Consuming beverages containing 10%, 17.5%, or 25% Ereq from HFCS produced dose-dependent increases in circulating lipid/lipoprotein risk factors for CVD and uric acid within 2 wk. These results provide mechanistic support for the epidemiologic evidence that the risk of cardiovascular mortality is positively associated with consumption of increasing amounts of added sugars. This trial was registered at clinicaltrials.gov as NCT01103921.

ObjectiveIdentify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function.MethodsAssociations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models.ResultsIn humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations.ConclusionsIn humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

Background: Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors. Methods: Adults (18-40 years; BMI 18-35 kg/m 2 ) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc. Findings: 145 subjects (26.0 ± 5.8 years; body mass index 25.0 ± 3.7 kg/m 2 ) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [−0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [−0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340). Conclusion: A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption.

Context Studies in rodents and humans suggest that high fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets. Objective To compare the effects of consuming sucrose-sweetened beverage (-SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans. Design A parallel, double-blinded, NIH-funded study. Setting Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Participants 75 adults (18-40 years) were assigned to beverage groups matched for sex, BMI (18-35kg/m 2), fasting triglyceride, lipoprotein and insulin concentrations. Intervention 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main Outcome Measures %Hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI. Results Sucrose-SB increased %hepatic lipid (absolute change: 0.6±0.2%) compared with aspartame-SB (-0.2±0.2%, P&lt;0.05) and compared with baseline (P&lt;0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4±0.2%, P&lt;0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P&lt;0.01) and sucrose-SB (P&lt;0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P&lt;0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight. Conclusions Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks.