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The potential effects of chlorogenic acid, the main phenolic components in

coffee, on health: a comprehensive review of the literature

Article  in  European Journal of Nutrition · October 2017

DOI: 10.1007/s00394-017-1379-1

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Eur J Nutr
DOI 10.1007/s00394-017-1379-1
REVIEW
The potential effects of chlorogenic acid, the main phenolic
components in coffee, on health: a comprehensive review
of the literature
Narges Tajik1   · Mahboubeh Tajik2 · Isabelle Mack1 · Paul Enck1 
Received: 15 February 2016 / Accepted: 10 January 2017
© Springer-Verlag Berlin Heidelberg 2017
Abstract  Chlorogenic acid (CGA), an important bio-
logically active dietary polyphenol, is produced by cer-
tain plant species and is a major component of coffee.
Reduction in the risk of a variety of diseases following
CGA consumption has been mentioned in recent basic
and clinical research studies. This systematic review dis-
cusses in  vivo animal and human studies of the physi-
ological and biochemical effects of chlorogenic acids
(CGAs) on biomarkers of chronic disease. We searched
PubMed, Embase, Amed and Scopus using the follow-
ing search terms: (“chlorogenic acid” OR “green coffee
bean extract”) AND (human OR animal) (last performed
on April 1st, 2015) for relevant literature on the in  vivo
effects of CGAs in animal and human models, includ-
ing clinical trials on cardiovascular, metabolic, cancero-
genic, neurological and other functions. After exclu-
sion of editorials and letters, uncontrolled observations,
duplicate and not relevant publications the remaining 94
studies have been reviewed. The biological properties of
CGA in addition to its antioxidant and anti-inflammatory
effects have recently been reported. It is postulated that
CGA is able to exert pivotal roles on glucose and lipid
metabolism regulation and on the related disorders,
e.g. diabetes, cardiovascular disease (CVD), obesity,
cancer, and hepatic steatosis. The wide range of poten-
tial health benefits of CGA, including its anti-diabetic,
* Paul Enck
paul.enck@uni‑tuebingen.de
1
Department of Internal Medicine VI: Psychosomatic
Medicine and Psychotherapy, University Hospital Tuebingen,
Frondsbergstr 23, 72076 Tuebingen, Germany
2 5-caffeoylquinic acid (5-CQA) [6, 7]. A limited number
Faculty of Physical Education and Sport Sciences,
International Branch of Ferdowsi University of Mashhad,
Mashhad, Iran
anti-carcinogenic, anti-inflammatory and anti-obesity
impacts, may provide a non-pharmacological and non-
invasive approach for treatment or prevention of some
chronic diseases. In this study, the effects of CGAs on
different aspects of health by reviewing the related litera-
tures have been discussed.
Keywords  Green coffee bean extracts · Chlorogenic
acid · Antioxidant · Anti-inflammatory
Introduction
Coffee, as one of the favourite beverages worldwide,
comprised a variety of chemicals which maintain the
greatest health benefits among the commonly consumed
beverages. Most investigations have so far focused on the
beneficial effects of caffeine [1–3]. However, knowledge
on potential health benefits of non-caffeine coffee com-
pounds is scarce [4]. Coffee contains many polyphenols,
especially CGAs, which have purported antioxidant abil-
ities [5]. Caffeoylquinic acid, as one of the major coffee
polyphenols, is an ester of caffeic acid with quinic acid
[6] and is often referred to as chlorogenic acid. The term
chlorogenic acids (CGAs), however, stand for the whole
set of hydroxycinnamic esters with quinic acid, includ-
ing caffeoyl-, feruloyl-, dicaffeoyl-and coumaroylquinic
acids. In addition, there are several isomeric forms of
CGA for each of subgroups and different coffee extracts
usually contain different CGAs but the most common
isomer in green coffee beans (76–84% of the total CGA)
or coffee beans (10  g/100  g) and other plant sources is
of studies exist on the metabolism and bioavailability of
the CGAs in humans. Lafay et al. [8] reported that CGA
13
Vol.:(0123456789)

absorbed in an intact form in the stomach of rats. The
majority of CGA hydrolized to caffeic acid and quinic
acid before being absorbed in the gastrointestinal tract
through the action of special esterases in both small and
large (microbial esterases) intestine [9]. After absorption
it is metabolized to glucuronide and sulphate metabo-
lites as the circulating forms in human plasma [5]. Mon-
teiro et  al. [10] reported a large inter-individual differ-
ence in absorption and metabolism of CGAs. Hence,
the variability observed between studies may be a con-
sequence of this difference. CGAs exists in raw coffee
and is also widespread in many kinds of seeds and fruits
such as sunflower seeds and blueberries. Lower content
of CGAs has also been detected in potatoes, tomatoes,
apples, pears and eggplants, but consumption of these
sources accounts for nearly 5–10% of that from coffee
beverage source [11]. While much of the CGA is eradi-
cated during the roasting process, coffee beans are still
considered to be a main source of CGA in the human
diet and 5-CQA still remained the major CGA isomer
in roasted coffee [11, 12]. The CGA content of a cup
of coffee (200  ml) differs substantially between 70 and
350 mg, depending on the coffee variety [11, 13]. Some
studies reported that green Coffea Robusta beans contain
the most amount of CGA on average while green Coffea
Arabica beans contain the least [14, 15]. Furthermore,
it has also been shown that the brew processing of cof-
fee affects the content of CGA significantly which leads
to existence of various CGA content in different coffee
brew. Ludwig et  al. [16] reported that the espresso cof-
fee brew had relatively a higher content of CGA than the
other brew methods. Accumulating evidence has dem-
onstrated that CGA is known for its antioxidant, anti-
carcinogenic, and anti-inflammatory properties; these
health benefits have lately been the focus of many epi-
demiologic studies [17, 18]. It has been proposed to have
benefits on type-2 diabetes (T2DM) [19], obesity [20],
Alzheimer’s disease [21], stroke [22] and on endothe-
lial function as well blood pressure [23, 24]. Despite
the beneficial effects of CGA on health, some studies
revealed the adverse effects of CGA, including head-
ache, diarrhoea and complications in higher doses for
a person with a sensitive stomach [25]. However, there
is no comprehensive investigation regarding the side
effects of chlorogenic acid.
With the increasing incidence of degenerative dis-
eases, the general public is now turning to natural herbal
supplements. As one of these agents, CGAs have been
biologically and medically emphasized and can be
expected to be addressed as a topic for future studies,
medical trends and pharmacology. The purpose of this
review article is to summarize in vivo animal and human
13
Eur J Nutr
studies of the biological effects of CGAs on biomarkers
of chronic disease risk.
Methods
We performed electronic searches from the PubMed,
Embase, Amed and Scopus databases using the follow-
ing search terms: (“chlorogenic acid” OR “green coffee
bean extract” OR ‘coffee’) AND (human OR animal)
(last performed on April 1st, 2015). The resulting cita-
tions (n = 1024) were hand-screened to identify in-vitro
studies (CGA effects on cell lines, tissue preparation,
e.g.) (n = 364), these 364 in vitro studies were excluded.
Furthermore, we also excluded editorials and letters,
uncontrolled observations, and duplicate and not relevant
publications (n = 566). The remaining papers (n = 94)
were divided according to animal data (n = 69) and
human studies (n = 25), and were subsequently classified
according to CGA effects on cancer genesis, the cardio-
vascular system, metabolic functions and obesity, hepatic
health, inflammation and pain, and central (brain) func-
tions. Study selection was performed by two independent
reviewers. Within each of these subheadings, we will dis-
cuss relevant experimental and clinical findings. Figure 1
provides a flowchart on the study selection.
1024 Articles retrieved from
search of literatures
364 Excluded for in vitro
studies
566 Articles retrieved for
detailed evaluation
Excluded for: uncontrolled
observations, No relevant and
duplicate publications,
editorials and letters
94 Articles retrieved
69 Animal data
25 Human data
Fig. 1  Flowchart for article selection process
Eur J Nutr
Results
Cardiovascular health and CGA
Effects of CGA on blood pressure
There were 23 studies that examined the association
between CGAs consumption and cardiovascular health
(Table 1). 15 were on animal models and eight on humans.
To the best of our knowledge, the first study to report an
association between green coffee been extracts (GCE) and
its metabolites on blood pressure was published in 2002
[23]. Suzuki et al. compared the effects of oral administra-
tion of green coffee bean extract rich in CGA in spontane-
ously hypertensive rats (SHR). The short-term administra-
tion of 180, 360, and 720  mg GCE (CGA content: 28%)
decreased blood pressure levels in a dose-dependent man-
ner for each group. The long-term administration of GCE
(0.25, 0.5 and 1% of diet) decreased the systolic blood pres-
sure (SBP) dose dependently (199, 186 and 179  mmHg,
respectively, vs. 211  mmHg on control diet). It is notable
that they did not find any significant change in the normo-
tensive group (control rats) [23].
In 2006, Suzuki et  al. [24] reported a difference in
the hemodynamic effect between roasted instant cof-
fee (200  mg CGA) and GCE (200  mg CGA). Single oral
administration of GCE significantly decreased SBP in SHR
while roasted coffee had little effect on it, both groups
received the same amounts of CGA and in spite of the pres-
ence of caffeine (6%) in the GCE-treated group. So they
performed another experiment and found that hydroxyhyd-
roquinone (HHQ) inhibited the hypotensive effects of CGA
in SHR dose-dependently [24]. However, HHQ generated
by roasting coffee beans inhibits the blood pressure lower-
ing effects of CGA in SHR [26].
Several mechanisms have emerged on how chlorogenic
acid decreases blood pressure, including the stimulation of
NO production through the endothelial-dependent pathway,
the reduction of free radicals through inhibiting NAD(P)H
oxidase expression and activity, and inhibition of angioten-
sin-converting enzyme [27, 28].
The findings mentioned above were subsequently
confirmed in further research in humans with moderate
hypertension. In one randomized, double-blind placebo-
controlled trial, the effects of GCE rich in CGA on blood
pressure in 117 untreated patients with mild hypertension
were analyzed. Test subjects were randomly divided into
four groups who then consumed 180  ml of drink, con-
taining 0 (placebo), 46, 93 and 185  mg of GCE (CGA
content: 54%). After 28  days, it was found that GCE pro-
moted a remarkable decrease in systolic (1.3, 3.2, 4.7
and 5.6  mmHg, respectively) and diastolic blood pres-
sure (DBP) (0.8, 2.9, 3.2 and 3.9  mmHg, respectively) in
a dose dependent fashion [29]. In a placebo-controlled,
randomized clinical trial, Watanabe et  al. [30] studied 28
patients with mild hypertension who consumed a diet rich
in GCE in fruit and vegetable juice (140  mg CGA) or a
daily placebo for 12  weeks. Systolic and diastolic blood
pressure was significantly reduced by 10/7  mmHg at the
end of treatment. Finally, in another double-blind, rand-
omized controlled trial with more participants (n = 203),
Yamaguchi et  al. [31] reported the beneficial effects of
CGA on blood pressure in mild hypertension patients. The
participants were assigned to five groups to receive HHQ-
free coffee containing 0 (control), 82 (low-dose), 172 (mid-
dle-dose) and 299 mg (high-dose) of CGA. After 4 weeks,
a dose-dependent decrease in blood pressure was seen. It is
noticeable that all above human studies used beverages free
of HH-Q.
In addition, the effects of CGA on blood pressure in
healthy subjects were reported. Ochiai et  al. [32] did not
find any significant changes in both SBP and DBP after
4 months of treatment with 125  ml of drink containing
140  mg of CGA in normotensive males. However, in a
randomized pilot crossover trail, opposite outcomes were
reported. Twenty-three healthy participants consumed
high CGA (400  mg CGA dissolved in 200  ml of water)
drinks and water (control), with a 1 week washout between
testing days. For 16  h prior to the study, the participants
refrained from a high polyphenol diet. A significant SBP
and DBP reduction was observed compared to the controls
at 120 min post-treatment [33]. On one hand, Ochiai et al.
did not get any positive response on blood pressure perhaps
because they used 140 mg CGA, the regular doses of CGA;
on the other hand, Watanabe et al. got a positive response
with the same dose of CGA in a diet rich in CGE in fruit
and vegetable juice. Thus, dose alone does not convinc-
ingly explain the difference in the hemodynamic effects of
CGA, the influence of the type of food matrix on bioavail-
ability of CGA and other sources of CGAs in daily diet are
important too. In a more recent pilot crossover study on
healthy subjects, Revuelta-Iniesta et al. [34] also found that
the consumption of green coffee rich in CGA compared to
black coffee for 2 weeks significantly reduced SBP.
In summary, the dietary consumption of chlorogenic
acid causes a significant reduction in systolic and diastolic
blood pressure; however, the size of the effects is moderate.
It is notable that most trials took place in Asia and it is not
known whether these results can be replicated in individu-
als with different ethnicity.
Effects of CGA on endothelial function
It is well-known that the impairment of endothelial func-
tion, which develops in diseases, such as hypertension,
diabetes [35], metabolic syndrome [35, 36] and others,
13


Table 1  Summary of animal and human studies that assessing the effects of CGA on cardiovascular health
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main result

13
Suzuki et al. [19]
Suzuki et al. [20]
Blood pressure Male SHR and Wistar Kyoto rats SHR GCE (720, 360, 180 mg/kg)
and SHR control
WKY GCE (720 mg/kg) and WKY 6 weeks
control
SHR GCE (0.25, 0.5, or 1.0% GCE
0 f moderate fat diet) and control
(moderate fat diet)
WKY GCE (1.0% of moderate fat
diet) and control (moderate fat
diet)
Single Oral Administration of 50,
100, or 200 mg/kg 5-CQA
Blood pressure Male SHR/Izm rats Experiment 1
Single oral administration of 5 ml/
kg GCE (200 or 300 mg/kg
CGA) or roasted instant coffee
containing 5-CQA (300 mg/kg)
and HHQ (0.03, 0.3, and 3 mg/
kg)
Experiment 2
Control diet
Dried HHQ-free coffee diet (CGA
300 mg/kg/day)
2 days GCE significantly decreased blood
pressure decreased blood pressure
in SHR dose-dependently
In SHR GCE-treated group the
increase in blood pressure was
significantly inhibited compared to
the control diet group after single
oral ingestion
25 h 5-CQA decreased blood pressure
dose-dependently
Singel administration of GCE
significantly decreased SBP while
coffee had little effect on it
25 h
8 weeks After 8 weeks the increase in SBP
was significantly inhibited in
treated group compared to the
control diet group
Eur J Nutr
 Table 1  (continued)
Reference Relevant outcome Type of subjects (animal/human) Treatments
Suzuki et al. [22] Endothelial function Male SHR and WKY rats Experiment 1
Blood pressure SHR rats received 30, 100, 300,
and 600 mg/kg CQA by single
oral administration
WKY rats received 300 mg/kg
CQA by single oral administra-
tion
Experiment 2
SHR control diet or CQA diet
(300 mg/kg per day)
WKY control diet or CQA diet
(300 mg/kg per day)
Suzuki et al. [23] Endothelial function 14-week-old Male SHR and WKY Control diet
rats
Blood pressure 0.005% HHQ diet
0.5% CQA diet
HHQ + CQA diet
Kosuma et al. [26] Blood pressure 117 Midly hypertensive patients 180 ml drink (soy soup) contain-
ing 0, 46, 93 and 185 mg GCE
containing 54% CGA
Watanabe et al. [27] Blood pressure 28 Midly hypertensive patients 125 ml fruit and vegetable juice
containing 140 mg CGA
125 ml drink free of CGA (Pla-
cebo)
Yamaguchi et al. [28] Blood pressure 183 Midly hypertensive patients HHQ-free coffee containing 0, 82,
172 and 299 mg CGA
Ochiai et al. [29] Blood pressure 20 Normotensive males 125 ml drink containing 140 mg
CGA
Endothelial function 125 ml drink free of CGA (Pla-
cebo)
Mubarak et al. [30] Blood pressure 23 Healthy adults 200 ml water containing 400 mg
CGA
Endothelial function 200 ml drink free of CGA (control)
13
Duration Main result
Eur J Nutr
Single ingestion of CQA at
30–600 mg/kg reduced blood pres-
sure in SHR
9 h
Consumption of diet rich in CQA
for 8 weeks inhibited development
of hypertension in SHR compared
with the control diet group
8 weeks
In CQA -treated SHR, acetylcholine-
induced endothelium-dependent
vasodilation in the aorta signifi-
cantly improved
Administration of HHQ + CQA
inhibited the CQA-induced
improvement in hypertension and
endothelial dysfunction in SHR
8 weeks
4 weeks GCE decreased SBP and DBP dose-
dependently
12 weeks CGA decreased SBP and DBP by
10/7 mmHg
4 weeks CGA decreased BP dose-depend-
ently
16 weeks No significant differences in BP with
control group
Homosysteine decreased signifi-
cantly
2 h SBP and DBP decreased sig-
nificantly compared to the control
group
No significant change on endothelial
function -related status

Table 1  (continued)
Reference Relevant outcome
13
Revuelta-Iniesta et al. [31] Blood pressure
Arterial elasticity
Olthof et al. [39] Endothelial function
Taguchi et al. [35] Endothelial function
Cheong et al. [37] Endothelial function
Kanno et al. [40] Chronic ventricular remodeling
after myocardial ischemia
Rodriguez de Sotillo et al. [43] Plasma and liver TG and choles-
terol levels
Blood glucose
Huang et al. [47] Serum and liver lipid levels
Zhang et al. [49] Plasma, liver and skeletal muscle
lipid levels
Fasting plasma glucose
Type of subjects (animal/human)
18 healthy volunteers
20 Healthy adults
Diabetic mic
30 Male C57BL6 mice (6–8 weeks (n = 10/group)
old)
C57BL6 mice (7–9 weeks old)
9-week-old male
Sprague–Dawley
Zucker (fa/fa) rats
40 Sprague–Dawley male rats
Male db/db mice
Treatments
Consumption of 100 ml green cof-
fee bean rich in CGA for 2 weeks
Consumption of 100 ml black cof-
fee for 2 weeks
One week wash out phase
2 g CGA
4 g black tea (4.3 mmol polyphe-
nols)
440 mg quercetin-3-rutinoside
placebo
CGA (0.03 mmol/kg/day)
Morin (0.03 mmol/kg/day)
Resveratrol (0.03 mmol/kg/day)
Normal diet
High-fat diet
HFD + GCE (70% CGA)
MI + CGA (30 mg/kg/day orally)
MI + vehicle
Sham + vehicle
Sham + CGA (30 mg/kg/day orally)
Infusion of 5 mg/Kg/day CGA
Infusion of vehicle
Normal control
HFD control
HFD + CGA (20 mg/kg)
HFD + CGA (90 mg/kg)
CGA (90 mg/kg)
80 mg/kg/d CGA by gavage
80 mg/kg/d PBS by gavage
Duration Main result
In the GCE-treated group SBP
and arterial elasticity decreased
significantly
5 weeks
7 days CGA and black tea-treated groups
increased homosysteine levels
No significant change on homosys-
teine levels in quercetin-treated
group
5 days All poly phenols activated NO
production
GCE did not improve endothelial
dysfunction caused by high-fat diet
12 weeks
14 days In the CGA-MI group
ventricular contraction significantly
improved compared to the vehicle-
MI group
CGA attenuated myocardial fibrosis
3 weeks Plasma cholesterol and TG levels
decreased by 44 and 58%, respec-
tively, Liver TG levels decreased
by 24%
CGA improved glucose tolerance
CGA decreased serum lipid levels
dose-dependently
12 weeks
12 weeks CGA decreased TG levels in plasma,
liver and skeletal muscle
CGA decreased fasting plasma
Eur J Nutr
glucose
 Table 1  (continued)
Reference
Li et al. [50]
Wan et al. [51]
Karthikesan et al. [52]
Frank et al. [53]
Mubarak et al. [54]
Lecoultr e et al. [86]
5-CQA 5-caffeoylquinic acid, HHQ hydroxyhydroquinone, SHR spontaneously hypertensive rats, HFD high-fat diet, PBS phosphate buffered saline, THC tetrahydrocurcumin, IHCLs increase
intrahepatocellular lipids, SBP systolic blood pressure; DBP, Diastolic blood pressure; GCE, green coffee bean extract; CGA, chlorogenic acid; MI, myocardial infarction
13
Relevant outcome Type of subjects (animal/human) Treatments
Serum and liver lipid and glucose 20 Male golden hamsters Peritoneal injection of 80 mg/kg/d 8 weeks
profile CGA + 15% HFD
Control 80 mg/kg/d PBS 15% HFD
Plasma lipid profile Sprague–Dawley rats Normal diet
High-cholesterol diet
High-cholesterol diet + CGA (1 or
10 mg/kg/day p.o.)
Lipid profile Adult male albino Wistar rats Normal
Diabetic control
Diabetic + THC (80 mg/kg)
Diabetic + CGA (5 mg/kg)
Diabetic + THC/CGA (80/5 mg/kg)
Lipid profile Sprague–Dawley male rats Consumption of 2 g/kg/ of CGA, 4 weeks
Tocopherol caffeic acid and ferulic acid
Liver lipid Male C57BL/6 mice Normal diet control
HFD control
HFD + CGA (1 g/kg)
CGA (1 g/kg)
Fatty acid oxidation Ten healthy subjects High-fructose diet (HFr)
Insulin resistance
Caffeinated coffee with high (9%)
amounts of CGA + HFr
Decaffeinated coffee with high
amounts of (9%) CGA + HFr
Decaffeinated coffee with regular
(3%) amounts of CGA + HFr
Control, diet without fructose sup-
plementation
Duration Main result
Eur J Nutr
CGA decreased lipid and glucose
profile significantly
4 weeks CGA significantly decreased total
cholesterol and LDL
45 days THC + CGA treated group reduced
induced lipid abnormalities in
diabetic rats compared to the CGA
or THC alone
CGA and caffeic acid treatment
groups increased cholesterol and
tocopherol levels in liver and a
tendency to do so in plasma
12 weeks CGA increased liver lipid content
and insulin resistance compared to
HFD group
Hfr diet increased IHCLs and
decreased fasting lipid oxidation
compared to control
14 days
Caffeinated coffee with high CGA
and Decaffeinated coffee with
regular amounts of CGA increased
fasting lipid oxidation

may also contribute to the development of arteriosclerosis.
However, while the cardiovascular protection of polyphe-
nols appears to be better understood [37], the mechanisms
of CGA on endothelial dysfunction as a major event in the
development of atherosclerosis remain unclear. The evi-
dence suggests that it may be attributed to the antioxidant
and anti-inflammatory properties of CGA. The other mech-
anism is related to the protective effects on endothelial
function through the release of vasoactive molecules such
as nitric oxide (NO) and thromboxane A2 (TXA2) [38].
Suzuki et al. published two studies which demonstrated
that ingestion of CGA-rich diet (300  mg/kg per day of
CGA) for 8  weeks induced a progressive and significant
decrease in blood pressure in the SHR animals compared to
the control diet group. In addition, it was found that CGA
inhibited reactive oxygen species (ROS) production, that
in turn reduced oxidative stress and enhanced NO bioavail-
ability in the vasculature, suggestive for a positive effect
of CGA on the endothelial function [26, 39]. However,
Cheong et  al. [40] examined the effects of CGA on sys-
temic oxidative stress and endothelial dysfunction in mice
fed with a high-fat diet for 12 weeks and did not find any
dietary benefits. Three separate groups (n = 10) were tested
with a normal diet, a high-fat diet, and a high-fat diet rich
in CGA (0.5% w/w GCE rich in CGA). The CGA rich diet
did not impact on the metabolic deterioration caused by a
high-fat diet and endothelial dysfunction. As mentioned
previously, the ability of CGA to improve endothelial
function could be secondary to its anti-oxidative and anti-
inflammatory activities; however, there is preliminary evi-
dence indicating that CGA possess a special property that
can itself regulate the vascular tone [41]. In this context,
Taguchi et al. used polyphenols, including chlorogenic acid
(0.03  mmol/kg/day), morin (0.03  mmol/kg/day) and res-
veratrol (0.03 mmol/kg/day) in streptozotocin-induced dia-
betic mice for 5 days, to evaluate the endothelium-depend-
ent relaxation of aortic rings in response to acetylcholine
(Ach). The results showed that polyphenols activate NO
production, suggesting that they can acutely activate NO-
mediated processes through the suppression of TXA2 lev-
els, but not the NO production under Ach stimulation [41].
More recently, Kanno [42] reported the beneficial effect of
CGA on chronic ventricular remodelling after myocardial
infarction in murine myocardial ischemia models through
the suppression of macrophage infiltration.
CGA may display further various effects on endothe-
lial function in healthy subjects. Evidence suggests that
homocysteine may induce vascular endothelial dysfunc-
tion [43]. Ochiai et  al. examined the effects of GCE on
homocysteine levels and blood vessels in 20 healthy males.
After 4 months of daily intake of a drink containing GCA
(140  mg/day) or placebo, a significant decrease in plasma
total homocysteine levels and improvement in the reactive
13
Eur J Nutr
hyperemia ratio (RHR) (calculated as the antebrachial arte-
rial blood flow at reactive hyperemia/basic blood flow)
was observed in the CGA-treated group compared with the
placebo [32]. Contrasting results have been published by
Olthof et al. in a crossover study performed in 20 healthy
men and women; it concluded that CGA increased the
homocysteine concentration in plasma. It should be pointed
out that they analyzed the acute effects of CGA [44]. In 23
healthy men and women (aged 32–65  years; 19 females),
Mubarak et al. examined the acute effects of CGA on nitric
status, blood pressure, and endothelial function in a rand-
omized, double-blind, placebo-controlled crossover trial.
The participants consumed high-CGA (400  mg CGA dis-
solved in 200 ml of water) drinks and water (control) with a
7 day washout between testing periods. The results showed
that the mean flow-mediated dilation (FMD) in the bra-
chial artery measured by ultrasonography and markers of
nitric oxide status were not influenced at120 min, while a
significant blood pressure reduction relative to control was
observed [33].
CGA and lipid metabolism
Dyslipidemia can induce glycometabolic disorders linked
with the risk of non-alcoholic fatty liver disease and CVD.
It is claimed that lipid and glucose metabolism can be mod-
ulated by CGA [45].
In a 2002 study, Rodriguez de Sotillo and Hadley [45]
analyzed the impacts of CGA on glucose and lipid pro-
file in obese, hyperlipidemic and insulin resistant (ƒa/ƒa)
Zucker rats. It was found that CGA promoted a significant
reduction in the postprandial peak response to glucose
changes, but did not affect sustained hypoglycaemia in
comparison to the pre-CGA treatment phase in the same
rat group. They also found that in rats fed with CGA, fast-
ing plasma cholesterol and triacylglycerol (TG) levels were
significantly reduced, similar to liver triacylglycerol lev-
els. They concluded that in vivo CGA was associated with
decreased various plasma and liver lipids and improved
glucose tolerance.
