Impact of Coffee Consumption on Fructose-Related Metabolic Alterations: Potential Mechanisms and Implications for Metabolic Diseases

1. Introduction

Coffee is one of the most widely consumed beverages worldwide and has been valued since ancient times for its stimulant properties and distinctive flavor. Its chemical composition is highly complex, comprising more than 1000 phytochemicals, including methylxanthines, amino acids, phenolic acids, and other polyphenols [1]. This composition varies according to species, bean quality, roasting degree, and brewing method [1]. Roasting may reduce antioxidant polyphenols, whereas caffeine content is generally higher in Coffea robusta than in Coffea arabica [1]. Based on the brewing process, coffee can be broadly classified as boiled unfiltered, filtered, or decaffeinated coffee, with its final chemical profile influenced by grind size, water-to-coffee ratio, temperature, and extraction time [2].

Coffee consumption varies markedly across countries in terms of per-capita intake, total volume, and preferred coffee type, suggesting that exposure to coffee-derived bioactive compounds may differ according to population and consumption patterns [3,4].

In recent years, coffee and its bioactive compounds, including caffeine, chlorogenic acid (CGA), and caffeic acid, have received increasing attention due to their potential contribution to the health benefits associated with coffee intake [5]. In this context, coffee consumption may represent a potential protective dietary factor against metabolic alterations promoted by Western dietary patterns, particularly those associated with high fructose intake.

Excessive fructose intake, mainly through sugar-sweetened beverages (SSBs), has emerged as an important dietary factor associated with metabolic disturbances, including insulin resistance (IR), dyslipidemia, hepatic lipid accumulation, oxidative stress, and low-grade inflammation. Globally, the prevalence of high SSB consumption among young adults increased from 6.58% in 1990 to 11.13% in 2021 [6]. In the same year, high SSB consumption reached a global summary exposure value of 30.56%, with the highest levels observed in high-income countries and in Latin America and the Caribbean [7]. In Mexico, SSBs are the most frequently consumed beverage category across age groups, with reported consumption of 82.6% in preschool children, 93.6% in school-aged children, 90.3% in adolescents, and 76.3% in adults. Moreover, global SSB consumption is projected to increase by 9.54% by 2050, highlighting the growing relevance of sugar-related metabolic risk [7].

This review aims to summarize current evidence on whether coffee consumption and coffee-derived bioactive compounds can modulate fructose-induced metabolic alterations and to discuss the potential mechanisms involved.

2. Fructose intake from sugar-sweetened beverages and metabolic disease risk

Evidence from pediatric and adult populations supports a positive association between fructose intake from SSBs and the increasing prevalence of obesity and other non-communicable diseases, with the magnitude of these effects depending on the amount, frequency, and duration of exposure [8]. For instance, in children and adolescents, higher SSB consumption, represented by the highest quartile of intake with a median of 142 mL/day, was associated with an increased risk of incident metabolic syndrome, abdominal obesity, and hypertension compared with those in the lowest quartile, with a median intake of 9.3 mL/day [9]. This association has also been observed in adults, in whom consumption of ≥1 SSB/day was associated with higher diastolic blood pressure (DBP), while in women, it was positively associated with body mass index (BMI), DBP, triglycerides, and fasting glucose [10]. Furthermore, adults with high SSB consumption (>285 kcal/day) had a 2.83-fold higher risk of cardiovascular mortality compared with those with the lowest SSB intake (<128 kcal/day), whereas no associations were found with other dietary patterns [11]. Frequent SSB consumption (≥3/week) in adults has also been associated with higher odds of metabolic dysfunction-associated steatotic liver disease (MASLD) [12].

Evidence from intervention studies further supports these metabolic effects. In healthy volunteers, a three-week intervention with different SSBs (600 mL/day) showed that high-fructose beverages (80 g/day) reduced hepatic insulin sensitivity, as reflected by lower suppression of hepatic glucose production during the clamp, despite no changes in fasting glucose, insulin, or C-peptide compared with high-glucose beverages (80 g/day) [13]. In addition, moderate-fructose (40 g/day), high-fructose (80 g/day), and high-sucrose beverages (80 g/day) increased low-density lipoprotein cholesterol (LDL-C) and total cholesterol [13]. Similarly, in healthy men, daily consumption of moderate-fructose and sucrose-sweetened beverages (80 g/day) for seven weeks led to a 2-fold increase in basal hepatic fractional secretion rates of newly synthesized fatty acid compared with moderate glucose SSB [14]. Consistently, in healthy women, a fructose-rich single meal with an SSB providing approximately 18–25 g of fructose increased postprandial triglycerides (TG) and leukocyte concentrations at 240 minutes compared with sucrose- and glucose-rich meals [15]. In contrast, high-fructose intake (150 g/day) for eight weeks did not alter ectopic lipid deposition, hepatic glycogen storage, myocardial function, or myocardial mass in healthy individuals [16]. However, these alterations were evident in insulin-resistant patients with non-alcoholic fatty liver disease (NAFLD) [16], suggesting that the metabolic effects of fructose intake may depend on the underlying metabolic status.

