IMR Press / FBL / Volume 24 / Issue 2 / DOI: 10.2741/4713
Open Access Review
Fructose at the crossroads of the metabolic syndrome and obesity epidemics
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1 Glycation, Oxidation and Disease Laboratory, Department of Research, Touro University College of Osteopathic Medicine. 1310 Club Drive, 94592, Vallejo, CA, USA
2 Department of Medical Science, University of Guanajuato, 20 de Enero 929, 37320, Leon, Guanajuato, Mexico
*Correspondence: alejandro.gugliucci@tu.edu (Alejandro Gugliucci)
Front. Biosci. (Landmark Ed) 2019, 24(2), 186–211; https://doi.org/10.2741/4713
Published: 1 January 2019
Abstract

In this review, we highlight the specific metabolic effects of fructose consumption that are involved in the development of metabolic syndrome non-alcoholic fatty liver disease and its association with obesity. The specifics effects of fructose on the liver are particularly germane to the development of a vicious cycle that starts with liver steatosis driving insulin resistance. These effects include 1) increased de novo lipogenesis, 2) increased liver fat, 3) dyslipidemia 4) increased uric acid production which feeds back on increased fructose metabolism and, 5) increased methylglyoxal and Maillard reaction that may affect adenosyl-monophosphate-dependent kinase Fructose increases cortisol activation especially in visceral fat. The hormones involved in satiety control are affected by fructose consumption. Fructose derived advance glycation end-products may also induce a state of inflammation by engaging its receptor, RAGE. Directionality for the effect of fructose on metabolic syndrome is becoming clear: fructose drives hepatic fat, which in turn drives insulin resistance. There is an urgent need for more clinical and educational interventions to regulate/reduce fructose consumption in our population, especially in children and adolescents.

Keywords
Fructose
Obesity
Metabolic syndrome
Leptin
Fatty liver
Insulin resistance
Maillard reaction
AGEs
RAGE
De novo lipogenesis
Review
2. INTRODUCTION

Obesity is a global health problem that is increasing in prevalence around the world, affecting adults as well as children and adolescents. One out of three adults and three out of ten children or adolescents are obese or overweight (1, 2). Obesity is a risk factor for the development of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) (3), metabolic syndrome (MetS) (4-6), and is related to various chronic conditions including: high blood pressure (7), insulin resistance (IR) (8), dyslipidemia, atherosclerosis, a low-grade chronic inflammation, non-alcoholic fatty liver disease (NAFLD) and cancer (9).

Both obesity and metabolic syndrome are associated with various factors including genetics, physical activity, environment, and diet (6, 10). Diet, a component of lifestyle, plays a significant role in this epidemic specifically diets rich in fats, protein, sodium, and sugar (11). Since the past century, as the intake of added sugar has increased, at par, the effect of sugar on health has also been studied (12, 13). In 1900, sugar had already been shown to be related to various diseases (14). Currently, a large body of evidence has defined sugar as a toxic substance that contributes largely to non-communicable diseases, mainly due to the metabolic effects of fructose and its components (13, 15, 16). Despite the known metabolic effects of fructose, its dietary intake has continued to increase in recent years (17-19). Evidence is increasing for a key role of hepatic fructose metabolism leading to liver and visceral fat accumulation as a key factor that generates insulin resistance, which dovetails and generates MetS and ends up in obesity (20). Therefore, the purpose of this review is to highlight the specific metabolic effects of fructose consumption (beyond the caloric content) in the development of MetS, NAFLD and their association with obesity. Other aspects such as fructose’s addictive potential and central nervous system (CNS) actions will not be discussed at large and the reader is referred to other comprehensive reviews in these areas.

3. FRUCTOSE METABOLISM
3.3. Fructose is an isomer of glucose, but their metabolisms are quite different

Fructose is a monosaccharide found mainly in sucrose (50% glucose and 50% fructose), fruits, honey as well as in processed forms like fructose-containing caloric sweeteners (FCCS), high fructose corn syrup (HFCS) and employed in processed foods and beverages called sugar-sweetened beverages (SSBs) (21). Epidemiological studies have related fructose consumption (in sugar, or HFCS form) with obesity (22), MetS , T2DM (23), CVD (24) and NAFLD (6,25-27). The correlation with SSBs is particularly strong (28, 29). The mechanism of how fructose participates in these pathologies is not completely clear yet, however, different studies in both animals and humans (30, 31) has allowed the dissection of some of its metabolic effects.

Free fructose is absorbed directly in the intestinal lumen, whereas from larger molecules like sucrose, both glucose and fructose are acquired by the cleavage of sucrase (invertase), an enzyme found in the brush border of the villi or enterocyte of the small intestine (32, 33). Intestinal fructose is mostly transported via the glucose transporter 5 (GLUT5) via diffusion on the luminal side and glucose transporter 2 (GLUT2) on the basolateral side (33, 34). Fructose enters the liver from the portal circulation (32, 35). The liver contains two glucose and two fructose transporters, GLUT 2 and GLUT 8 respectively (Figure 1). Fructose transport and metabolism within hepatocytes is regulated by GLUT 8. (36, 37). Fructose is metabolized mostly in the liver (more than 80% undergoes first pass extraction), whereas when consumed in isolation, approximately 50% is converted to glucose, 15-20% into hepatic glycogen and 15-25% into lactate or fatty acids (FA) which are secreted as very low-density lipoproteins (VLDL) triglycerides (TG) or stored as intrahepatic fat (38-40).

Figure 1

It’s not all about the calories nor about all carbohydrates but a specific one. This diagram shows the comparison of the major pathways for the fate of either A) 100 g of glucose (from starch) or B) 100 of sugar (50% glucose and 50% fructose). A). After digestion of starch 1), glucose enters the portal vein 2). In the liver it is converted, in part, to glycogen 3) and most of it goes into the bloodstream 4) to feed the tissues as it increases insulin secretion 5) and glucose enters muscle and adipose tissues 6). The rest is used to fuel the liver itself via glycolysis 7) leading to Acetyl coenzyme A (AcCoA) 8) which generates energy in the mitochondria. Very little is converted to fat 9) via the process of de novo lipogenesis (DNL). B). After digestion of sugar 1), glucose and fructose enter the portal vein in equal amounts 2). In the liver, glucose will be turned, in part, into glycogen 3). Most of it enters the bloodstream 4) to feed the tissues as it increases insulin secretion 5) and glucose enters muscle and adipose tissues 6). Fructose does not leave the liver for the most part. Instead, it is quickly phosphorylated by FFK C, bypassing regulatory steps in glycolysis and flooding the system 7), 8). The trapped metabolites have one fate: they are turned into fat by de novo lipogenesis 9) and 10). This process impairs FA oxidation by the mitochondrion because malonylCoA inhibits carnitine palmitoyl transferase I (CPT I) and FA transport into the mitochondrion 9). Some of the trioses are also transformed into the toxic metabolite methylglyoxal (MG), which can be detoxified to D-lactate 11). These processes have dire consequences as explained in the next figures. Finally, as further developed in other diagrams, quick phosphorylation of fructose leads to energy depletion and uric acid production, which in turn stimulates fructose metabolism 12).

In the liver, three key enzymes metabolize fructose. First, fructose is phosphorylated to fructose 1 phosphate (fructose-1-P) by the enzyme fructokinase C (FFK C), also named ketohexokinase (KHK). Fructose-1-P is then converted into di-hidroxyacetone-phosphate (DHAP) by the enzyme aldolase B and glyceraldehyde-3-phosphate (G-3-P) via thiokinase (TKFC). These trioses participate in other metabolic pathways: glycolysis, lipid synthesis, gluconeogenesis, and glycogenesis (41, 42) (Figure 1). It is important to note that fructose enters glycolysis more directly, and consequently is not tightly regulated as glucose (19).

Most of the ingested fructose is extracted from the portal blood via first pass hepatic metabolism while only a small fraction of the ingested fructose will eventually enter the systemic circulation (40). It needs to be said that we rarely consume pure fructose, rather, it is co-ingested with glucose and this makes all the difference. To better highlight these differences, Figure 1 A and B compares what happens with a load of glucose (from pasta, for instance) and the same load of sucrose (fructose and glucose).

Some studies in animals (43, 44) and humans (45, 46) have shown that fructose, compared with glucose or starch in diets with the same number of calories, is able to increase food intake, visceral fat, circulating TGs, blood pressure and reduces fatty acid oxidation, insulin sensitivity and energy metabolism (47, 48). All of these characteristics are related to the presence of MetS and various scientific evidence shows that drinks sweetened with fructose or HFCS have a role in the pathogenesis of MetS and its components (6, 11, 23).

It is noteworthy that while glucose generates energy in the form of ATP during its metabolism, fructose consumption is able to the decrease the levels of intracellular ATP due to the quick process of phosphorylation by FFK C (Figure 1B). As we show further below, replenishing of the ATP increases AMP leading to its catabolism into uric acid. The lack of ATP in turn generates a mitochondrial oxidative stress that favors an increase of lipogenesis, blockade of the oxidation of FA (46) and stimulates gluconeogenesis (49-51) as we further elaborate in section 3.2. On the other hand, while the metabolism of glucose is limited by the amount of ATP and insulin, the metabolism of fructose is not limited by these factors.

As previously mentioned, the result of fructose ingestion (Figure 1) may first be evidenced by an increase in hepatic glucose production and the conversion to lactate in the liver which can be measured in the blood. After this, an increase in plasma lipids is observed due to the production of fat from fructose in the liver. As reported by multiple authors, high fructose concentrations converts pyruvate to acetyl-CoA by the reaction of pyruvate dehydrogenase. The flux of pyruvate dehydrogenase from increased entry into the TCA cycle also results in an increased acetyl-CoA and citrate cycled in the synthesis of fatty acids (52) which are stored as intrahepatic fat and/or secreted into the bloodstream as VLDL triglyceride. Liver fat accumulation is a key link to IR, an entity linked to MetS and NAFLD (53-55).

There is a close relationship between fructose consumption, DNL (FA and TG synthesis) and NAFLD. Fructose increases hepatic FFK C and induces DNL (25) which is increased in NAFLD (56, 57), a process characterized by an imbalance between the lipids synthesized via DNL or lipolysis and lipid oxidation or VLDL export from liver (58). The excess fat in the liver may lead to the development of hepatic IR (59) as well as nonalchoholic steatohepatitis (NASH), a stage that predisposes to cirrhosis (60, 61) and its complications (32, 35, 62).

Isotopic studies have shown that people with NAFLD produce 2 times more liver fat and secrete more VLDL-triglycerides via DNL compared to IR obese subjects and 3 times more compared with healthy subjects (9, 32). Moreover, prolonged exposure of lipids in the liver causes oxidative stress in the endoplasmic reticulum ER and this alters apolipoprotein B100 degradation as well as VLDL secretion (63), a condition described in people with NASH (61).

The main deleterious effects of fructose at the hepatic and systemic level include: insulin resistance, inflammation, stress hepatic, ATP depletion (64), DNL (triglyceride and fatty acid synthesis) (65-69), NAFLD, nonalcoholic steatohepatitis (NASH) (67, 70), acid uric production (47, 71), endoplasmic reticulum stress (ER), fibrosis (9)(71). These will be explored further in the following sections. In addition, we have proposed that the increase in trioses flux that increases lipogenesis should also greatly increase the generation of methylglyoxal (MG) and its detoxification product, D-lactate (72, 73). The importance of fructose metabolism in fatty liver disease is highlighted clearly by the fact that Pfizer is developing (phase 1) PF-06835918 a FK C inhibitor.

3.2. Fructose may be deleterious via methylglyoxal and the Maillard reaction

Fructose participates in formation of methylglyoxal compound (MG), a powerful precursor of advanced glycation end products (AGEs) formed in vivo (which are described in another section of this review). MG is detoxified as D-lactate. Trioses formed in the unregulated metabolism of fructose may increase the MG production in the liver (74, 75). This increase of MG generates dicarbonyl stress, which is characterized by modification/dysfunction of proteins (MG attacks especially arginine residues) and DNA (76-78). We have advanced the hypothesis that MG inactivates the enzyme adenosyl-monophosphate-dependent kinase (AMPK), which under normal conditions would activate the catabolic pathways in the liver. However, MG may have affinity for the three arginines of the subunit gamma of AMPK. When coupled to them, AMPK is inactivated thereby favoring the anabolic processes including lipogenesis and IR which are widely related to obesity, metabolic syndrome and NAFLD (73).

AMPK is a master regulatory enzyme that controls the cellular energy state (79-81). A decrease in energy activates AMPK by initiating catabolic pathways and inhibiting anabolic pathways (79, 82). AMPK is comprised of three sub units: alpha, beta and gamma (its allosteric site). The epsilon subunit is linked to AMP by 3 Arginine residues (79, 82). The allosteric regulation is influenced by the AMP/ATP ratio and blocking the allosteric site of AMP can inhibit activation of AMPK. Related to this, as previously described, the particular metabolism of fructose leads to the formation of triose (catalyzed by FFK C), a process that favors a rapid depletion of ATP (51, 83), while at the same time, AMP production forms uric acid. This change in proportion of ATP/AMP should activate AMPK with its consequent effects, however, under the consumption of fructose this does not happen. To explain this flagrant metabolic paradox, as shown in Figure 2.

Figure 2

Some of the deleterious actions of fructose on the liver may be due to the actions of methylglyoxal on master regulatory enzyme AMPK. As shown in Figure 1 B, fructose metabolism is largely hepatic. we have proposed that a surge of fructose (40 g in liquid form which is not uncommon in our diet), through unregulated metabolism, generates MG 1), which can be detoxified to D-lactate 2), and we use as a marker of this flux (76), a process that may be overwhelmed. MG is very reactive and may bind to the 3 key arginine residues in the allosteric site of AMPK, rendering it non responsive 3). AMPK favors energy generation, its cumulative actions may be summarized as anti-diabetic. If rendered inactive, the processes favored are gluconeogenesis 4), increasing hepatic production of glucose even in the fed state, lipogenesis 5) and cholesterol synthesis 6). These are precisely the processes which research has shown are stimulated by fructose, with the consequences of ectopic fat accumulation 7), hyperlipidemia 8), insulin hypersecretion 9) and therefore insulin resistance (53, 84). Further research is needed to fully establish the above as a clinically relevant mechanism.

It has been demonstrated that MG is metabolized by the glyoxalases system which is diminished in the presence of clinical obesity and glyceroneogenesis (74-76,85). Large loads of fructose can alter the metabolism of MG (86) increasing the excess of triose, MG and D-Lactate. D-lactate is of particular interest since its plasma levels have been used as a surrogate marker of MG flux (87-89). In support of our contention, Thornalley has found increased MG and D-lactate in obese adults (74, 76) and we have shown the same in adolescents in a cross sectional study (Reyna Rodriguez, Claudia Luevano, Sergio Solorio, Russell Caccavello, Yasmin Bains, Ma. Eugenia Garay and Alejandro Gugliucci, CCLM, in press 2018). Further, in an intervention study, fructose restriction resulted in a 38% decrease in D-lactate levels in just 10 days) (Yasmin Bains, Caccavello Russell, Michael Wen, Susan Noworolski, Kathleen Mulligan, Viva Tai, Jean-Marc Schwarz, Ayca Erkin-Cakmak, Robert Lustig and Alejandro Gugliucci unpublished results 2018).

Therefore, fructose, by increasing MG (and its product D-lactate) may play a key role in obesity and metabolic syndrome through the MG postulated mechanism on AMPK (73). More research is needed to ascertain this contention. It has also been proposed that the dicarbonyl stress promoted by MG (acting on many other proteins) can play an important role in the development of IR in obesity and increase the risk of developing DMT2 and NAFLD (76).

3.3. Fructose increases uric acid formation and has hypertensive effects

Uric acid, produced from the AMP generated by the metabolism of fructose, activates the renin-angiotensin system and inhibits endothelial nitric oxide (NO) a vasodilator, causing an increase in blood pressure (45,90-92) which, together with the mitochondrial effects of fructose contribute to MetS development (45,93-95). The fluxes of uric acid generated by fructose are a result of transient energy deficits generated by quick unregulated phosphorylation of fructose as depicted in Figure 1B. In Figure 3, we expand on the details of this process.

Figure 3

Some of the deleterious actions of fructose on the liver may be due to ATP depletion and uric acid formation. As depicted in Figure 1B, fructose bypasses the 2 key regulatory steps in glycolysis because The liver has the very active FFK C 1), that floods the cytosol with trioses and AcCoA 2), which lead to lipogenesis 3), fatty liver 4) and hyperlipidemia 5), especially because fructose is co-ingested with glucose which is used for glycogen production (instead of fructose, Figure 1 A) vs 1 B)). This drives insulin secretion which enhances lipogenesis 3). The rapid, unregulated phosphorylation of fructose leads to quick cytosolic ATP depletion 6). In order to replenish the cytosolic ATP the cells use adenylate kinase 7) to generate 1 ATP and 1 AMP from 2 ADP 8). AMP is an endproduct that is degraded into uric acid. Uric acid quenches NO, leading to impaired vascular tone and hypertension 10). One important feature of uric acid is that it has been shown to be a FFK C activator, and therefore a perpetuator of this cycle (93). Actually, the mutation by which we lost uricase during evolution has been proposed as an evolutionary advantageous feature, facilitating fruit fructose assimilation in times of plenty (96). Uricase expression in experimental animals reduces fructose deleterious effects (97). The importance of FFK C is further evidenced by recent studies showing that its activity is enhanced in both obese humans with NASH (98) and fructose-fed mice (99). Its knockdown prevents fructose-induced steatosis and IR 11) (45, 93).

Since uric acid is a consequent product of ATP depletion and increased AMP in fructose metabolism, it has been used as a marker of hepatic decrease of ATP (100, 101). Studies have reported that acid uric induces oxidative stress and inflammation increasing lipogenesis, decreasing FA oxidation as well as AMPK activity (49, 50, 100) similar to what happens when systems such as nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and nuclear factor-kappa B (NF-kB) are activated (102, 103).

Studies where the uric acid synthesis inhibitor allopurinol has been used, have shown that a decrease in uric acid improves the MetS induced by fructose (93) and that this decrease in uric acid has a beneficial impact on both blood pressure and IR in humans (104-106), besides, acid uric promotes to NALFD due it effect of increase lipogenesis (49, 50, 107).

The group of Lustig et al has shown that SSBs have an impact on uric acid levels and blood pressure even in adolescents (90), highlighting the need for timely interventions in this age group to prevent future complications. Furthermore, these authors have highlighted that in addition to a regulation of salt intake, a regulation in sugar consumption, and therefore fructose, should be a treatment goal to prevent both hypertension and the metabolic syndrome (91).

3.4. Fructose and cross-talk between visceral adipose tissue and hepatocytes. The role of cortisol

Fructose exerts effects on both adipose tissue and liver, including adipogenesis, oxidative stress, inflammation, and glucocorticoid activation (71, 108, 109) which induces an increase in proliferation and differentiation of adipocytes (110).

The activation of inactive glucocorticoids such as cortisone in humans and 11-dehydrocorticosterone in rodents to their active forms, cortisol and corticosterone respectively (110) refers to an increase in bioavailability of these active forms within cells (7, 111). This glucocorticoid transformation is exerted by the enzyme 11 beta-hydroxysteroid dehydrogenase (11-beta-OHSDH), which is expressed both in the liver and in adipose tissue (and in other tissues such as the kidney and skeletal muscle) and is found in the luminal membrane of the endoplasmic reticulum (ER) (110, 112).

This enzyme is crucial for glucocorticoid activation via its reductase activity, which is dependent on NADPH (7, 71, 113). This reductase activity is increased in the presence of hexose 6 phosphate dehydrogenase (H6PDH), which forms NADPH in the ER lumen and therefore maintains the reducing power (109,114-116). In addition to these cofactors, 11-beta-OHSDH is induced in the presence of pro-inflammatory cytokines (114,117-119). Thus, the way in which fructose activates glucocorticoids is via stimulating an inflammatory state and activating NADPH, which in turn induces 11-beta-OHSDH (110). In addition, studies have shown that fructose is capable of affecting the gene expression of 11-beta-OHSDH (120, 121). We summarize these data in Figure 4.

Figure 4

Fructose and cross-talk between visceral adipose tissue and hepatocytes. The role of cortisol. Fructose in hepatocytes (over 90% percent of intake) or visceral adipose tissue (minor but non-negligible concentrations) also induces local inflammation and activation of G6PDH 1). This leads to activation of 11βOHSDH which turns inactive cortisone into cortisol 2). Cortisol stimulates fat synthesis 3) in both tissues as well as deposit of ectopic fat 4). Visceral adipose tissue cross-talks via portal circulation with inflammatory molecules as well as FA which enhance liver IR. Cortisol stimulates gluconeogenesis and hepatic glucose output 7), as wells as hyperlipidemia 8).

Regarding the inflammation caused by fructose (122), studies have reported that its consumption can lead to infiltration of macrophages in adipocytes, which promotes release of pro-inflammatory cytokines and increased inflammation (116,119,123-125). In addition, fructose also participates in the development of inflammation and insulin resistance which induces ER stress in adipocytes (122) which depletes the expression of endoplasmic reticulum oxidoreductase 1 alpha (ERO-1alpha), an ER chaperon responsible for regulating the secretion of adiponectin, adipokine considered anti-inflammatory and insulin sensitizer (126). This state of inflammation caused by fructose stimulates 11-beta-OHSDH and elevates cortisol within cells with its consequent effects involved in different metabolic alterations including components of MetS (113, 124, 127, 128).

A close relationship has been reported between 11-beta-OHSDH, cortisol, obesity and MetS (127-130) since the cellular bioavailability of cortisol induces processes involved in the components of MetS. In fact studies have reported that people with metabolic syndrome show an increased expression of 11-beta-OHSDH and intracellular cortisol (131), a state similar to key metabolic processes present in Cushing's syndrome, which is characterized by an excess of glucocorticoids (132).

In regards to the effects of glucocorticoids active in adipose tissue, it has been documented that there is an increase of intracellular cortisol in subcutaneous adipocytes (110) (where 11-beta-OHSDH activity is doubled) (133, 134). This can be induced by the effects of fructose, resulting in insulin resistance in subcutaneous adipocytes, thereby inhibiting the entry of FA and promoting greater flow and storage of unesterified FA in visceral deposits, mainly liver and visceral adipose tissue (VAT) (110,130,135-137).

11-beta-OHSDH also has an effect on hypertension since it is expressed in vascular tissue and can influence the homeostasis of blood pressure. It has been described that glucocorticoids produce a vasoconstrictor effect (138) which can induce endothelial dysfunction (139).