The oxidative modification of low-density lipoproteins
(LDL) is a strong risk factor in the pathogenesis of arte-
riosclerosis [46]. Evidence suggests that consumption of
coffee induces a decrease in LDL-cholesterol and malon-
dialdehyde (MDA) levels [47]. Bagdas et  al. found that
in rats receiving CGA (100  mg/kg), MDA levels were
decreased in comparison to the model group [48]. Con-
sequently, Huang et  al. [49] ascertained these results by
investigating the effect of 5-CQA on lipid metabolism
in Sprague–Dawley (SD) rats fed a high-fat diet (HFD).
Forty male rats were randomly assigned to (1) a normal
control (NC) group, (2) a HFD control group, (3) a HFD
with low-dose CGA (20  mg/kg) group, and (4) a HFD
Eur J Nutr
with high-dose CGA (90  mg/kg). These doses of CGA
corresponded to approximately 3.85 mg/kg (low doses of
CGA) and 15.39 mg/kg (high doses of CGA) for a 70 kg
man. CGA was provided orally by gavage once per day
for 12  weeks. In high-dose CGA-treated rats, hepatic
total cholesterol (TC), TG and MDA levels were signifi-
cantly lower than the HFD control group. However, Pan-
chal et  al. [50] failed to observe any significant changes
in plasma TG, but TC significantly decreased in rats fed
Colombian coffee extract (CE) with a high carbohydrate,
HFD. It is noticeable that CE contain high amounts of
caffeine in addition to CGAs.
In a 2011 study, Zhang et al. [51] assessed the effect of
CGA on deranged metabolism of lipid and glucose in db/
db mice. The authors reported that CGA applies benefi-
cial effects to the levels of triglycerides in plasma, liver,
and skeletal muscle, and fasting plasma glucose through
increased upregulation of the expression of peroxisome
proliferator-activated receptor-ɣ (PPAR-ɣ). This study sug-
gested that CGA ameliorates deranged lipid/glucose metab-
olism in db/db mice, indicating a possible role for CGA as
a modulator of the adipokines secretion, upregulating the
expression of hepatic peroxisome proliferator-activated
receptor-α (PPAR-α). Li [52] also examined the effects
of CGA on the metabolism of lipid and glucose follow-
ing a high dietary fat burden in male golden hamsters and
explored the role that PPAR-α may have in these effects.
They concluded that PPAR-α played the role of a facilitator
in clearing lipid from the liver and enhancing the sensitiv-
ity of insulin.
Current evidence suggested that the cholesterol-lower-
ing effects of CGA in SD rats are most likely mediated by
increasing fatty acid utilization in the liver via the upregu-
lation of PPAR-α mRNA [53].
Karthikesan et  al. [54] evaluated the effects of tet-
rahydrocurcumin (THC) (80  mg/kg bw) and CGA (5  mg/
kg bw) alone and in combination, on lipid metabolism
in experimental type-2 diabetic rats. After 45  days, the
combination of THC and CGA could potently ameliorate
lipid abnormalities compared to CGA or THC alone. On
the other hand, Frank [55] reported caffeic acid (CA) and
CGA increased cholesterol concentrations in the liver and
showed a tendency to do so in plasma in SD rats. Mubarak
[56] found that CGA supplementation in a high-fat diet is
associated with impaired fatty acid oxidation, and conse-
quently hepatic lipid accumulation in diet-induced obese
mice. The distinct outcomes were likely to be due to dif-
ferent doses or diet, methods of CGA administration or
study protocols. Finally, in the only human study to date
Lecoultre et al. reported the positive effects of caffeinated
coffee with high (9%) and decaffeinated coffee with regular
(3%) amounts of CGA on glucose and lipid metabolism in
healthy men [57].
Diabetes mellitus and CGA
Glucose metabolism
Type-2 diabetes mellitus is a metabolic disease that
involves impaired metabolism of glucose and fat [58].
Studies have shown contrary associations between the
consumption of coffee and lower risk of T2DM [59–62].
Caffeine exerts but is not fully responsible for its benefi-
cial effects on glucose metabolism; some other components
including CGAs play a key role in this respect [63–65]. For
example, it is reported that for those who drink 3–4 cups of
decaffeinated coffee containing high contents of CGA, the
risk of T2DM is reduced by 30% [66]. There were 17 stud-
ies that examined the association between CGAs consump-
tion and Diabetes mellitus (Table  2). 12 were on animal
models and five on humans.