In addition to hepatic and metabolic effects, high fructose intake may also influence metabolic risk through changes in the gut microbiota. In healthy women, a pilot study showed that a fruit-rich diet providing 100 g/day of fructose increased Firmicutes and butyrate-producing bacteria, whereas a high-fructose syrup diet reduced beneficial taxa such as Faecalibacterium and Erysipelatoclostridium [17]. However, these findings are not consistent across studies and may depend on the fructose source, fiber content, and food matrix [18,19]. In murine models, fructose-rich diets have been associated with intestinal dysbiosis, including reduced Bacteroidetes, increased Proteobacteria, and changes in taxa related to short-chain fatty acids (SCFA) production, intestinal barrier integrity, and inflammatory responses [20,21,22]. Therefore, alterations in the gut microbiota may be another mechanism by which high fructose intake contributes to metabolic alterations.

Taken together, current evidence supports fructose intake from SSBs as an important dietary contributor to obesity, metabolic alterations, liver disease, and cardiovascular risk.

3. Coffee Consumption

According to consolidated data from the International Coffee Organization, global coffee consumption is projected to reach a record 169.4–172.5 million 60-kg bags, equivalent to an approximate daily intake of 2.25 billion cups worldwide [3]. Northern Europe has the highest density of chronic coffee exposure. Finland ranks as the leading country in per-capita consumption, with an estimated per-capita consumption of approximately 12 kg/person/year. In contrast, the United States represents the largest critical mass in terms of total volume, consuming 1.43 million tons annually, while 66% of adults report daily coffee intake [4].

Although Mexico ranks among the world’s leading coffee-producing countries, its domestic per-capita consumption remains moderate to low compared with that of major importing nations. Average individual intake is estimated at only 0.3 cups/day (approximately 5 cups/week), corresponding to an annual per-capita consumption of roughly 1.3–1.7 kg/person/year [23]. Nevertheless, United States Department of Agriculture reports indicate that total domestic consumption reaches approximately 3.9 million 60-kg bags annually, underscoring the substantial size of the internal market despite relatively low individual intake [23]. In addition, instant coffee continues to dominate the Mexican market, accounting for 57% of total domestic consumption, whereas ground coffee represents the remaining 43% [23]. These differences in coffee consumption patterns are relevant because coffee type, preparation method, and additive use may influence the metabolic effects associated with coffee intake.

4. Coffee intake and metabolic disease-related outcomes

4.1. Obesity

Emerging evidence suggests that the association between coffee consumption and obesity-related outcomes is heterogeneous. A cross-sectional study including 1,855 participants found that moderate coffee intake (2–3 cups/day) was associated with a more favorable body composition and inflammatory profile. Similar findings were observed among individuals who consumed unsweetened coffee compared with those who consumed sweetened coffee [24]. Moreover, a randomized crossover interventional study including 38 participants with overweight or obesity found that consumption of 3 cups/day of both roasted and lightly roasted coffee for 12 weeks reduced fat mass and body fat percentage, while slightly increasing muscle mass percentage. Notably, the reduction in body fat percentage was greater after consumption of lightly roasted coffee than after roasted coffee [25]. Conversely, a prospective study with a 2-year follow-up in 170 kidney transplant recipients showed that, compared with lower coffee consumption (0–1 times/day), higher intake (2–3 times/day) was associated with greater waist circumference, higher waist-to-height ratio, increased odds of central obesity, and poorer muscle quality [26]. Overall, the available evidence suggests that the health effects of coffee consumption are not uniform and may vary according to underlying health status.