It is important to note that unlike glucose, fructose induces this glucocorticoid activation; in vitro studies have reported that glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) stimulate the reductase activity of 11-beta-OHSDH (71, 110) both in liver microsomes and in adipose tissue microsomes. In the latter, the presence of ER-luminal F6P isomerase forms G6P through the formation of NADPH dependent of hexose-6-phosphate dehydrogenase (H6PDH) (109). In addition, studies have reported that fructose compared to glucose generates more ER-luminal NADPH since fructose is easily transported through the plasma membrane and F6P through the ER membrane compared to glucose and G6P (71).

Finally, although more studies are required, it has been suggested that cortisol effects induced by fructose can be mediated by the activity of FFK-C from the liver through a metabolic crosstalk and inflammation (126).

Therefore, when 11-beta-OHSDH increases cortisol within the cells, it plays a role in the increase of visceral fat, inflammation, IR, hyperlipidemia and hypertension; characteristics of MetS.

3.5. Dietary AGEs, role of fructose ages preformed on food and generated in the intestine

Fructose-mediated advanced glycation endproducts (AGEs) formation via the Maillard reaction in foods may also be implicated in inflammation and MetS (140). Though well known by food chemists for decades, the Maillard reaction by fructose at physiological temperatures and pressures was studied starting only in the 80’s (141). These early studies helped establish the potential harmful effects of fructose on proteins as far more potent than those from glucose. The Maillard reaction (adduct formation between reactive carbonyls in glucose, fructose and their metabolites-such as methylglyoxal or deoxyglucosone-with amino groups in protein, DNA and lipids) has been implicated in diabetes complications. Fructose is 8 to10 times more reactive than glucose for Maillard reaction product formation as a result of the higher stability of its open chain form and its keto group. It does not form the Amadori but the Heyns product (141). The common methods employed for glucose glycation do not detect the Heyns products and/or other fructose-mediated adducts which has slowed down research on the potential role of fructose glycation in the pathogenesis of chronic disease in humans. Fructose-AGE concentration was measured in more than 100 commercial products (142). The highest levels of Fructose-AGE were shown in yoghurt beverages. Glycation adducts in food can be absorbed (up to 10% of dietary AGEs are absorbed) and exert their deleterious effects via engagement of the pro-inflammatory receptor for advanced glycation end products (RAGE) (141). In Figure 5 we summarize two pathways by which fructose may exert pro-inflammatory effects by yet another mechanism.

Figure 5

Fructose-derived advanced glycation products: the role of dietary AGEs in inflammation and insulin resistance. The Maillard reaction between carbonyls and proteins has been implicated in the pathogenesis of diabetic complications. Fructose (10 times more reactive than glucose) forms AGEs in processed foods. 1) Preformed AGE proteins in food (processed food is very high in fructose) results in intestinal digestion and absorption of AGE peptides 2) which bind to RAGE and are pro-inflammatory and generators of IR 3). Another putative pathway, for which epidemiological evidence (143, 144) and our own in vitro (145, 146) data vouch for is intestinal formation of AGEs 5) and 6) when excess fructose and amino acids or peptides are found in the intestinal lumen as a result of the co-ingestion of sugar and proteins 4). These AGEs, when absorbed, will generate the same effects as shown in 3). More evidence should be forthcoming on the relative role of these processes in fructose-induced pathogenesis of IR.

4. FRUCTOSE AND WEIGHT GAIN

Different scientific evidence has shown a positive association between sugar-sweetened beverages (SSBs) and weight gain or obesity, and concluded that this type of beverages or free consumption of sugar in people who ingest them influence body weight by increasing both intake energy through its consumption and increasing appetite (113, 147, 148). Indeed, more than 80% of the studies without conflicts of interest with the food industry find a positive correlation between SSBs and obesity. The way in which fructose increases appetite or decreases satiety is through inducing an insulin and leptin resistance (44,149-151) state as shown in Figure 6. This has deleterious effects promoting metabolic diseases such as obesity, MetS, and cardiovascular disease (152).

Figure 6

Main pathways of fructose metabolism that lead to insulin resistance, metabolic syndrome and obesity. This diagram summarizes the key mechanisms at the whole body level. Surges of fructose 1) (together with glucose that increases insulin secretion) increase DNL 2) and liver fat 3). These in turn generate hepatic IR 4). Hyperinsulinemia ensues as a compensating mechanism 5). Subcutaneous fat, less resistant to insulin, accumulates fat 6) but also increases output of FFA 7). Visceral fat uptakes fatty acids and accumulates TG 8), increases in size and is inflamed. In situ cortisol production enhanced by fructose increases the effect 9). The mass of visceral fat uploads its inflammatory molecules as well as FFA to the portal vein which then increases hepatic IR 11). Subcutaneous fat increase leptin secretion (which would lead to decreased appetite and more energy expenditure) 12). However, hyperinsulinemia leads to CNS leptin resistance. This leads to less satiety, more food intake and the cycle goes on.

Leptin is a hormone synthesized mainly in adipose tissue which circulates in proportion to body fat. This hormone is a key regulator of energy intake via its interaction with hypothalamic centers, increasing satiety and energy expenditure (44, 153). However, both obesity and fructose consumption induce an alteration in the function of leptin, called leptin resistance (44, 154) where the hypothalamic centers become resistant to its action, consequently the satiety response that should be produced is inhibited resulting in greater food consumption (6). Studies have reported that a chronic consumption of fructose is associated with increased plasma leptin levels and insulin alteration (155-158), however under an acute consumption of fructose there are contrasting results (44, 155).

In addition to the effects on leptin, unlike glucose or starch, fructose has also an effect on intestinal hormones related to satiety, where it may not inhibit the release of ghrelin from the intestine leading to an orexigenic effect and releases, to a lesser extent, satiety hormones such as glucagon-like peptide 1 (GLP-1) and peptide YY (PPY) (13, 157). Further studies are required to establish these effects of fructose on intake since most of the related studies are based on indirect markers of control of food intake (13) and studies with direct measures of consumption intake or satiety have not been able to establish differences between fructose and other sugars in humans (159).

Some authors have indicated hunger can be stimulated when ATP concentrations are reduced in the liver by blocking FA oxidation, (160) a characteristic of fructose metabolism fructose. They suggest increased energy intake compensates for ATP levels but when intake is from sugar, the consequences include an accumulation of fat which may increase corporal weight (161).

Another mechanism involved in the weight gain associated with fructose consumption could be the effect that sugar has on inducing pleasurable responses by stimulating dopamine in the nucleus accumbens and midbrain (150, 162). A repeated stimulation of dopamine by sugar could alter the function of dopaminergic receptors, this has been demonstrated in obese subjects through image studies, while animal studies show signs of abstinence when removing sugar (43, 163).

Therefore, weight gain and obesity induced by fructose could be related to the addictive response to sugar consumption (150, 151), reduced ATP in liver as well as a promotion of resistance to leptin (6, 164).

5. OVERALL EFFECTS OF FRUCTOSE ON HUMAN METABOLISM

Although there are different epidemiological studies that evaluate the consumption of fructose in humans, causal relationships are more difficult to infer because it is challenging to separate the impact of the confounding variables that participate in these processes (13). However, among the main associations found in prospective studies is the associated fructose consumption (either through FCCS, SSBs or HFCS) with body weight gain (165), increased energy intake (166, 167), dyslipidemia, IR, T2DM (168), gout (169), chronic kidney disease (170), MetS (20) and NAFLD (9), and CVD (171).

In addition to weight, or fat mass, the total intake of energy is a confounding variable in these studies that evaluate the effects of fructose, however, studies where excess energy has been compared with diets high vs low in fructose have shown excess fructose can increase body fat and body weight in a few days (171), increase liver glucose production (53, 155, 172), increase TG (155, 172) intrahepatic fat accumulation (173), and increased uric acid concentrations (13, 172, 174).

It must be noted that fructose can be produced endogenously in the liver (and other tissues during hyperglycemia) and exerts its consequent metabolic effects through diets with high glycemic index and diets high in sodium that stimulate the enzyme aldose reductase and therefore an endogenous fructose secretion and contributing to MetS (175) (MA Lanaspa, Andres-Hernando, M Kuwabara, N Li, C Cicerchi, T Jensen, DJ Orlicky, C Roncal-Jimenez, T Ishimoto, T Nakagawa, et al. unpublished results, 2017).

As previously mentioned, is noteworthy that while glucose generates energy in the form of ATP during its metabolism, fructose consumption is able to the decrease the hepatic levels of ATP due to the quickly phosphorylaton by FFK C (Figure 1B), stimulating gluconeogenesis (49-51), lipogenesis, mitochondrial oxidative stress that alters the oxidation of fat and at the same time promotes depletion of ATP (46). Related to this it has been reported these effects can be observed after an oral ingestion of fructose equivalent to that containing a soft drink (64). A clinical study compared the effects of the consumption of glucose versus fructose sweetened beverages (which covered 25% of the total energy requirements) after 10 weeks in overweight and obese participants. The noteworthy results show that weight gain was similar with both beverages, but only the fructose beverage group showed DNL and, lipid in VAT, dyslipidemia and insulin resistance were augmented in overweight/obese participants (71, 172).

Summarizing the effects at the adipose tissue level, fructose can conduce adipogenesis, oxidative stress, inflammation, adipokine production, adipocyte hypertrophy, and as in the liver, fructose activates corticosteroids production through reductase activity of 11-beta-OHSDH (71, 112). Some studies have shown a high adipogenic potential in adipocyte precursor cells (APCs) related to fructose consumption that cause hypertrophy in adipocytes (71). An observational and longitudinal study evaluated changes in VAT after six years and evidenced that fructose may be a cause of insulin resistance and increased VAT found in consumers of major sugar-sweetened beverages amounts (176). However, the authors cannot clarify if these results were attributed only to fructose, glucose or both. Others related studies which compared the effects of fructose versus glucose have reported fructose excess mainly increase VAT while glucose excess increase subcutaneous fat (172). In addition, hypercaloric fructose-containing caloric sweeteners (FCCS) diets increase TG and acid uric levels while hypercaloric high-glucose or high-fat diets did not, without difference in weight-maintenance diet (177).

Regarding the effects of fructose on systemic IR, while some studies have reported that fructose induces IR (178-180), other studies report that fructose does not increase IR in muscle (measured by hyperinsulinemic-euglycemic clamps) (53,54,84,155,180).

Finally, regarding the effect of fructose on weight gain, studies have shown a stimulation of neural and pleasurable responses at the level of brain that are conducive to excessive energy intake (181-183), while at the hormonal level, besides insulin resistance, fructose can induce leptin resistance that can enhance hedonic responses by suppressing satiety (6,43,44,49,150,151,157,159)

The evidence from animal and human studies reviewed in this article converges to indicate a specific deleterious role of fructose in metabolism that favors DNL, liver steatosis and insulin resistance. The main pathways involved are summarized in Figure 6. Surges of fructose 1) (together with glucose that increases insulin secretion) increase DNL 2) and liver fat 3). These in turn generate hepatic IR 4). Hyperinsulinemia ensues as a compensating mechanism 5). Subcutaneous fat, less resistant to insulin, accumulates fat 6) but also increases output of FFA 7). Visceral fat uptakes fatty acids and accumulates TG 8), increases in size and is inflamed. In situ cortisol production enhanced by fructose increases this effect 9). The mass of visceral fat uploads its inflammatory molecules as well as FFA to the portal vein which then increases hepatic IR 11). Subcutaneous fat increases leptin secretion which would typically lead to decreased appetite and more energy expenditure 12). However, hyperinsulinemia leads to CNS leptin resistance leading to less satiety, increase food intake and the cycle goes on.

