Sugar-sweetened beverages and vascular function: food for thought.

OBESITY IS A well-recognized major global health problem, and the World Health Organization estimates that there are more than 600 million obese adults worldwide as of 2014. Because obesity is often the result of excess caloric intake, there has been a significant effort invested into understanding how various nutrients (e.g., carbohydrates and fatty acids) consumed in surplus adversely affect organ function and metabolic homeostasis. For example, there has been a multitude of research illustrating differences between saturated (e.g., palmitate) and unsaturated (e.g., oleate) fatty acids on obesity-related insulin resistance and type 2 diabetes (T2D), with a number of studies demonstrating that saturated fatty acids may be worse for insulin sensitivity due to promoting organ ceramide accumulation (1, 14). Extensive study has also taken place comparing the effects of various carbohydrates, primarily glucose versus fructose consumption in the form of sugar-sweetened beverages (SSBs), as SSBs are the primary source of added sugars in the diet. The main sweeteners used by the food industry for SSBs are high-fructose corn syrup and sucrose, which both contain approximately equal amounts of fructose and glucose (12). As such, robust research efforts have been invested into delineating the metabolic consequences of excess glucose and fructose consumption, with a number of studies highlighting fructose as the more detrimental sugar of the two. Indeed, it has been widely suggested that excess fructose consumption in animals increases hepatic de novo lipogenesis (DNL), dyslipidemia, and promotes obesity and insulin resistance (16). Similarly, observations in human studies from Stanhope and colleagues (13) have recapitulated these findings, as obese subjects consuming 25% of their daily energy requirements from fructose SSBs exhibited increases in fasting plasma insulin and glucose, as well as increases in hepatic DNL and visceral adiposity versus subjects consuming glucose SSBs. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Sangüesa et al. (10) add to the growing body of evidence implicating fructose as a more detrimental sugar than glucose with regard to metabolic homeostasis, with a specific focus on vascular health. Using a number of sophisticated techniques to assess lipid metabolism, insulin signaling, and vascular reactivity in hepatic and/or aortic tissues, Sangüesa et al. observed that although total caloric consumption was higher in glucose-supplemented female rats, fructose ingestion had a more significant negative impact on metabolic homeostasis and vascular function. It has been well documented that vascular dysfunction is a key contributor to obesity-related insulin resistance (11), and both insulin resistance and vascular dysfunction have been implicated as critical factors responsible for obesity-induced cardiomyopathy (2, 21). Thus it is tempting to speculate that fructosemediated vascular dysfunction is a precipitating event driving the increased risk for insulin resistance, T2D, and cardiovascular disease (CVD) in humans consuming fructose SSBs in surplus. Sangüesa et al. investigated the negative actions of fructose on endothelial function by assessing endotheliumdependent vasodilation to acetylcholine and bradykinin [nitric oxide (NO)-dependent vasodilators], or the NO donor sodium nitroprusside (SNP), as well as the vasoconstrictor response to phenylephrine. They observed that fructose had minimal effects on NO-dependent vasodilation but worsened NO donormediated vasodilation via SNP, whereas glucose augmented NO donor-mediated vasodilation. Interestingly, fructose had no negative effects on phenylephrine-induced contractions, whereas glucose actually reduced phenylephrine-induced contractions. To potentially explain the molecular mechanism behind the differential vascular responses in rats supplemented with glucose versus fructose, Sangüesa et al. evaluated a number of signaling pathways controlling vascular relaxation. Despite fructose SSB consumption impairing and glucose SSB consumption enhancing NO donor-mediated vasodilation, cyclic GMP (cGMP)-dependent protein kinase (PKG) protein expression and activity, as indicated by phosphorylation at serine 239 of the PKG downstream target vasodilator-stimulated phosphoprotein (VASP), were not different between these two groups. However, total VASP protein expression was significantly reduced only following fructose SSB supplementation. Furthermore, changes in NO-independent vasodilation appeared to be occurring following fructose SSB consumption, as cyclic AMP (cAMP)-dependent protein kinase-mediated phosphorylation of VASP at serine 157 was impaired, while mRNA expression of the cAMP phosphodiesterase 4, which specifically hydrolyzes cAMP, was increased by ~50%. Based on these findings, it would seem prudent for future studies to assess NO-independent vasodilation in thoracic aortic rings from animals consuming either fructose or glucose SSBs, though the authors did note that it has been previously reported that SNP-induced relaxation may also involve a cGMP-independent response (19). Of particular relevance, Sangüesa et al. also suggested that part of the beneficial actions of glucose versus fructose SSB consumption on vascular function might be due to increases in circulating adiponectin. To validate this, the authors treated endothelial EA.hy926 cells with either 25 mM glucose, 25 mM fructose, or various concentrations of adiponectin and observed that only adiponectin increased NO levels in the cell culture Address for reprint requests and other correspondence: J. R. Ussher, 2-020C Katz Centre for Pharmacy and Health Research, 11361 87 Ave., University of Alberta, Edmonton, AB T6G 2E1, Canada (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 312: H285–H288, 2017; First published December 30, 2016; doi:10.1152/ajpheart.00783.2016.