In addition, studies suggest that the association between coffee consumption and adiposity may vary according to sex. A meta-analysis of 12 epidemiologic studies found that higher coffee intake was modestly associated with lower BMI and waist circumference, particularly in men [27]. Another meta-analysis of 23 studies reported a significant positive association between coffee consumption and the odds of general obesity in women [28]. Individual studies further support these sex-specific differences, showing that light coffee intake was associated with lower odds of sarcopenia in men, whereas more frequent coffee consumption was linked to higher odds of both general and central obesity in women [29]. This is particularly relevant because obesity is one of the main metabolic outcomes associated with chronic high-fructose intake.

4.2. Type 2 diabetes

Accumulating evidence suggests that coffee consumption may be inversely associated with the risk of type 2 diabetes (T2D), although the magnitude of this association may vary according to coffee composition, additive use, and population characteristics. In a cohort study including 334 individuals with prediabetes followed for 3 years, coffee consumption was associated with a nearly twofold higher likelihood of returning to normoglycemia [30]. In addition, compared with non-drinkers, coffee drinkers showed significantly lower 2-hour serum glucose concentrations over time [30]. A meta-analysis including 15 studies found that sugar-sweetened beverage consumption was associated with a higher risk of both incident type 2 diabetes and mortality, whereas coffee intake was associated with a lower risk of T2D incidence and mortality [31]. Moreover, in three large prospective cohorts comprising 3,665,408 person-years of follow-up, each additional cup of coffee consumed without additives was associated with a 10% lower risk of T2D. However, the addition of sugar or artificial sweeteners significantly attenuated this inverse association, suggesting that these additives may weaken the protective association of coffee with T2D risk [32]. Furthermore, evidence from two large prospective cohorts with median follow-ups of 13.9 and 7.4 years showed that each 1-cup/day increase in coffee consumption was associated with a 4% lower risk of T2D. Higher coffee intake was also associated with lower homeostatic Model Assessment for Insulin Resistance and C-reactive protein levels, as well as higher adiponectin and IL-13 concentrations and lower leptin levels, suggesting that improvements in insulin resistance and inflammatory status may partially underlie this inverse association [33]. Consistently, a dose-response meta-analysis of 12 cohort studies including 266,183 men found that each additional daily cup of coffee was associated with a lower risk of T2D, although the association appeared to be nonlinear, suggesting that moderate intake may confer greater benefit than higher consumption levels [34]. In a cross-sectional study including 6,311 women with a median age of 53 years, higher intake of caffeinated coffee (>3 cups/day) was associated with a lower risk of T2D, but not with gestational diabetes mellitus [35]. Notably, this inverse association appeared to be more pronounced among individuals with obesity and those with lower levels of physical activity [35]. Overall, current evidence supports an inverse association between coffee consumption and T2D risk, with moderate intake and coffee consumed without additives appearing to show the most consistent favorable associations. These associations are relevant in the context of fructose-induced insulin resistance, one of the central mechanisms linking SSB intake with metabolic disease.

4.3. Liver diseases and MASLD

Because MASLD has recently replaced NAFLD in the updated nomenclature, both terms are used according to the terminology applied in the cited studies. Accumulating evidence suggests that the association between coffee consumption and liver-related outcomes may vary according to coffee type, sweetener use, and the specific hepatic endpoint evaluated. In a longitudinal cohort of 170,044 participants followed for a median of 12.4 years, unsweetened coffee consumption (>3.5 cups/day) was associated with the lowest risk of chronic liver disease and liver-related events, suggesting a protective effect [36]. In contrast, sweetened coffee showed less consistent associations, while added sugar or artificial sweeteners were linked to a higher risk of adverse liver outcomes, particularly at higher artificial sweetener intake [36]. Similarly, in a cross-sectional study of 8062 participants, coffee consumption was inversely associated with NAFLD risk, with a 21% lower risk among those consuming >4 cups/day; this association appeared stronger in women and in individuals with lower educational attainment [37]. In addition, in a cohort study of 1,079 participants with a median age of 59 years, higher coffee consumption was associated with a lower risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), with the greatest reduction observed among those consuming 4–6 cups/day (59.3%) [38]. Consistently, another cohort including 185,437 participants with a median follow-up of 10.49 years found that intake of >2.5 cups/day of unsweetened coffee, caffeinated coffee, or both was associated with a lower risk of MASLD, with the inverse association being particularly evident for caffeinated coffee [39]. Taken together, the available evidence suggests that unsweetened and caffeinated coffee may be more consistently associated with favorable liver-related outcomes than sweetened coffee or coffee with added sweeteners.

