the mean intake of total added sugar), without accounting for any other dietary sources of sugars. The large standard deviations in several of these reports [16-18] suggest that at least 16% of the studied populations were consuming greater than two times the mean intake, and therefore well over 25% of daily energy requirements from sugar-sweetened beverages. Based on these more recent intake data [16-18] and the current DRI guideline for maximal added sugar intake [17], as well as our short-term results suggesting 25% of energy HFCS or sucrose increases postprandial triacylglycerol concentrations comparably to fructose alone [18], long-term dose-response studies investigating the metabolic effects of consuming HFCS and/or sucrose consumption up to the level of 25% of energy are needed.