Metabolic syndrome (MetS) encompasses a constellation of cardiometabolic risk factors, i.e., visceral adiposity, glucose intolerance, elevated blood pressure, and dyslipidemia, defined to help identify people at increased risk of cardiovascular diseases and type-2 diabetes mellitus (T2D) [1
]. Long-term follow-up studies have indicated that MetS can also predict the future risk of cardiovascular mortality [2
]. Visceral adiposity and the concomitant insulin resistance (IR) are the driving forces behind the metabolic derangements of the MetS [3
]. Since this syndrome affects 25% of the world’s population [4
], effective preventive measures will confer immense public health benefits.
The effect of coffee on health has historically been a controversial topic. However, evidence is now convincing that coffee consumption diminishes the risk of all-cause mortality as well as several types of cancer, cardiovascular disease, chronic liver disease, Parkinson’s disease, and T2D, while the risk of urinary tract and lung cancer can slightly be increased [5
]. The potential role of coffee in the prevention of T2D was originally identified through observational research [6
]. To understand how coffee affects the risk of T2D, it is necessary to study its effects on T2D risk factors clustered in the definition of MetS. Epidemiological data show a non-linear reverse relationship between coffee intake and risk of MetS [7
] and its hepatic component, non-alcoholic fatty liver disease (NAFLD) [8
]. NAFLD is a manifestation of ectopic fat deposition, which is strongly associated with all features of the MetS [9
]. As yet, long-term interventional research on the effects of coffee on different features of the MetS is lacking.
While coffee is a blend of more than 1000 volatile and non-volatile compounds, only a minority reach bioactive concentrations with moderate daily consumption, comprising alkaloids (including caffeine and trigonelline), phenolic acids (including chlorogenic acids, CGA), diterpenes (including cafestol and kahweol), and Maillard reaction and degradation products formed during the roasting process (including melanoidins and quinides) [10
]. However, the debate still continues as to which compound or combination of compounds explains the preventive potential of coffee on T2D risk factors.
The present study aimed to assess the long-term effects of a realistic dosage of unfiltered coffee on the development of the key features of MetS and to compare coffee with a combination of its main bioactive compounds. The second goal was to determine whether or not phenolic acids and trigonelline are the main compounds behind the metabolic efficacy of coffee in MetS subjects. A combination rather than single compounds was used in the study based on the hypothesis that synergy plays an essential role in the biological effects of coffee.
In the current study, a high-fat-/high-sugar-fed model of MetS was employed. This model is among the best animal models of MetS since this Western-type diet can induce several signs and symptoms of human MetS in rodents [29
]. Adding fructose to a high-fat diet is shown to intensify its deleterious effects on hepatic steatosis and lipid metabolism [30
]. Fructose was added to drinking water, rather than the food, to cover the pungency of coffee brew and balance fluid consumption between groups.
Contrary to the nutraceuticals, whole coffee brew consumption diminished the overall food intake and rate and amount of weight gain caused by HFHF food. Cowan et al. mirrored these results with a higher dosage of instant coffee using a similar animal model [31
]. Modest weight modifying effects of coffee have also been observed in some [32
] but not all [34
] of the previous comparable studies. Caffeine is known to induce weight loss in rodents [36
] and help to maintain weight loss in humans [38
], but it may not be the only player. CGA-rich green coffee extracts [21
] and pure CGAs [40
] have been proved effective in reducing body weight. Insignificant effects of a phenolic acid-rich chemical mixture may be related to the lower dosage compared to other studies [40
] or different route/frequency of administration [41
]. It is likely that in moderate dosages the synergy between caffeine and CGAs plays an important role in reducing weight gain. A comprehensive review of the anti-obesity effects of coffee and their proposed mechanisms has recently been published [44
In the present study in rats, fasting insulin showed an unsteady increase over time, with an upsurge between weeks 10 and 14 indicating a delayed development of IR, which was alleviated, but not halted, by coffee. This observation, confirmed by a significant reduction in HOMA-IR index, points to insulin-sensitizing effects of coffee and further corroborates the OGTT results. Although the literature is not consistent [31
], the present findings correspond to some earlier reports [35
]. It is puzzling though why the nutraceuticals did not show significant insulin-sensitizing efficacy. The reason might lie in the lower bioavailability of pure chemicals or the lack of other coffee compounds such as lignans and cafestol, which were shown to possess insulinotropic and insulin-sensitizing activities [46
]. Moreover, the role of caffeine should not be neglected. Acute caffeine administration decreases insulin sensitivity [49
]; however, in a time span of several weeks, this methylxanthine exhibits enhancing effects on glucose disposal rate [34
]. Comparable FPG levels in all groups were not surprising based on the knowledge that this index of liver glucose production was either unaltered [32
] or increased [31
] in the former studies. Nevertheless, lower HbA1C in the coffee group signifies a better long-term glycemic control, which is a better predictor of cardiovascular disease and all-cause mortality than the FPG [50
Noticeably, unfiltered coffee exhibited a significant triglyceride-lowering effect in this study. On the contrary, neither coffee nor nutraceuticals altered the plasma levels of cholesterol and NEFAs after 14 weeks of intervention. Current knowledge suggests that coffee contains compounds with opposing effects on lipoprotein metabolism i.e., diterpenes (cafestol and kahweol) in unfiltered coffee can increase total cholesterol, Low-density lipoprotein cholesterol (LDL-C), and triglyceride levels [51
], while CGAs and melanoidins show the opposite effects on both triglycerides and LDL-C [52
]. In rodents, however, this balance tends to shift towards the lipid-lowering effect since they are relatively resistant to the effects of cafestol [54
]. This characteristic may reflect differences in lipoprotein metabolism between rats and humans [55
]. An unchanged lipid profile in the nutraceuticals group can be due to the absence of other active substances such as the melanoidins.