Conversely, a study including 5266 participants without MASLD and 1326 with MASLD but without advanced liver fibrosis found that coffee consumption was not associated with a lower risk of incident MASLD, but intake of ≥2 cups/day was linked to a lower risk of fibrosis progression in those with pre-existing MASLD, suggesting a hepatoprotective effect on disease progression rather than disease onset [40]. Moreover, a meta-analysis of 14 randomized controlled trials including 897 participants found no significant effect of coffee consumption on liver enzymes, although it increased adiponectin concentrations, suggesting a potential benefit on liver dysfunction [41]. Overall, coffee consumption appears to be more consistently associated with a lower risk of adverse liver outcomes and fibrosis progression than with incident MASLD.

4.4. Liver diseases and MASLD

Several studies have suggested a protective role of coffee consumption against cardiovascular disease (CVD). In a cohort study including 449,563 participants with a median age of 58 years and a median follow-up of 12.5 years, consumption of all coffee subtypes (decaffeinated, ground, and instant) was associated with a lower risk of incident CVD, with the lowest risk generally observed at 2–3 cups/day, particularly for decaffeinated and instant coffee [42]. In addition, consumption of both ground and instant coffee was associated with a lower risk of incident arrhythmia, with the greatest risk reduction observed at 4–5 cups/day for ground coffee [42]. Similarly, among never-smoking adults with T2D, moderate coffee consumption (2–4 cups/day) was associated with a lower risk of total CVD, coronary heart disease, myocardial infarction, and heart failure, suggesting a favorable association with cardiovascular health even in metabolically vulnerable populations. Notably, this inverse association with total CVD was observed for instant and ground coffee, but not for decaffeinated coffee, whereas the lower risk of major vascular disease was evident for decaffeinated and instant coffee, with a similar but non-significant trend for ground coffee [43]. By contrast, subgroup analyses from a meta-analysis of 32 prospective cohort studies suggested that coffee consumption was associated with an increased risk of coronary heart disease (CHD) in men, whereas a potentially reduced risk was observed in women [44]. The same meta-analysis also reported a higher risk of CHD in studies with follow-up periods of 20 years or longer [44]. Therefore, the available evidence suggests that the cardiovascular effects of coffee may vary according to the subtype consumed. However, further experimental and longitudinal studies are required to better define the specific impact of each coffee subtype and to elucidate the mechanisms underlying these associations.

In addition to its potential protective effects, coffee consumption has been associated with a lower risk of cardiovascular mortality. In a meta-analysis of ten prospective cohort studies including 82,270 participants with T2D, coffee consumption (4 cups/day) was associated with a lower risk of cardiovascular mortality, CHD mortality, CHD, and total cardiovascular events [45]. In a study including 10,639 participants, coffee consumption of ≥540 g/day was associated with a reduced risk of CVD mortality, and this risk decreased significantly with increasing coffee intake among coffee consumers, suggesting an inverse dose–response association [46]. In the same study, prolonged sedentary behavior was associated with increased all-cause mortality only among non-coffee drinkers, indicating that the harmful effect of sedentary time may be more pronounced in the absence of coffee consumption [46]. In contrast, a study including 11,697 women with a median age of 66 years found no association between filtered caffeinated coffee consumption or caffeine intake and cardiovascular mortality, suggesting no clear beneficial or harmful effect of coffee in this population [47]. Taken together, the evidence suggests a potential protective role of coffee against CVD and cardiovascular mortality in some populations. However, the findings are not entirely consistent, as null or adverse associations have also been reported in specific subgroups and study settings.

4.5. Gut microbiota modulation and dysbiosis-related taxa

Evidence suggests that individuals who consume moderate amounts of coffee (< 4 cups/day) exhibit greater gut microbial diversity and a higher abundance of beneficial microorganisms when compared to non-consumers. Particularly, the abundance of Bifidobacterium spp. tends to consistently increase across studies, whereas the abundance of Enterobacteriaceae decreases [48,49]. Bifidobacterium species participate in the production of SCFA which has been associated with beneficial effects such as enhanced gut barrier function. Bifidobacterium can inhibit pathogenic bacteria growth as well [50]. On the other hand, bacteria of the Enterobacteriaceae family have been associated with gut dysbiosis, inflammatory conditions and the growth of opportunistic pathogens.