6. EVIDENCE SUPPORTING THE ROLES OF FRUCTOSE IN THE PATHOGENESIS PATHWAYS SUMMARIZED IN THIS REVIEW THAT STEM FROM OUR TEAM STUDIES ON HUMANS

All these observations, highlighting the relationship between fructose consumption and MetS, obesity, NAFLD, corticosteroid activation and MG and D-lactate production require relevant attention. Even organizations such as the World Health Organization (WHO) and the American Heart Association (AHA) (184, 185) suggest limiting sugar consumption. Despite these recommendations and with the accumulating evidence on the role of fructose in MetS and obesity, there has been no unanimous opinion about the specificity of fructose as a few authors (many of whom are partially funded by the sugar industry) continue to claim that the effects are merely due to an increase in caloric intake.

Figure 7

Evidence supporting the roles of fructose in the pathogenesis pathways summarized in this review that stem from our group studies on humans. Since overfeeding humans with sugar would lead to weight increase (and therefore a major confounding factor to interpret the data), we conducted a fructose restriction study as depicted in the figure, keeping, calories, CHO and macronutrients at the same level, so that changes could ascribed to the changes in fructose intake, which was reduced about 2/3rd from the diet of obese adolescents for only 10 days. Short-term fructose restriction with isocaloric substitution of complex carbohydrate in obese Latino & African American children whose habitual diets were high in sugar: Improved fasting lipids, lipoprotein subclasses, apo CIII, Improved fasting glucose, insulin and AUC during OGTT, Decreased hepatic de novo lipogenesis, Decreased liver fat. These results suggest that hepatic de novo lipogenesis may be an important mechanism contributing to liver fat accumulation in children, which can be reversed by short-term fructose restriction. These data suggest directionality for the effect of fructose on metabolic syndrome fructose drives hepatic fat, which in turn drives insulin resistance.

As a result, some of us decided to conduct a human intervention study that would help dissect this mechanism. We summarize our published results in Figure 7 (68, 186, 187). Since overfeeding humans with sugar would lead to a weight increase (and therefore a major confounding factor to interpret the data), we conducted a fructose restriction study as depicted in the figure, keeping calories, carbohydrate (CHO) and macronutrients constant so that changes could be ascribed to the changes in fructose intake, which was reduced by about 2/3rd from the diet of obese adolescents for only 10 days. Short-term fructose restriction with isocaloric substitution of complex carbohydrate in obese Latino & African American children whose habitual diets were high in sugar resulted in:

  • Improved fasting lipids, lipoprotein subclasses, apolipoprotein apo CIII
  • Improved fasting glucose, insulin and area under curve (AUC) during oral glucose tolerance test (OGTT)
  • Decreased hepatic de novo lipogenesis
  • Decreased liver fat
  • These results suggest that hepatic de novo lipogenesis may be an important mechanism contributing to liver fat accumulation in children, which can be reversed by short-term fructose restriction. This data suggests directionality for the effect of fructose on metabolic syndrome: fructose drives hepatic fat, which in turn drives insulin resistance. Further research is needed to fully establish the above mechanism, its long term effectiveness and the translation to adults.

    7. PERSPECTIVE

    We have highlighted the main metabolic effects of fructose consumption (unrelated to its caloric content) that are involved in the development of MetS, NAFLD and its association with obesity.

    We have made the case that the specifics effects of fructose (as compared with glucose) on the liver are particularly germane to the development of a vicious cycle that starts with liver steatosis. In addition, we have summarized the effects in adipose tissue, cortisol activation, and the hormones involved in satiety control, all of which are affected by fructose consumption. We put forward yet other mechanisms: the formation of MG and its effect on AMPK and other proteins, and fructose derived AGEs that induces a state of inflammation and oxidative stress by engaging RAGE and processes involved in the development of these aforementioned pathologies.

    These results underscore the need for more clinical and educational interventions within our population to regulate/reduce fructose consumption especially in children and adolescents, the main consumers of fructose, who have demonstrated significant metabolic alterations related to obesity and fructose consumption.

    8. ACKNOWLEDGMENT

    This work was funded in part by Touro University California. The authors are grateful to Dr. Ricardo Hermo for critical reading of the manuscript.

