A recent article by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ), in the British Journal of Nutrition, reported that chlorogenic acid (CGA) and caffeine inhibit fat accumulation by regulating hepatic function in mice. The authors investigated the effect of CGA and caffeine in female Imprinting Control Region (ICR) mice, drawing the conclusion that these components of coffee reduced serum and hepatic lipid levels and led to the suppression of body-weight gain and fat accumulation in treated animals( Reference Zheng, Qiu and Zhang 1 ). The evidence reported in the study suggested the hypothesis that CGA and caffeine exert their action by biological synergism and that, more generally, coffee polyphenols usually work through a synergistic mechanism. Comments, in brief, are discussed below.
Anti-obesity action of chlorogenic acid
CGA, namely (1S,3R,4R,5R)-3-{((2Z)-3-(3,4-dihydroxyphenyl)prop-2-enoyl)oxy}-1,4,5-trihydroxycyclohexanecarboxylic acid, is one of the most frequently assumed polyphenolic compounds in the daily diet, due to its usual presence in a widely diffused beverage such as coffee. CGA was reported to act as an anti-obesity natural molecule; however, a recent paper on the effect of coffee on the prevention of type 2 diabetes has raised yet some criticism( Reference Akash, Rehman and Chen 2 ). Despite the evidence reported by the authors( Reference Zheng, Qiu and Zhang 1 ), physiological supplementation (1·0 g/kg per d) in C57BL/6 male mice with CGA in combination with a high-fat diet did not reduce body weight compared with mice fed with the high-fat diet alone( Reference Mubarak, Hodgson and Considine 3 ). Yet, the anti-diabetic property of CGA along with caffeic acid or other phenolic acids and/or polyphenols was assessed in other experimental models, besides the above contribution by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 , Reference Cho, Jeon and Kim 4 , Reference Peng, Liu and Chuang 5 ). CGA alone was reported to inhibit in vitro animal fatty acid synthase (FAS) or bacterial β-chetoacyl reductase (EC 1.1.1.100) in a concentration-dependent manner with respective half-maximal inhibitory concentrations (IC50) of 94·8 and 88·1 μm ( Reference Li, Ma and Wu 6 ). This suggests that CGA can act directly on liver enzymes involved in metabolism. However, in the paper by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ), the effect of this ester of caffeic acid and ( − )-quinic acid on liver FAS was small, not statistically significant, while FAS activity was ameliorated by the addition of caffeine.
Mechanism of synergism and related complexity
The contribution of caffeine to improving the efficacy of CGA should stress the hypothesis that synergistic actions occur when two or more bioactive phenolic molecules share similar signalling or metabolic pathways. This may hamper any full elucidation of the biological effect of coffee polyphenols in different biological models. As a matter of fact, complexity pertains to the many, different issues regarding the biological activity of phytochemicals, fundamentally represented by raw-extract biochemistry, pharmacokinetics and bioavailability, in addition to the complex network of intracellular targets. In humans, gut absorption of CGA is at least one-third lower than that of other coffee-derived components, such as caffeic acid, but it exhibited high bioavailability in plasma( Reference Olthof, Hollman and Katan 7 – Reference Budryn, Nebesny and Rachwal-Rosiak 10 ). Moreover, CGA exists in the form of a mixture of different caffeoyl-quinic acids, the commonest being probably 5-caffeoyl-quinic acid( Reference Lallemand, Zubieta and Lee 11 ). Such specification may be important because different isomers of caffeoyl-quinic acids exhibit different patterns of activity on liver enzymes( Reference Henry-Vitrac, Ibarra and Roller 12 ). As a matter of fact, all these observations lead to the suggestion that, at least in animal or in vivo models, the anti-diabetic and obesity-preventing activity attributed to CGA may occur when the polyphenol is associated with another phenolic acid or plant-derived alkaloid, such as the 1,3,7-trimethylpurine-2,6-dione reported by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ), an occurrence that may also improve the bioavailability and biological action of CGA. Synergism between CGA and other components probably accounts for the action of CGA plus caffeine reported in the paper by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ). Caffeine improves glucose tolerance, insulin sensitivity and hyperinsulinaemia in C57BL/6J and ameliorates the inflammatory response of adipose tissue, which is notoriously involved in the metabolic syndrome( Reference Bandsma, Wiegman and Herling 13 ). In addition, CGA exerts inhibitory activity on hepatic glucose-6-phosphatase (EC 3.1.3.9), then influencing glucose homeostasis and contributing to the prevention of metabolic stress and type 2 diabetes( Reference Henry-Vitrac, Ibarra and Roller 12 ). The authors did not address any further hypothesis on the mechanism by which CGA and caffeine exerted an anti-diabetic action, except for a significant inhibition of liver FAS and increase in lipid β-oxidation.
Further comments and conclusions
In their paper, Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ) concluded that the observed enhancement of β-oxidation and suppression of lipogenesis were the major reasons for the reduction of fat accumulation and body-weight gain in mice. If true, lipid β-oxidation in hepatic and adipose tissue may be enhanced by the request of lipids from tissues, consequently leading to lipolysis in adipose tissue and changes in the plasma lipid profile. Unfortunately, the paper by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ) did not fully elucidate this issue by evaluating, for example, the serum lipoprotein profile. In this respect, inhibition of hepatic EC 3.1.3.9 by CGA should yet lead to an increase in lipogenesis, without affecting VLDL production and cholesterol synthesis by the liver( Reference Bandsma, Wiegman and Herling 13 ). Therefore, the effect reported by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ) on serum lipids might not be associated with the inhibition of liver glucose-6-phosphatase by CGA, but most presumably caused by other mechanisms. While synergism appears to possibly explicate the observed reduction in FAS activity, the effect of caffeine appears to overwhelm the action of CGA on carnitine acyltransferase (EC 2.3.1.21) and acyl-CoA-oxidase (EC 1.3.3.6), namely that the enhancement of the activity of enzymes involved in lipid oxidation in the mitochondria and peroxisomes should be attributed principally to caffeine, at least as emerging from the paper by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ). In addition, CGA may enhance the inhibitory effect on serum lipids, as it was reported that in Zucker rats, it lowers plasma cholesterol and TAG levels( Reference Rodriguez de Sotillo and Hadley 14 ), thus contributing to the overall observed effect( Reference Zheng, Qiu and Zhang 1 ). Both CGA and caffein shared the same liver enzyme system, which targeted to modulate glucose and lipid homeostasis. The interesting study by Zheng et al. ( Reference Zheng, Qiu and Zhang 1 ) raises many questions about how these components act in coffee, where many other polyphenolic substances, i.e. kaempferol, ferulic acid and caffeic acid, may participate in the synergistic/antagonistic mechanism characterising most of the plant-derived raw extracts. While a possible purpose of such studies is to highlight particular molecules as effective prodrugs against the metabolic syndrome, we should not forget that molecules in a complex mixture behave quite far from our in vitro and animal models, due to the many reasons such as synergism, gut microflora modification, adsorption rate, bioavailability and different cell responses to the indicated molecule.
Acknowledgements
The author has no conflict of interest to declare.