Coffee consumption has also been associated with increased abundance of Lawsonibacter asaccharolyticus, Alistipes and Faecalibacterium. Notably, L. asaccharolyticus showed the strongest association with coffee consumption in a multi-cohort study, exhibiting a 4.5- to 8-fold higher abundance in coffee drinkers than in non-drinkers. Such abundance increase was correlated with concentrations of quinic acid and its potential derivatives in plasma [51]. This compound can exert antioxidant properties by scavenging reactive oxygen species and reducing oxidative stress. Some evidence also suggests anti-inflammatory effects through modulation of inflammatory signaling pathways [52]. Faecalibacterium is another genus whose abundance is related to coffee consumption. Particularly, Faecalibacterium prausnitzii is one of the main butyrate producers and its abundance in the gut has been associated with anti-inflammatory effects, gut health and even proposed as a probiotic [53]. The role of Alistipes is more complex. Some studies suggest potential beneficial metabolic functions, but others have linked certain species to disease states such as depression, colorectal cancer and inflammation [54]. In this context, bacterial species or strain present in the gut may become paramount.

Due to the capacity of coffee to produce changes in the abundance of some bacterial species associated with beneficial effects, it may be regarded as a potential prebiotic. Several coffee compounds can be metabolized by the gut bacteria, leading to the production of short-chain fatty acids such as butyrate, acetate, and propionate [55]. Especially, the production of butyrate is of particular importance because its concentration in the intestine has been associated with an enhanced intestinal barrier integrity and reduced inflammation. Acetate, on the other hand, can affect gene expression regulation by participating in histone acetylation. It has been recognized as an important immunomodulatory metabolite as well [56].

Despite the evidence linking coffee consumption to changes in the gut microbiota, the magnitude of the microbiota modifications and effects is not homogeneous across studies. It may depend on factors such as baseline microbial composition, host genetics, overall dietary patterns, coffee preparation methods, and the use of additives such as sweeteners and milk.

5. Coffee and coffee-derived bioactive compounds under fructose-related conditions

Direct evidence evaluating coffee under fructose-related conditions remains limited, particularly in humans. However, the available clinical evidence suggests that coffee consumption may partially modulate fructose-induced metabolic alterations. In a randomized crossover trial in healthy young men, fructose overfeeding (4 g/kg/day for 6 days) increased intrahepatocellular lipid content and hepatic glucose production while reducing fasting lipid oxidation [57]. Under these conditions, intake of 4 cups/day of coffee attenuated the increase in hepatic glucose production, regardless of coffee type, suggesting an improvement in hepatic IR [57]. In addition, caffeinated coffee high in CGA and decaffeinated coffee with regular CGA content increased fasting lipid oxidation, whereas decaffeinated coffee high in CGA had no significant effect. None of the coffee preparations, however, prevented fructose-induced hepatic lipid accumulation [57]. Despite the growing number of experimental studies, human evidence on the effects of coffee consumption on fructose-related metabolic alterations remains very limited. To date, very limited human evidence has specifically addressed this issue, making it difficult to establish whether the beneficial effects observed in animal models can be translated to humans. This gap underscores the need for further clinical studies evaluating the impact of coffee intake under conditions of high fructose exposure.

In murine studies, coffee and coffee-derived preparations also showed beneficial metabolic effects under fructose-rich conditions. In rats fed a high-fat diet for 14 weeks, coffee and fructose provided in the same drinking bottle, corresponding to an approximate daily intake of 1.18 g of ground medium-roast coffee, improved metabolic status by reducing body weight, TG, and plasma glucose, while also attenuating hepatic steatosis and IR [58]. Likewise, in rats fed a high-fructose diet, coffee intake at doses of 213 and 284 mg/kg body weight/day reduced body weight, fasting glucose, and uric acid levels, whereas the higher dose additionally decreased fasting TG and LDL-C concentrations [59]. Consistent with these findings, oral administration of an aqueous coffee parchment extract (100 mg/kg/day) for 4 weeks in rats with high-fructose diet-induced obesity prevented adipose tissue accumulation and ameliorated hyperglycemia, hyperinsulinemia, hyperlipidemia, hepatic steatosis, and oxidative stress [60].

In an inflammatory setting, coffee intake also appeared to exert roast-dependent effects. In rats fed a high-fat/high-fructose diet, daily administration of 7.4 mL of coffee for 16 weeks reduced hepatic nuclear factor kappa B (NF-κB) levels, with the strongest effect observed in the very dark roast group (approximately 75%), followed by the dark roast group (about 50%) and the unroasted coffee group (about 30%) [61]. A similar pattern was observed for adipose tissue tumor necrosis factor alpha (TNF-α), which decreased significantly in all coffee-treated groups, with the greatest reduction occurring in the very dark roast group [61].