    References
    [1]
    MarieNg, TomFleming,MargaretRobinson,BlakeThomson,NicholasGraetz,ChristopherMargono,ErinC Mullany,StanBiryukov,CristianaAbbafati,Semaw Ferede Abera,JerryP Abraham, Niveen M EAbu-Rmeileh,TomAchoki,FadiaS AlBuhairan,Zewdie AAlemu,RafaelAlfonso,MohammedK Ali,Raghib Ali,Prof NelsonAlvis Guzman,Prof WalidAmmar,PalwashaAnwari,AmitavaBanerjee,SimonBarquera,SanjayBasu,DerrickA Bennett,ProfZulfiqar Bhutta,JedBlore, ProfNorberto Cabral,IsmaelCampos Nonato,Jung-ChenChang,RajivChowdhury, KarenJ Courville,ProfMichael H Criqui,David K Cundiff,KaustubhC Dabhadkar,ProfLalit Dandona,ProfAdrian Davis,Anand Dayama,SamathD Dharmaratne,EricL Ding,AdnanM Durrani,ProfAlireza Esteghamati,FarshadFarzadfar,DerekF J Fay,ProfValery L Feigin,AbrahamFlaxman, MohammadH Forouzanfar,AtsushiGoto,MarkA Green,RajeevGupta,NimaHafezi-Nejad,ProfGraeme J Hankey,HeatherC Harewood,RasmusHavmoeller,ProfSimon Hay,LuciaHernandez,AbdullatifHusseini,BulatT Idrisov,NayuIkeda,FarhadIslami,EimanJahangir,SimerjotK Jassal,ProfSun Ha Jee,MonaJeffreys,ProfJost B Jonas,EdmondK Kabagambe,ShamsEldin Ali Hassan Khalifa,AndrePascal Kengne,ProfYousef Saleh Khader,ProfYoung-Ho Khang,Daniel Kim,RuthW Kimokoti,JonasM Kinge,YoshihiroKokubo,SoewartaKosen,GeneKwan,TaaviLai,MallLeinsalu,YichongLi,XiaofengLiang,ShiweiLiu,GiancarloLogroscino,ProfPaulo A Lotufo,YuanLu,JixiangMa,NanaKwaku Mainoo,GeorgeA Mensah,TonyR Merriman,AliH Mokdad,JoannaMoschandreas,MohsenNaghavi,AliyaNaheed,DevinaNand,ProfK M Venkat Narayan,EricaLeigh Nelson,MarianL Neuhouser,MuhammadImran Nisar,ProfTakayoshi Ohkubo,SamuelO Oti,AndreaPedroza,ProfDorairaj Prabhakaran,ProfNobhojit Roy,UchechukwuSampson,HyeyoungSeo,SadafG Sepanlou,KenjiShibuya,RahmanShiri,IvyShiue,GitanjaliM Singh,JasvinderA Singh,ProfVegard Skirbekk,NicolasJ C Stapelberg,LelaSturua,BryanL Sykes,MartinTobias,BachX Tran,LeonardoTrasande,ProfHideaki Toyoshima,Stevenvan de Vijver,Prof Tommi J Vasankari,J Lennert Veerman,ProfGustavo Velasquez-Melendez,ProfVasiliy Victorovich Vlassov,ProfStein Emil Vollset,Theo Vos,ClaireWang,XiaoRongWang,ProfElisabete Weiderpass,Andrea Werdecker,JonathanL Wright,YClaire Yang,ProfHiroshi Yatsuya,JihyunYoon,ProfSeok-Jun Yoon,YongZhao,MaigengZhou,ProfShankuan Zhu,ProfAlan D Lopez,ProfChristopher J L Murray,ProfEmmanuela GakidouGlobal, regional, and national prevalence of overweight and obesity in children and adults during 19802013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet3847667812014
    [2]
    PAOWHO. Plan of action for the prevention of obesity in children and adolescents. 53rdDirecting Council. 66th Session of the Regional Committee of WHO for the Americans. Pan American Health Organization, Washington, D.C., U.S.A. 2014
    [3]
    AliMokdad,EarlFord,BarbaraBowman WilliamDietz FrankVinicor VirginiaBales James S.Marks Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.JAMA 2897679 200310.1001/jama.289.1.76
    [4]
    KathleenMartin,MitraMani,AryaManiNew targets to treat obesity and the metabolic syndrome.Eur J Pharmacol7636474201510.1016/j.ejphar.2015.03.093
    [5]
    Jean-Pierre Després,IsabelleLemieux Abdominal obesity and metabolic syndrome.Nature 14 881887 200610.1038/nature05488
    [6]
    RichardJohnson,LauraSanchez-Lozada,PeterAndrews,MiguelLanaspaA historical and scientific perspective of sugar and its relation with obesity and diabetes. Adv Nutr An Int Rev J8412422201710.3945/an.116.014654
    [7]
    MatthewA Bailey 11 beta-Hydroxysteroid dehydrogenases and hypertension in the metabolic syndrome. Curr Hypertens Rep, 19, 100 201710.1007/s11906-017-0797-z
    [8]
    EmilyGallagher,DerekLeRoithObesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol Rev 95727748 201510.1152/physrev.00030.2014
    [9]
    MetinBasaranoglu,GokcenBasaranoglu,TevfikSabuncu,HakanSentürkFructose as a key player in the development of fatty liver disease.World J Gastroenterol1911661172 201310.3748/wjg.v19.i8.1166
    [10]
    RobinRosset,AnnaSurowska,Luc Tappy Pathogenesis of cardiovascular and metabolic diseases: are fructose-containing sugars more involved than other dietary calories?. Curr Hypertens Rep 18 18201610.1007/s11906-016-0652-7
    [11]
    Vasanti S Malik,Frank B Hu Fructose and cardiometabolic health what the evidence from sugar-sweetened beverages tells us. J Am Coll Cardiol66161516242015
    [12]
    JohnYudkin Dietary carbohydrate and ischemic heart disease.Am Heart J 66 835836196310.1016/0002-8703(63)90301-6
    [13]
    LucTappy,Kim-AneHealth effects of fructose and fructose-containing caloric sweeteners: where do we stand 10 years after the initial whistle blowings?. Curr Diab Rep 15112201510.1007/s11892-015-0627-0
    [14]
    PCarton Les trois aliments meurtriers. Argentière. Imprimerie E Mazel; 1912.
    [15]
    RobertH Lustig,LauraA Schmidt,ClaireD Brindis Public health: the toxic truth about sugar. Nature4822729 201210.1038/482027a
    [16]
    GeorgeA Bray Fructose: pure, white, and deadly? fructose, by any other name, is a health hazard. J Diabetes Sci Technol 4 10031007 201010.1177/193229681000400432
    [17]
    RickA Vreman,AlexJ Goodell,LuisA Rodriguez,TravisC Porco TC,RobertH Lustig,JamesG Kahn Health and economic benefits of reducing sugar intake in the USA, including effects via non-alcoholic fatty liver disease: a microsimulation model. BMJ Open 7, e013543 201710.1136/bmjopen-2016-013543
    [18]
    Miriam B.Vos,JoelE Kimmons,CathleenGillespie,JeanWelsh,HeidiMichels Blanck Dietary fructose consumption among US children and adults: the third national health and nutrition examination survey. Medscape J Med 10, 160 2008
    [19]
    LucTappy,Kim-Ane Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 90 2346 201010.1152/physrev.00019.2009
    [20]
    AndrewA Bremer,MicheleMietus-Snyder,RobertH Lustig. Toward a unifying hypothesis of metabolic syndrome. Pediatrics 129 557570201210.1542/peds.2011-2912
    [21]
    L MHanover,JohnS White Manufacturing, composition, and applications of fructose. Am J Clin Nutr 58, 724S732S 199310.1093/ajcn/58.5.724S
    [22]
    MariaLuger,MaxLafontan,MairaBes-Rastrollo,EvaWinzer,VolkanYumuk,NathalieFarpour-Lambert sugar-sweetened beverages and weight gain in children and adults: a systematic review from 2013 to 2015 and a comparison with previous studies. Obes Facts 10 674693 201710.1159/000484566
    [23]
    FrankB Hu,VasantiS Malik Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav 1004754201010.1016/j.physbeh.2010.01.036
    [24]
    QuanheYang,ZefengZhang,EdwardW Gregg,W.Dana Flanders,RobertMerritt,FrankB Hu Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med 174 516524 201410.1001/jamainternmed.2013.13563
    [25]
    XiaosenOuyang,PietroCirillo,YuriSautin,ShannonMcCall,James L Bruchette,AnnaMae Diehl,Ricg¿hardJ Johnson,ManalF Abdelmalek Fructose consumption as a risk factor for non-alcoholic fatty liver disease.J Hepatol48993999 200810.1016/j.jhep.2008.02.011
    [26]
    KimberL Stanhope Sugar consumption, metabolic disease and obesity: the state of the controversy. Crit Rev Clin Lab Sci 535267201610.3109/10408363.2015.1084990
    [27]
    GeorgeA Bray,BarryM Popkin Dietary sugar and body weight: have we reached a crisis in the epidemic of obesity and diabetes?: health be damned! Pour on the sugar. Diabetes Care37950956201410.2337/dc13-2085
    [28]
    GeorgeA Bray,SamaraJoy Nielsen,BarryM Popkin Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79 537543 200410.1093/ajcn/79.4.537
    [29]
    DavidS Ludwig,KarenE Peterson,StevenL Gortmaker Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 357 505508 200110.1016/S0140-6736(00)04041-1
    [30]
    KimberL Stanhope,PeterJ HavelFructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Curr Opin Lipidol191624200810.1097/MOL.0b013e3282f2b24a
    [31]
    MarcK Hellerstein . Carbohydrate-induced hypertriglyceridemia: modifying factors and implications for cardiovascular risk. Curr Opin Lipidol 13 3340 200210.1097/00041433-200202000-00006
    [32]
    MetinBasaranoglu,GokcenBasaranoglu,ElisabettaBugianesi Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction. Hepatobiliary Surg Nutr 4 109116 2015
    [33]
    LaurieA Drozdowski,AlanBR Thomson Intestinal sugar transport. World J Gastroenterol12165716702006y
    [34]
    SharonBarone,StaceyL Fussell,AnuragKumar Singh,FredLucas,JieXu,CharlesKim,XudongWu,YilingYu,HassaneAmlal,UrsulaSeidler,JianZuo,ManoocherSoleimani: Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem28450565066200910.1074/jbc.M808128200
    [35]
    KasperW ter Horst,MireilleJ Serlie : Fructose consumption, lipogenesis, and non-alcoholic fatty liver disease. Nutrients 9, 981 201710.3390/nu9090981
    [36]
    ArmelleLeturque,EdithBrot-Laroche,MLe Gall,EmilieStolarczyk,VTobin the role of GLUT2 in dietary sugar handling. J Physiol Biochem 61 529537 200510.1007/BF03168378
    [37]
    BrianJ Debosch,ZhoujiChen,JessicaL Saben,BrianN Finck,KelleH Moley Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. J Biol Chem2891098910998201410.1074/jbc.M113.527002
    [38]
    GeorgeA Bray,BarryM Popkin Calorie-sweetened beverages and fructose: what have we learned 10 years later.Pediatr Obes8 242248201310.1111/j.2047-6310.2013.00171.x
    [39]
    VanessaC Campos,LucTappy Physiological handling of dietary fructose-containing sugars: implications for health.Int J Obes 40, S611201610.1038/ijo.2016.8
    [40]
    SamZ Sun,MarkW Empie Fructose metabolism in humans-what isotopic tracer studies tell us. Nutr Metab (Lond) 9, 89 201210.1186/1743-7075-9-89
    [41]
    PeterA Mayes Intermediary metabolism of fructose. Am J Clin Nutr 58, 754S765S 199310.1093/ajcn/58.5.754S
    [42]
    MadeehaAkram,AhmadHamid Mini review on fructose metabolism. Obes Res Clin Pract 7, e89e94 201310.1016/j.orcp.2012.11.002
    [43]
    NicoleM Avena,MiriamE Bocarsly,PedroRada,AgnesKim,BartleyG Hoebel After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance. Physiol Behav 94 309315 200810.1016/j.physbeh.2008.01.008
    [44]
    AlexandraShapiro,WeiMu,CarlosRoncal,Kit-YanCheng,RichardJ Johnson,PhilipJ Scarpace Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Integr Comp Physiol 29513701375200810.1152/ajpregu.00195.2008
    [45]
    TakahikoNakagawa,HanboHu,SergeyZharikov,KatherineR Tuttle,RobertA Short,OlenaGlushakova,XiaosenOuyang,DanielI Feig,EdwarR Block,JaimeHerrera-Acosta,JawaharlalM Patel,RichardJohnson A causal role for uric acid in fructose-induced metabolic syndrome.Am J Physiol Physiol 290, 625631 610.1152/ajprenal.00140.2005
    [46]
    SiriratReungjui,CarlosA Roncal,WeiMu,TitteR Srinivas,DhaveeSirivongs,RichardJ Johnson,TakahikoNakagawa Thiazide diuretics exacerbate fructose-induced metabolic syndrome. J Am Soc Nephrol 1827242731200710.1681/ASN.2007040416
    [47]
    ChadL Cox,KimberL Stanhope,JeanMarc Schwarz,JamesL Graham,BonnieHatcher,StevenC Griffen,AndrewA Bremer,BlasBerglud,JohnP McGahan,NancyL Keim,PeterJ Havel Consumption of fructose- but not glucose-sweetenedbeverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans.Nutr Metab (Lond) 9, 68 201210.1681/ASN.2007040416
    [48]