Direct measurements showed that coffee administration had reduced the hepatic deposition of triglycerides to almost half compare to the control rats. These results were further corroborated by semi-quantitative histological evaluations. Although this model did not display the advanced features of NAFLD or non-alcoholic steatohepatitis, a significant reduction of ectopic lipid deposition provides evidence for the protective properties of coffee against the development and progression of diet-induced NAFLD. Improvement in different aspects of the HF-diet-induced fatty liver was also documented previously in rats [35
]. Experimental evidence from human subjects is lacking.
The novel hyperpolarized-13
C MR spectroscopy technique enabled us to follow the formation of main pyruvate metabolites in living animals. Since pyruvate is at the intersection of energy metabolism, proportional quantification of its metabolites would provide valuable information about the flux of key enzymes namely pyruvate dehydrogenase complex, alanine aminotransferase, and lactate dehydrogenase [57
]. To the best of our knowledge, this technique has never been employed in investigating the effects of coffee or coffee chemicals in living animals. This experiment was aimed to explore a possible shift in hepatic carbohydrate metabolism caused by long-term consumption of coffee or its selected compounds. In theory, answering the question of which metabolite conversion rates are likely to be modified by coffee is challenging. However, reversing some of the changes induced by a HF diet appears to be a reasonable response. It was shown that six weeks of HF diet can increase alanine/pyruvate and lactate/pyruvate ratios, accompanied by a surge in serum ALT levels [58
]. Therefore, the tendency towards a lower alanine/pyruvate ratio in the coffee group compared to the control can be considered a metabolically favorable effect of coffee in this model. Non-significant differences between groups were probably due to the small sample size of four rats per group. In a previous study, four weeks of metformin therapy increased hepatic lactate/pyruvate but did not alter bicarbonate/pyruvate ratios in male Wistar rats [59
]. Future studies on the effects of coffee on intracellular carbohydrate metabolism and their relevance to its metabolic effects are needed.
The following limitations must be taken into consideration when evaluating the presented results. While it needs to be further confirmed, there are a few clues in the literature that pure CGAs may have lower absorption and different excretion behavior from CGAs from coffee [60
]. Lack of chemical analysis of the coffee brew used in the present study for chlorogenic acid, trigonnelline, and caffeic acid poses an important limitation in comparing the two intervention groups, even though the dose estimation had been performed based on high-quality published papers. It is, however, not likely that the insignificant results obtained in the nutraceuticals group can mainly be caused by differences in the concentration of compounds between the intervention groups. The absence of standardized degrees of roasting, which affects the CGAs and trigonelline content of coffee, in commercialized products reduces the reproducibility of coffee studies. Next point is that administering coffee and nutraceuticals in water makes it difficult to deliver the exact dosage and increases the probability of degradation and sedimentation (especially in case of caffeic acid). Furthermore, the poor solubility of caffeic acid in water necessitated the use of ethanol as a solvent. Accordingly, each rat received ~0.6 g of ethanol per day equal to 1.5 European standard drinks in a human. As described before, urine ethanol levels evidenced equal consumption in all groups, which eliminated the possibility of affecting our results. Ironically, including moderate amounts of ethanol in the rats’ regime might have made it more similar to a typical Western diet. Finally, the combination used in the current study was one of the many conceivable combinations of coffee compounds and not necessarily the most bioactive one. Multiple combinations need to be studied simultaneously in order to find the compounds with synergistic effects.