In addition to coffee intake per se, coffee-derived extracts and isolated bioactive compounds have also shown favorable effects in murine models of high fructose intake. In obese rats fed a high-fructose diet, coffee extracts improved metabolic alterations, obesity-related biomarkers, and oxidative stress parameters, while green coffee also reduced hepatic Interleukin (IL)-1β (IL-1β) and IL-6 levels, supporting an anti-inflammatory action [62]. Likewise, in rats fed a high-carbohydrate, high-fat diet with fructose, coffee extract improved glucose tolerance, reduced plasma insulin and systolic blood pressure, and attenuated cardiovascular and hepatic inflammation, fibrosis, and liver injury markers, despite having no effect on abdominal obesity [63]. These differences in dietary models should be considered when interpreting the magnitude and direction of the metabolic effects. Taken together, current evidence suggests that coffee, coffee-derived extracts, and isolated bioactive compounds may help alleviate metabolic and inflammatory disturbances under fructose-related conditions. In this context, growing evidence indicates that some of the beneficial effects of coffee on fructose-related alterations may be mediated by specific bioactive compounds, particularly caffeine, chlorogenic acid, and caffeic acid.

5.1. Caffeine

Available evidence suggests that caffeine may influence fructose-related metabolic responses in a context-dependent manner, with acute effects in humans and variable outcomes in experimental models. In healthy young and older adults, ingestion of 75 g fructose plus 300 mg caffeine elicited a greater increase in energy expenditure than glucose plus caffeine, whereas glucose and insulin responses remained lower after fructose than after glucose [64]. These findings suggest that caffeine may acutely influence the metabolic handling of fructose in humans.

In experimental models, caffeine administered at 15 mg/kg/day for 4 weeks to rats fed a high-fructose diet improved metabolic status, including insulin sensitivity and blood pressure [65]. This effect may be related to enhanced insulin sensitivity in the nucleus tractus solitarii through reduced receptor for advanced glycation end products (RAGE)-mediated superoxide generation and increased nitric oxide (NO) production via upregulation of insulin receptor substrate 1 (IRS1)- phosphoinositide 3-kinase (PI3K)-Akt-nNOS signaling (Figure 1) [65]. Given that fructose induces metabolic alterations, at least in part, through regulation of RAGE expression in insulin-sensitive tissues [66,67,68], the beneficial effects of caffeine may involve modulation of this pathway. In contrast, in rats fed a high-fat diet plus fructose, low-dose caffeine (5 mg/kg/day) did not reverse hepatic steatosis or improve insulin sensitivity. Moreover, caffeine increased hepatic stearoyl-CoA desaturase 1 expression, suggesting a limited effect on lipogenic pathways despite attenuating the increase in Cer 18:1 [69]. These findings suggest that caffeine may exert context-dependent effects, with potential benefits on insulin signaling but limited effects on hepatic lipid accumulation.

High fructose intake may promote metabolic disturbances, including increased production of AGEs, activation of RAGE-mediated signaling, upregulation of the SphK1/S1P/S1PR1/3 pathway, and lipid accumulation/FFA overload. These alterations may contribute to NADPH oxidase activation, increased ROS production, oxidative stress, inflammatory signaling, cellular damage, and impaired insulin signaling. Coffee-derived bioactive compounds, particularly caffeine and chlorogenic acid, may attenuate these effects by modulating RAGE/NADPH oxidase-dependent ROS production, enhancing antioxidant defenses through SOD and GPx, and reducing TLR4/NF-κB-mediated inflammatory responses. In addition, caffeine may improve central insulin signaling through the IRS1/PI3K/Akt/nNOS pathway, increasing NO bioavailability and contributing to blood pressure regulation. AGEs: Advanced glycation end products; RAGE: Receptor for advanced glycation end products; FFA: Free fatty acid; NADPH: Nicotinamide adenine dinucleotide phosphate; ROS: Reactive oxygen species; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; TLR4: Toll-like receptor 4; SphK1: Sphingosine kinase 1; S1P: Sphingosine-1-phosphate; S1PR1/3: Sphingosine-1-phosphate receptor 1 and -3; NF-κB: Nuclear factor kappa B; NO: Nitric oxide; IRS1: Insulin receptor substrate 1; Akt: Protein kinase B; nNOS: Neuronal nitric oxide synthase.