    ChadL Cox,KimberL Stanhope,JeanMarc Schwarz,JamesL Graham,BonnieHatcher,StevenC Griffen,AndrewA Bremer,BlasBerglud,JohnP McGahan,NancyL Keim,:Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women. Eur J Clin Nutr66201208201210.1681/ASN.2007040416
    [49]
    MiguelA Lanaspa,ChristinaCicerchi,GabrielaGarcia,NanxingLi,CarlosA Roncal-Jimenez,ChirstopherJ Rivard,BrandiHunter,AnaAndrés-Hernand,TakujiIshimoto,Laura G. Sánchez-Lozada,JeffreyThomas,RobertS Hodges,ColinT Mant,RichardJ JohnsonCounteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.PLoS One 7, e48801 201210.1371/journal.pone.0048801
    [50]
    MiguelA Lanaspa,LauraG Sanchez-Lozada,Yea-JinChoi,ChristinaCicerchi,MehmetKanbay M, CarlosA Roncal-Jimenez,TakujiIshimoto,NanxingLi,GeorgeMarek,MuratDunaray,GeorgeSchreiner,BernardoRodriguez-Iturbe,TakahikoNakagawa,Duk-HeeKang,YuriY Sautin,RichardJohnosn Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.J Biol Chem2874073240744201210.1074/jbc.M112.399899
    [51]
    RoichardJ Johnson,TakahikoNakagawa,LGabriela Sanchez-Lozada,MohamedShafiu,ShikhaSundaram,MyphoungLe,TakujiIshimoto,YuriY Sautin,MiguelA Lanaspa Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62 33073315 201310.2337/db12-1814
    [52]
    VijayalakshmiVarma,LasloG Boros,GregT Nolen,Ching-WeiChang,MartinWabitsch,RichardD Beger,JimKaput.Metabolic fate of fructose in human adipocytes: a targeted 13C tracer fate association study. Metabolomics 11 529544 201510.1007/s11306-014-0716-0
    [53]
    DavidFaeh,KaoriMinehira,JeanMarc Schwarz,RajPeriasamy,SeongooPark,LucTappy Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes5419071913200510.2337/diabetes.54.7.1907
    [54]
    IsabelleAeberli,MichelHochuli,PhilipA Gerber,LisaSze,StefanieB Murer,LucTappy,GiatgenA Spinas,KasparBerneis Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial.Diabetes Care36150156201310.2337/dc12-0540
    [55]
    MirjamDirlewanger,PhilippeSchneiter,EricJéquier, LucTappy Effects of fructose on hepatic glucose metabolism in humans.Am J Physiol Metab 279, E907-E9011 200010.1152/ajpendo.2000.279.4.E907
    [56]
    LucTappy,Kim-Anne Does fructose consumption contribute to non-alcoholic fatty liver disease? Clin Res Hepatol Gastroenterol36554560201210.1016/j.clinre.2012.06.005
    [57]
    ClareFlannery,SylvieDufour,RasmusRabol,GeraldShulman,KittFalk Petersen skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes61 27112717201210.2337/db12-0206
    [58]
    Seung-HoiKoo Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis.Clin Mol Hepatol19210215201310.3350/cmh.2013.19.3.210
    [59]
    ShinjiTamura,IshiroShimomura Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease: J Clin Invest11511391142200510.1172/JCI24930
    [60]
    RalucaPais,FrédericCharlotte,LarissaFedchuk,PierreBedossa,PascalLebray,Thierry Poynard,VladRatziu: A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol59550556 201310.1016/j.jhep.2013.04.027
    [61]
    StuartMcPherson,TimHardy,ElsbethHenderson,AlastairD Burt,ChristopherP Day,QuentinM Anstee Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management.J Hepatol6211481155201510.1016/j.jhep.2014.11.034
    [62]
    GiulioMarchesini,ElisabettaBugianesi,GabrieleForlani, FernandaCerrelli,MarcoLenzi,RitaManini,StefaniaNatale,EsterVanni,NicolaVillanova,NazarioMelchionda,MarioRizzeto:Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology37917923200310.1053/jhep.2003.50161
    [63]
    MeihuiPan,ArthurI Cederbaum,Yuan-LiZhang,HenryN Ginsberg,KevinJon Williams,EdwardFisher Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Invest 113 12771287 200410.1172/JCI19197
    [64]
    StephenJ Bawden,MaryC Stephenson,ElisabettaCiampi,KarlHunter,LucaMarciani,IanMacdonald,GuruprasadP Aithal,PeterMorris,PennyGowland Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study.Clin Nutr35645649201610.1016/j.clnu.2015.04.001
    [65]
    JeanMarc Schwarz,MichaelClearfield,KathleenMulligan.Conversion of Sugar to FatIs hepatic de novo lipogenesis leading to metabolic syndrome and associated chronic diseases? J Am Osteopath Assoc117520527201710.7556/jaoa.2017.102
    [66]
    JeanMarc Schwarz,KathleenNoworolski,MichaelJ Wen,ArtemDyachenko,JessicaPrior,MelissaE Weinberg,LaurieA Herraiz,VivaW Tai,NathalieBergeron,ThomasP Bersot,MadhuN Rao,MorrisSchambelan,KathleenMuligan Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat.J Clin Endocrinol Metab10024342442 201510.7556/jaoa.2017.102
    [67]
    RobertH Lustig Fructose and Nonalcoholic Fatty Liver Disease. J Calif Dent Assoc446136172016
    [68]
    JeanMarc Schwarz,SusanM Noworolski,AycaErkin-Cakmak,NatalieJ Korn,MichaelJ Wen,Viva WTai,GraceM Jones,SergiuP Palii,MoisesVelasco-Alin,KarenPan,BruceW Patterson,AlejandroGugliucci,RobertH Lustig,KathleenMulligan: Effects of dietary fructose restriction on liver fat, de novo lipogenesis, and insulin kinetics in children with obesity. Gastroenterology153743752201710.1053/j.gastro.2017.05.043
    [69]
    Payton J Jones Tracing lipogenesis in humans using deuterated water.Can J Physiol Pharmacol 74755760199610.1139/y96-070
    [70]
    JungSub Lim,MicheleMietus-Snyder,AnnieValente,JeanMarc Schwarz,RobertH Lustig The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome.Nat Rev Gastroenterol Hepatol 7251264201010.1038/nrgastro.2010.41
    [71]
    BalazLegeza,PaolaMarcolongo,AlessandraGamberucci,ViolaVarga,GaborBánhegyi,AngioloBenedetti,AlexOdermatt Fructose, glucocorticoids and adipose tissue: Implications for the metabolic syndrome. Nutrients 9, 426 201710.3390/nu9050426
    [72]
    AlejandroGugliucciFormation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv Nutr An Int Rev J85462201710.3945/an.116.013912
    [73]
    AlejandroGugliucci Fructose surges damage hepatic adenosyl-monophosphate-dependent kinase and lead to increased lipogenesis and hepatic insulin resistance. Med Hypotheses938792201610.3945/an.116.013912
    [74]
    NailaRabbani N,PaulJ Thornalley Glyoxalase in diabetes, obesity and related disorders.Semin Cell Dev Biol22309317201110.1016/j.semcdb.2011.02.015
    [75]
    NailaRabbani,PaulJ Thornalley Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease.Biochem Biophys Res Commun458221226201510.1016/j.semcdb.2011.02.015
    [76]
    JinitMasania,MalgorzataMalczewska-Malec,UrszulaRazny,JoannaGoralska,AnnaZdzienicka, BeataKiec-Wilk,AnnaGruca,JulitaStancel-Mozwillo,AldonaDembinska-Kiec,NailaRabbani,PaulJ ThornalleyDicarbonyl stress in clinical obesity.Glycoconj J33581589201610.1007/s10719-016-9692-0
    [77]
    PaulJ Thornalley,SinnanBattah,NailaAhmed,NikolaosKarachalias,StamatinaAgalou,RoyaBabaei-Jadidi,AnneDawnay: Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J375581592200310.1042/bj20030763
    [78]
    PaulJ Thornalley,SaharWaris,ThomasFleming,ThomasSantarius,SarahJ Larkin,BrigitteWinklhofer-Roob,MichaelR Stratton,NailaRabanni Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Res3854325442201010.1093/nar/gkq306
    [79]
    GraemeJ Gowans,SimonA Hawley,FionaA Ross,DGrahame Hardie AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation.Cell Metab18556566 201310.1016/j.cmet.2013.08.019
    [80]
    DGrahame Hardie AMPK: positive and negative regulation, and its role in whole-body energy homeostasis.Curr Opin CellBiol3317 201510.1016/j.ceb.2014.09.004
    [81]
    DGrahame Hardie AMPK-sensing energy while talking to other signaling pathways.Cell Metab206,939952201410.1016/j.cmet.2014.09.013
    [82]
    DGrahame Hardie,BethanyE Schaffer,AnneBrunet AMPK: An energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol26190201.201610.1016/j.tcb.2015.10.013
    [83]
    RichardJ Johnson,MiguelA Lanaspa,CarlosRoncal-Jimenez,LauraSanchez-LozadaEffects of Excessive Fructose Intake on Health.Ann Intern Med 156, 905 201210.7326/0003-4819-156-12-201206190-00024
    [84]
    Kim-AnneLe,MichaelIth,RolandKreis,DavidFaeh,MurielleBortolotti,ChristelTran,ChrisBoesch,LucTappy Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr8917601765200910.3945/ajcn.2008.27336
    [85]
    NailaRabbani,PaulJ Thornalley The critical role of methylglyoxal and glyoxalase 1 in diabetic nephropathy.Diabetes635052 201410.2337/db13-1606
    [86]
    SantoshSatapati,BlankaKucejova,JoaoA Duarte,JustinA Fletcher,LacyReynolds,NishanthE Sunny,TiantengHe,LArya Nair,KennethA Livingston,XiaorongFu,MatthewE Merrit,ADean Sherry,CraigR Malloy,JohnM Shelton,JenniferLambert,ElizabethJ Parks,IanCorbin,MarkA Magnuson,JeffreyD Browning,ShawnC Burgess: Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 126, 1605 201610.1172/JCI86695
    [87]
    ManS Oh,JaimeUribarri,DenisseAlveranga,IraLazar,NadineBazilinski,HughJ Carroll Metabolic utilization and renal handling of D-lactate in men. Metabolism34621625198510.1016/0026-0495(85)90088-5
    [88]
    JeanL J M Scheijen,NordinM J Hanssen,MarjoP H van de Waarenburg,DaysiM A E Jonkers,CoenD A Stehouwer,CasperG Schalkwijk L(+) and D(-) lactate are increased in plasma and urine samples of type 2 diabetes as measured by a simultaneous quantification of L(+) and D(-) lactate by reversed-phase liquid chromatography tandem mass spectrometry.Exp Diabetes Res 234812 2012
    [89]
    AngelikaBierhaus,ThomasFleming,StoyanStoyanov,AndreasLeffler,AlexandruBabes,CristianNeacsu,SusanneK Sauer,MirjamEberhardt,MartinaSchnolzer,FelixLasitschka,WinfriendL Morcos,TatjanaI Kichko,IlzeKonrade,RalfElvert,WalterMier,ValdisPirags,IvanK Lukic,MichaelMorcos,ThomasDehmer,NailaRabanni,PaulJ Thornalley,DianeEdelstein,CarlaNau,JosephineForbes,PerM Humpert,MarkusSchwaninger,DanZiegler,David M Stern,MarkE Cooper,UweHaberkorn,MichaelBrownlee,PeterW Reeh,PeterP Nawroth: Methylglyoxal modification of Nav1.8. facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med18926933201210.1038/nm.2750
    [90]
    StephanieNguyen,HyonK Choi,RobertH Lustig,Chi-yuanHsu Sugar-Sweetened Beverages, Serum Uric Acid, and Blood Pressure in Adolescents.J Pediatr154807813201810.1016/j.jpeds.2009.01.015
    [91]
    StephanieNguyen,RobertH Lustig Just a spoonful of sugar helps the blood pressure go up.Expert Rev Cardiovasc Ther814971479201010.1586/erc.10.120
    [92]
    UdayM Khosla,SergeyZharikov,JenniferL Finch,TakahikoNakagawa,CarlosRoncal,WeiMu,KarinaKrotova,EdwardR Block,SharmaPrabhakar,RichardJ Johnson: Hyperuricemia induces endothelial dysfunction. Kidney Int 6717391742200510.1111/j.1523-1755.2005.00273.x
    [93]
    WilliamBaldwin,StevenMcRae,GeorgeMarek,DavidWymer,VarinderpalPannu,ChrisBaylis,RichardJ Johnson,YuriY Sautin: Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 6012581269201210.2337/db10-0916
    [94]
    AlexOdermattThe western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Renal Physiol 301, F919-F91931 201110.1152/ajprenal.00068.2011
    [95]
    MingJin, FanYang,IreneYang,YingYin,Jin JunLuo,HongWang,Xiao-Feng Yang: Uric acid, hyperuricemia and vascular diseases. Front Biosci17 656669201210.2741/3950
    [96]
    SusumuWatanabe,Duk-HeeKang,LiliFeng,TakahikoNakagawa,JohnKanellis,HuiLan,MarildaMazzali,RichardJ Johnson: Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertens40355360200210.1161/01.HYP.0000028589.66335.AA