5.2. Chlorogenic acid

Among coffee-derived compounds, chlorogenic acid (CGA) appears to exert particularly relevant hepatoprotective and anti-inflammatory effects under fructose-rich conditions. In a model of fructose-induced NAFLD, CGA administered at 40 mg/kg/day for 8 weeks reduced serum lipids, glucose, IR, and liver injury markers, while increasing hepatic Glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity. These effects were accompanied by attenuation of hepatic inflammation, including lower IκB kinase (IKK), TNF-α, toll-like receptor 4 (TLR4), and NF-κB signaling, as well as suppression of the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) pathway [70]. Since fructose has been shown to activate SphK1/S1P/Sphingosine-1-phosphate receptor 1 (S1PR1)/3 signaling in liver and kidney tissues [71,72], CGA may exert part of its hepatoprotective effect by modulating this fructose-induced proinflammatory axis (Figure 1). Moreover, in rats fed a high-fat and high-fructose diet, dietary CGA at 2.6 mmol/kg reduced fasting glucose, total cholesterol, hepatic TG accumulation, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, and proinflammatory markers, while increasing adiponectin levels, despite not significantly affecting body weight or adiposity [73]. Taken together, the available evidence suggests that CGA improves the metabolic and inflammatory alterations induced by high fructose intake. However, further studies are needed to clarify the cellular mechanisms underlying its beneficial effects in this context.

5.3. Caffeic acid

Caffeic acid has also shown consistent beneficial effects in experimental models of high fructose intake. Caffeic acid administered at 40 mg/kg body weight exerted metabolic, anti-inflammatory, and antioxidant effects in rats with high-fructose diet-induced metabolic syndrome. Treatment improved hyperglycemia, IR, dyslipidemia, and adipokine imbalance, while reducing TNF-α, IL-6, and IL-8 levels [74]. In addition, caffeic acid restored hepatic antioxidant enzyme activities and attenuated oxidative damage markers, supporting its protective effect against fructose-induced metabolic disturbances [74]. Similarly, in rats fed a high-fat and high-fructose diet, caffeic acid supplied at an equimolar concentration of 2.6 mmol/kg diet showed potential hepatoprotective and anti-inflammatory effects [73]. Treatment improved fasting glucose and total cholesterol, reduced hepatic TG accumulation, lowered serum ALT and ALP activities, and attenuated inflammatory markers, including IL-6, IL-1β, and C-reactive protein, while increasing adiponectin levels [73]. These findings suggest that caffeic acid may contribute to the protective effects of coffee-derived compounds against fructose-induced metabolic dysfunction.

6. Future directions

• Conduct studies assessing the effects of coffee and/or coffee-derived bioactive compounds on the regulation of non-coding RNAs (microRNAs and long non-coding RNAs) associated with metabolic alterations induced by chronic fructose intake.
• Explore the molecular mechanisms underlying the effects of coffee in metabolically relevant tissues beyond the liver, such as adipose tissue and skeletal muscle.
• Investigate whether coffee intake modulates key molecular pathways involved in fructose-induced metabolic alterations, including oxidative stress, inflammation, insulin signaling, lipid metabolism, mitochondrial function, and gut microbiota-derived signaling.
• Investigate whether coffee intake modulates endocrine-like signaling mediated by extracellular vesicle-derived non-coding RNAs microRNAs and long non-coding RNAs), and whether these signals contribute to the systemic metabolic effects of coffee.
• Conduct well-controlled clinical trials to determine whether coffee intake can attenuate fructose-induced metabolic alterations in humans, considering coffee type, dose, roasting degree, brewing method, and additive use.

7. Conclusions

Current evidence suggests that coffee consumption and coffee-derived bioactive compounds may attenuate fructose-induced metabolic alterations, including insulin resistance, hepatic lipid accumulation, oxidative stress, inflammation, cardiovascular risk, and gut microbiota dysbiosis. These effects may be mediated by caffeine, chlorogenic acid, and caffeic acid through the regulation of glucose and lipid metabolism, inflammatory signaling, antioxidant defenses, and gut microbiota composition. However, human evidence remains limited and heterogeneous. Therefore, well-controlled clinical studies are needed to determine whether the protective effects observed in experimental models translate to humans.