    [97]
    BStavric,WilliamJ Johnson,ScottClayman,R EGadd,AllisonM ChartrandEffect of fructose administration on serum urate levels in the uricase inhibited rat. Experientia 32373374197610.1007/BF01940847
    [98]
    AntonellaMosca,ValerioNobili,RitaDe Vito,AnnalisaCrudele,EleonoraScorletti,AlbertoVillani,AnnaAlisi,ChristopherD Byrne Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents.J Hepatol6610311036201710.1016/j.jhep.2016.12.025
    [99]
    AnaAndres-Hernando,NanxingLi,ChristinaCicerchi,ShinichiroInaba,WeiChen,CarlosRoncal-Jimenez,MyphuongT Le,MichaelF Wempe,TamaraMilagres,TakujiIshimoto,MehdiFini,TakahikoNakagawa,RichardJ Johnson,MiguelA Lanaspa:Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat Commun 8, 14181 201710.1038/ncomms14181
    [100]
    LauraGabriela Sánchez-Lozada,MiguelA Lanaspa,MagdalenaCristóbal-García,FernandoGarcía-Arroyo,VirgiliaSoto,DavidCruz-Robles,TakahikoNakagawa,Min-AYu,Duk-HeeKang,RichardJ JohnsonUric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations.Nephron Exp Nephrol 121, e71e78 201210.1159/000345509
    [101]
    John LPetrie,Gillian LPatman,IshitaSinha,Thomas DAlexander,Helen LReeves,LoranneAgius The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am J Physiol Endocrinol 305, E1255-E1265 201310.1159/000345509
    [102]
    TakujiIshimoto,Miguel ALanaspa,MyPhuong TLe,Gabriela EGarcia,Christine PDiggle,Paul SMacLean,Matthew RJackman,ArunaAsipu,Carlos ARoncal-Jimenez,Tomoki Kosugi,Christopher JRivard,ShoichiMaruyama,BernardoRodríguez-Iturbide,Laura GSánchez-Lozada,David TBonthron,Yuri YSautin,Richard JJohnson Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci 109 43204325 201210.1073/pnas.1119908109
    [103]
    PietroCirillo,Michael SGersch,WeiMu,Philip MScherer,KyungMee Kim,LoretoGesualdo,George NHenderson,Richard JJohnson,Yuri YSautin:Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular Cells. J Am Soc Nephrol 20 545553 200910.1681/ASN.2008060576
    [104]
    Daniel IFeig,BethSoletsky,Richard JJohnson Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. JAMA 300 924932 200810.1001/jama.300.8.924
    [105]
    BethSoletsky,Daniel IFeig Uric acid reduction rectifies prehypertension in obese adolescents. Hypertens 60 11481156 201210.1161/HYPERTENSIONAHA.112.196980
    [106]
    MumtazTakir,OsmanKostek,AbdulanOzkok, OmerCelal Elcioglu,AliBakan,AybalaErek,HasanHuseyin Mutulu,OzgeTelci,AysunSemerci,AliRiza Odabas,BarisAfsar,GerardSmits, MiguelALanaspa,ShailendraSharma,RichardJohnson,MehmetKanbay: Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Investig Med 63 924929 201510.1097/JIM.0000000000000242
    [107]
    Miguel ALanaspa,Laura GSanchez-Lozada,ChristinaCicerchi,Nanxing JLi,Carlos ARoncal-Jimenez,TakujiIshimoto,MyphuongLe,Gabriela EGarcia,Jeffrey BThomas,Christopher JRivard,AnaAndres-Hernando,BrandiHunter,GeorgeSchreiner,Bernardo Rodriguez-Iturbide,Yuri YSautin,Richard JJohnson Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 7, e47948 201210.1371/journal.pone.0047948
    [108]
    EdraLondon,Thomas WCastonguay. High fructose diets increase 11β-hydroxysteroid dehydrogenase type 1 in liver and visceral adipose in rats within 24-h exposure. Obesity (Silver Spring) 19 925932 201210.1038/oby.2010.284
    [109]
    SilviaSenesi,BalazsLegeza,ZoltanBalázs,MilkosCsala,PaolaMarcolongo,EvaKereszturi E,PeterSzelenyi,ChristineEgger,RossellaFulceri,JozsefMandl,RobertaGiunti,AlexOdermatt,GaborBanhegyi,AngeloBenedetti: Contribution of fructose-6-phosphate to glucocorticoid activation in the endoplasmic reticulum: possible implication in the metabolic syndrome. Endocrinology 151 48304839 201010.1210/en.2010-0614
    [110]
    GaborBánhegyi,AngeloBenedetti,RosellaFulceri,SilviaSenesi Cooperativity between 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the lumen of the endoplasmic reticulum. J Biol Chem 279 2701727021 200410.1074/jbc.M404159200
    [111]
    KarenChapman,MeganHolmes,JonathanSeckl 11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of tissue glucocorticoid action. Physiol Rev 93 11391206 201310.1152/physrev.00020.2012
    [112]
    AlexOdermatt,Denise VKratschmar Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases. An overview. Mol Cell Endocrinol 350 168186 201210.1016/j.mce.2011.07.020
    [113]
    James JDiNicolantonio,VarshilMehta,NeemaOnkaramurthy,James HO’Keefe Fructose-induced inflammation and increased cortisol: a new mechanism for how sugar induces visceral adiposity. Prog Cardiovasc Dis S00330620, 3016230167 2017
    [114]
    Jeremy WTomlinson,Jasbir SMoore,Mark SCooper,IwonaBujalska,MohsenShahmanesh,BurtCatherine,AlastairStrain,MartinHewison,Regulation of expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines 1. Endocrinology 142 19821989 200110.1210/endo.142.5.8168
    [115]
    Perrin CWhite,DanielaRogoff,DRandy McMillan,Gareth GLavery Hexose 6-phosphate dehydrogenase (H6PD) and corticosteroid metabolism. Mol Cell Endocrinol 265266, 8992 2006
    [116]
    Claudia AStaab,EdmundMaser: 11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. J Steroid Biochem Mol Biol 119 5672 201010.1016/j.jsbmb.2009.12.013
    [117]
    Karen EChapman,AgnesCoutinho,MohiniGray,James SGilmour,John SSavill,JonathanSeckl. Local amplification of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response. Ann N Y Acad Sci 1088 265273 200610.1196/annals.1366.030
    [118]
    KarenChapman,Agnes ECoutinho,MohiniGray,James SGilmour,John SSavill,Jonathan RSeckl The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response. Mol Cell Endocrinol 301 123131 200910.1016/j.mce.2008.09.031
    [119]
    Tian-QuanCai,BirmingWong,Steven SMundt,RolfThieringer,Samuel DWright,AnneHermanowski-Vosatka Induction of 11beta-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli. J Steroid Biochem Mol Biol 77 117122 200110.1016/S0960-0760(01)00041-3
    [120]
    BalazLegeza,ZoltanBalázs,AlexOdermatt Fructose promotes the differentiation of 3T3-L1 adipocytes and accelerates lipid metabolism. FEBS Lett 588 490496 201410.1016/j.febslet.2013.12.014
    [121]
    ZoltanBalázs,Roberto AS Schweizer,Felix JFrey,FrancoiseRohner-Jeanrenaud,AlexOdermatt DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins. J Am Soc Nephrol 19 92101 200810.1681/ASN.2007030263
    [122]
    GeorgeMarek,VarinderpalPannu,PrashanthShanmugham,BriannaPancione,DominicMascia,SeanCrosson,TakujiIshimoto,Yuri YSautin: Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway. Diabetes 64 508518 201510.2337/db14-0411
    [123]
    Gokhan SHotamisligil,Narinder SShargill,Bruce MSpiegelman Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259 8791 199310.1126/science.7678183
    [124]
    RolfThieringer,Cherly BLe Grand,LindaCarbin,Tian-QuanCai,BirmingWong,Samuel DWright,AnneHermanoswski-Vosatka:11 Beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol 167 3035 200110.4049/jimmunol.167.1.30
    [125]
    ShotaroNakajima,VivienKoh,Ley-FuangKua,JimmySo,LomantoDavide,Kee SiangLim,SvenHans Petersen,Wei-PengYoung,AsimShabbir,KojiKono: Accumulation of CD11c + CD163 + adipose tissue macrophages through upregulation of intracellular 11β-HSD1 in human obesity. J Immunol 197 37353745 201610.4049/jimmunol.1600895
    [126]
    Zhao VWang,Todd DSchraw,Ja-YoungKim,TayebaKhan,Michael WRajala,AntoniaFollenziandPhilip EScherer Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention. Mol Cell Biol 27 37163731 200710.1128/MCB.00931-06
    [127]
    Brian RWalker,RuthAndrew Tissue production of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 and metabolic disease. Ann N Y Acad Sci 1083 165184 200610.1196/annals.1367.012
    [128]
    HiroakiMasuzaki,JanicePaterson,HiroshiShinyama,Nicholas MMorton,John JMullins,Jonathan RSeckl,Jeffrey SFlier: A transgenic model of visceral obesity and the metabolic syndrome. Science 294 21662170 200610.1126/science.1066285
    [129]
    Roland HStimson,JonasAndersson,RuthAndrew,Doris NRedhead,FredrikKarpe,Peter CHayes,TommyOlsson,Brian R Walker cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes 58 4653 200910.2337/db08-0969
    [130]
    EdraLondon,Thomas WCastonguay Diet and the role of 11β-hydroxysteroid dehydrogenase-1 on obesity. J Nutr Biochem 20 485493 200910.1016/j.jnutbio.2009.02.012
    [131]
    EvaRask,Brian RWalker,StefanSöderberg,Dawn EW Livingstone,MatsEliasson,OweJohnson,RuthAndrew,TommyOlson Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87 33303336 2002
    [132]
    JohnNewell-Price,XavierBertagna,AshleyGrossman,Lynnette KNieman Cushing’s syndrome. Lancet (London, England) 367, 1605-1617610.1016/S0140-6736(06)68699-6
    [133]
    Dawn ELivingstone,Gregory CJones,KenSmith,Pauline MJamieson,RuthAndrew,ChristopherKenyon,Brian RWalker Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 141 560563 200010.1210/endo.141.2.7297
    [134]
    EvaRask,TommyOlsson,StefanSoderberg,RuthAndrew,Dawn EW Livingstone,OweJohnson,Brian RWalker: Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86 14181421 200110.1210/jcem.86.3.7453
    [135]
    MireilleSnel,Jacqueline TJonker,JanSchoones,HildoLamb,Albertde Roos,HannoPijl,Johannes WA Smit,AEdo Meinders,Ingrid MJazet Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions. Int J Endocrinol 2012, 983814 201210.1155/2012/983814
    [136]
    AnaVasiljević,BiljanaBursać,AnaDjordjevic,DanijelaVojnovic Milutinović,MarinaNikolić,GordanaMatić,NatasaVelickovic: Hepatic inflammation induced by high-fructose diet is associated with altered 11βHSD1 expression in the liver of Wistar rats. Eur J Nutr 53 13931402 201410.1007/s00394-013-0641-4
    [137]
    EdraLondon,Thomas WCastonguay High fructose diets increase 11β-hydroxysteroid dehydrogenase type 1 in liver and visceral adipose in rats within 24-h exposure. Obesity (Silver Spring) 19 925932 201110.1007/s00394-013-0641-4
    [138]
    Patrick WF Hadoke,ClareChristy,Yuri VKotelevtsev,Brent CWilliams,Christopher JKenyon,JonathanSeckl,John JMullins,Brian RWalker Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11beta-hydroxysteroid dehydrogenase. Circulation 104 28322873 200110.1161/hc4801.100077
    [139]
    Jamaira AVictorio,Stefano PClerici,RobertoPalacios,Maria JAlonso,Dalton VVassallo,Iris ZJaffe,Luciana VRossoni,Ana PDavel Spironolactone prevents endothelial nitric oxide synthase uncoupling and vascular dysfunction induced by β-adrenergic overstimulation: role of perivascular adipose tissue. Hypertens 68 726735 201610.1161/HYPERTENSIONAHA.116.07911
    [140]
    JaimeUribarri,MariaDolores del Castillo,MariaPía de la Maza,RosanaFilip,AlejandroGugliucci,ClaudiaLuevano-Contreras,Maciste HMacias-Cervantes,Deborah HMarkowicz,AlejandraMedrano,TeresitaMenini,ManuelPortero-Otin,ArmanoRojas,GeniRodrigues Sampaio,KazimierzWrobel,KatarzynaWrobel,Ma EugeniaGaray-Sevilla: Dietary advanced glycation end products and their role in health and disease. Nut Adv 6 461473 201510.3945/an.115.008433
    [141]
    AlejandroGugliucci Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Adv Nut 8 5462 201710.3945/an.116.013912
    [142]
    MasayoshiTakeuchi,MinaIwaki,Jun-IchiTakino,HikariShirai,MihokoKawakami,RichardBucala,Sho-IchiYamagishi: Immunological detection of fructose-derived advanced glycation end-products. Lab Investig 90 11171127 201010.1038/labinvest.2010.62
    [143]
    LuanneRobalo DeChristopher,JaimeUribarri,Katherine LTucker.Intake of high-fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent arthritis in US adults, aged 2030 years. Nutr Diabetes 6, e199 201610.1038/nutd.2016.7
    [144]
    LuanneRobalo DeChristopher,JaimeUribarri,Katherine LTucker Intake of high fructose corn syrup sweetened soft drinks is associated with prevalent chronic bronchitis in U..S. Adults ages 20-55 y. Nutr J 14, 107 201510.1186/s12937-015-0097-x
    [145]
    YasminBains,AlejandroGugliucci,RussellCaccavello Advanced glycation endproducts form during ovalbumin digestion in the presence of fructose: Inhibition by chlorogenic acid. Fitoterapia 120 15 201710.1016/j.fitote.2017.05.003
    [146]
    YasminBains,AlejandroGugliucci Ilex paraguariensis and its main component chlorogenic acid inhibit fructose formation of advanced glycation endproducts with amino acids at conditions compatible with those in the digestive system. Fitoterapia 117 610 201710.1016/j.fitote.2016.12.006
    [147]
    MairaBes-Rastrollo,Matthias BSchulze,MiguelRuiz-Canela,Miguel AMartinez-Gonzalez Financial conflicts of interest and reporting bias regarding the association between sugar-sweetened beverages and weight gain: a systematic review of systematic reviews. PLoS Med 10, e1001578 201310.1371/journal.pmed.1001578
    [148]
    Lisa ATe Morenga,Alex JHowatson,Rhiannon MJones,JimMann Dietary sugars and cardiometabolic risk: systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids. Am J Clin Nutr 100 6579 201410.3945/ajcn.113.081521
    [149]
    Jonh LSievenpiper,LucTappy,FredBrouns Fructose as a driver of diabetes: an incomplete view of the evidence. Mayo Clin Proc 90 984988 201510.1016/j.mayocp.2015.04.017
    [150]
    Robert HLustig Fructose: it’s “alcohol without the buzz.” Adv Nutr An Int Rev J 4 226235 201310.3945/an.112.002998
    [151]
    ElviraIsganaitis,Robert HLustig Fast food, central nervous system innsulin resistance, and obesity. Arterioscler Thromb Vasc Biol 25 24512462 200510.1161/01.ATV.0000186208.06964.91
    [152]
    JamesDiNicolantonio,Sean CLucan,James HO’Keefe The evidence for saturated fat and for sugar related to coronary heart disease. Prog Cardiovasc Dis 58 464472 201610.1016/j.pcad.2015.11.006
    [153]
    Rexford SAhima,Jeffrey SFlier Leptin. Annu Rev Physiol 62 413437 200010.1146/annurev.physiol.62.1.413
    [154]
    AbhiramSahu Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 24 225253 200510.1016/j.yfrne.2003.10.001
    [155]
    Kim-Anne,DavidFaeh,RodrigueStettler,MichaelIth,RolandKreis,PeterVermathen,ChrisBoesch,EricRavussin,LucTappy: A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Am J Clin Nutr 84 13741379 200610.1093/ajcn/84.6.1374
    [156]
    Ying-ChungLee,Ya-HuiKo,Yung-PeiHsu,Low-ToneHo: Plasma leptin response to oral glucose tolerance and fasting/re-feeding tests in rats with fructose-induced metabolic derangements. Life Sci 78 11551162 200610.1016/j.lfs.2005.06.009
    [157]
    Karen LTeff,Sharon SElliott,MatthiasTschöp,TimothyKieffer,DanielRader,MarkHeiman,Raymond RTownsend,Nancy LKeim,DavidD’Alessio,Peter JHavel: Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89 29632972 200410.1210/jc.2003-031855
    [158]
    Arshag DMooradian,JoeChehade,RobertHurd,Michael JHaas Monosaccharide-enriched diets cause hyperleptinemia without hypophagia. Nutrition 16 439441 200110.1016/S0899-9007(00)00229-X
    [159]
    AndreasLindqvist,AnnemieBaelemans,CharlotteErlanson-Albertsson Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul Pept 150 2632 200810.1016/j.regpep.2008.06.008
    [160]
    HongJi,GrazynaGraczyk-Milbrandt,Mark IFriedman Metabolic inhibitors synergistically decrease hepatic energy status and increase food intake. Am J Physiol Regul Integr Comp Physiol 278, R1579-R1582 200010.1152/ajpregu.2000.278.6.R1579
    [161]
    DanutacWlodek,MichaelGonzales Decreased energy levels can cause and sustain obesity. J Theor Biol 225 3344 200310.1016/S0022-5193(03)00218-2
    [162]
    PedroRada,Nicole MAvena,Bartley GHoebel Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134 737744 200510.1016/j.neuroscience.2005.04.043
    [163]
    RodolphSpangler,Knut MWittkowski,Noel LGoddard,Nicole MAvena,Bartley GHoebel,Sarah FLeibowitz Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Brain Res Mol Brain Res 124 134142 200410.1016/j.molbrainres.2004.02.013
    [164]
    Nora DcVolkow,Gene-JackWang,FrankTelang,Joanna SFowler,Panayotis KThanos,JeanLogan,DavidAlexoff,Yu-ShinDing,ChristopherWong,YemingMa,KithPradhan Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 42 15371543 200810.1016/j.neuroimage.2008.06.002
    [165]
    LarsLibuda,UteAlexy,Anette EBuyken,WolfgangSichert-Hellert,PeterStehle,MathildeKersting. Consumption of sugar-sweetened beverages and its association with nutrient intakes and diet quality in German children and adolescents. Br J Nutr 101 15491557 200910.1017/S0007114508094671
    [166]
    VasantiMalik,AnPan,Walter CWillett,Frank BHu Sugar-sweetened beverages and weight gain in children and adults: a systematic review and meta-analysis. Am J Clin Nutr 98 10841102 201310.3945/ajcn.113.058362
    [167]
    LisaTe Morenga,SimonetteMallard,JimMann Dietary sugars and body weight: systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ 346, e7492 201310.1136/bmj.e7492
    [168]
    Matthias BSchulze,JaAnn EManson,David SLudwig,Graham AColditz,Meir JStampfer,Walter CWillett,Frank BHu Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. JAMA 292 927934 200410.1001/jama.292.8.927
    [169]
    Wei-TingLin,Han-LiHuang,Ming-ChyiHuang,Ting-FungChan,Shin-YouCiou,ChangYoung Lee,Yi-WenChiu,Tsai-HuiDuh, Po-Lin Lin,Tsu-NaiWang,TinYan Liu,Chang-HongLee Effects on uric acid, body mass index and blood pressure in adolescents of consuming beverages sweetened with high-fructose corn syrup. Int J Obes (Lond) 37 532539 201310.1038/ijo.2012.121
    [170]
    WisitCheungpasitporn,CharatThongprayoon,Oisin AO’Corragain,Peter JEdmonds,WonngarmKittanamongkolchai,Stephen BErickson: Associations of sugar-sweetened and artificially sweetened soda with chronic kidney disease: A systematic review and meta-analysis. Nephrology 19 791797 201410.1111/nep.12343
    [171]
    QuanheYang,ZefengZhang,Edward WGregg,WDana Flanders,RobertMerritt,Frank BHu Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med 174 516524 201410.1001/jamainternmed.2013.13563
    [172]
    Kimebr LStanhope,JeanMarc Schwarz,Nancy LKeim,Steven CGriffen,Andrew ABremer,James LGraham,BonnieHatcher,Chad LCox,ArtemDyachenko,WeiZhang,John PMcGahan,AnthonySeibert,Ronald MKrauss,SallyChiu,Ernst JSchaefer,MasumiAi,SeikoOtokozawa,KatsuyukiNakajima,TakamitsuNakano,CarineBeysen,Marc KHellerstein,LarsBerglund,Peter JHavel Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 119 13221334 200910.1172/JCI37385
    [173]
    VirgileLecoultre,LeonieEgli,GuillaumeCarrel,FannyTheytaz,RolandKreis,PhilippeSchneiter,AndersBoss,KarinZwygart,Kim-AnneLe,MurielBortolotti,ChrisBoesch,LucTappy: Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity (Silver Spring) 21 782785 201310.1002/oby.20377
    [174]
    Santos EPerez-Pozo,JesseSchold,TakahikoNakagawa,LauraGabriela Sánchez-Lozada,Richard JJohnson,Joseph LLillo Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond) 34 454461 201010.1038/ijo.2009.259
    [175]
    Miguel ALanaspa,TakujiIshimoto,NanxingLi,ChristinaCicerchi,David JOrlick,PhilipRuzycki,ChristopherRivard,ShinichiroInaba,Carlos ARoncal-Jimenez,Elise SBales,Christine PDiggle,ArunaAsipu,J.Mark Petrash,TomokiKosugi,SchoichiMaruyama,Laura GSanchez-Lozada,James LMcManaman,David TBonthron,Yuri YSautin,Richard JJohnson Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun 4, 2434 2013
    [176]
    JinatoMa,Nicola MMcKeown,Shih-JenHwang,UdoHoffman,Paul FJaques,SCaroline Sugar-sweetened beverage consumption is associated with change of visceral adipose tissue over 6 years of follow-up. Circulation 133 370377 201610.1161/CIRCULATIONAHA.115.018704
    [177]
    DDavid Wang,John LSievenpiper,Russell Jde Souza,Adrian ICozma,LauraChiavaroli,VanessaHa,ArashMirrahimi,Amanda JCarleton,MarcoDi Buono,Alexandra LJenkis,Lawrence ALeiter,Thomas MS Wolever,JosephBeyne,Cyril WC Kendall,David JA Jenkins Effect of fructose on postprandial triglycerides: A systematic review and meta-analysis of controlled feeding trials. Atherosclerosis 232 125133 201410.1016/j.atherosclerosis.2013.10.019
    [178]
    Kimber LStanhope Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. Annu Rev Med 63 329343 201210.1146/annurev-med-042010-113026
    [179]
    AlbaRebollo,NuriaRoglans,MartaAlegret,Juan CLaguna Way back for fructose and liver metabolism: bench side to molecular insights. World J Gastroenterol 18 65526559 201210.3748/wjg.v18.i45.6552
    [180]
    Anne WThorburn,Phyllis ACrapo,KayGriver,PennyWallace,Rober RHenry Long-term effects of dietary fructose on carbohydrate metabolism in non-insulin-dependent diabetes mellitus. Metabolism 39 5863 199010.1016/0026-0495(90)90148-6
    [181]
    Robwrt HLustig. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc 110 13071321 201010.1016/j.jada.2010.06.008
    [182]
    Sonia YBernal,IrinaDostova,AsherKest,YanaAbayev,EsterKandova,KhalidTouzani,AnthonySclafani,Richard JBodnar Role of dopamine D1 and D2 receptors in the nucleus accumbens shell on the acquisition and expression of fructose-conditioned flavor–flavor preferences in rats. Behav Brain Res 190 5966 200810.1016/j.bbr.2008.02.003
    [183]
    MDaniel Lane,SeungCha Effect of glucose and fructose on food intake via malonyl-CoA signaling in the brain. Biochem Biophys Res Commun 382 15 200910.1016/j.bbrc.2009.02.145
    [184]
    Richard KJohnson,Lawrence JAppel,MichaelBrands,Barbara VHoward,MichaelLefevre,Robert HLustig,FrankSacks,Lyn MSteffen,JudithWylie-Rosettand on behalf of the American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism and the Council on Epidemiology and Preventionon Dietary sugars intake and cardiovascular health: a scientific statement from the American Heart Association. Circulation 120 10111020 200910.1161/CIRCULATIONAHA.109.192627
    [185]
    FredBrouns WHO Guideline: “Sugars intake for adults and children” raises some question marks. Agro Food Ind Hi Tech 26 3436 2015
    [186]
    AlejandroGugliucci,Robert HLustig,RussellCaccavello,AycaErkin-Cakmak,Susan MNoworolski,Viva WTai,Michael JWen,KathleenMulligan,Jean-MarcShwarz: Short-term isocaloric fructose restriction lowers apoC-III levels and yields less atherogenic lipoprotein profiles in children with obesity and metabolic syndrome. Atherosclerosis 253 171177 201610.1016/j.atherosclerosis.2016.06.048
    [187]
    RoberH Lustig,KathleenMulligan,SusanNoworolski,VivaJ Tai,MichaelWen,AycaErkin-Cakmak,AlejandroGugliucci,JeanMarc Schwarz Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity 10417341832017
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