Hypoglycemic effect  CGA is defined as a pioneer insulin
sensitizer, strengthening insulin functions such as the thera-
peutic action of metformin [67]. CGA carries antidiabetic
potential at a single acute dose (5  mg/kg body weight) in
streptozotocin-nicotinamide-induced diabetic rats [68–70].
Evidence suggests that glycaemia fell after the utiliza-
tion of 50  mg/kg of CGA derivatives in rats [71], whilst
Bassoli et  al. reported 70  mg/kg of CGA is sufficient for
the same results. They found a significant reduction in the
plasma glucose peak and proposed the beneficial effects of
CGA on reducing glycaemic index of food through alle-
viating the intestinal absorption of glucose in rats [72]. It
should be pointed out that Herling et al. used CGA driva-
tives, and it is unknown at this time whether this difference
in intervention would affect the results.
The immediate effects of CGA on glucose tolerance
were examined in overweight men following an oral glu-
cose tolerance test (OGTT). It was found that treatment
with CGA improved insulin responses and early fasting
plasma glucose in comparison to placebo [73]. Ahrens
et  al. found that if supplement contains of CGA is con-
sumed regularly, it is able to lower the glycaemic impact
of food and chronically lower background blood glucose
levels of T2DM [74]. In  vitro evidence demonstrated that
CGA increases cell insulin secretion [75]. Johnston et  al.
found the same effect in humans [19].
Glucose tolerance and  insulin sensitivity  Insulin resist-
ance is a main obstacle in diabetes treatment and plays a
pivotal role in the pathogenesis and clinical course of sev-
eral important diseases. For the first time, Ong et  al. [76]
demonstrated the efficacy of CGA on glucose uptake in
skeletal muscle of db/db mice through the stimulating activ-
ity of AMP-activated protein kinase (AMPK). The same
authors [77] also found that CGA enhanced glucose metab-
13

Table 2  Summary of animal and human studies that assessing the effects of CGA on Diabetes mellitus
Reference Relevant outcome
13
Rodriguez de Sotillo et al. [41] Plasma insulin
Karthikesan et al. [65] Potential antihyperglycemic effect
Karthikesan et al. [66] Protective effect of CGA and THC
against oxidative stress induced
type 2 diabetes
Pari et al. [67] Plasma glucose and insulin
Bassoli et al. [69] Blood glucose
Glucose tolerance
Jung et al. [75] Plasma insulin and glucose
Type of subjects (animal/human) Treatments
9-week-old male Sprague–Dawley Control
Zucker (fa/fa) rats, obese and CGA-treated rats (CGA injected
type 2 diabetic intravenously every day for
3 weeks at 5 mg/kg bw)
Male albino Normal
Wistar rats Diabetic control
Diabetic + THC (80 mg/kg)
Diabetic + CGA (5 mg/kg)
Diabetic + THC/ CGA (80/5) mg/
kg
Adult Wistar rats Normal
Diabetic control
Diabetic + THC (80 mg/kg)
Diabetic + CGA (5 mg/kg)
Diabetic + THC/ CGA (80/5) mg/
kg
6-week-old male albino Wistar rats Normal
Diabetic control
Diabetic + THC (80 mg/kg orally)
Diabetic + CGA (5 mg/kg orally)
Diabetic + THC/ CGA (80/5) mg/
kg orally
Male albino Blood glucose test: Intravenous
Wistar rats injection of 70 mg kg/bw CGA,
control (buffer without CGA)
Glucose tolerance test: Oral admin- 90 min
istration of 3.5 mg kg/1.bw CGA,
control (water)
15 Male C57BL/KsJ-db/db mice ControL
Caffeic Acid
Duration Main results
3 weeks In the CGA-treated group, plasma
insulin and blood glucose
improved significantly
45 days In the THC/CGA group glyco-
sylated haemoglobin significantly
decreased and the levels of plasma
insulin, C-peptide, haemoglobin
and glycogen decreased signifi-
cantly
45 days Combination of THC and CGA nor-
malized all biochemical parameters
induced by diabetes
45 days Combination of THC and CGA nor-
malized insulin and glucose levels
induced by diabetes
60 min No significant reduction in blood
glucose levels after intravenous
injection of CGA
CGA made a significant reduction
on plasma glucose peak at 10 and
15 min
5 weeks Caffeic acid decreased blood glucose
and increased insulin levels sig-
nificantly compared to the control
group
Eur J Nutr
 Table 2  (continued)
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main results
Eur J Nutr

Ma et al. [76] FBS 6-week-old male C57BL/6 Regular or HFD diet with twice 15 weeks CGA decreased FBS compared
Glucose tolerance Obese mice intraperitoneal injection of HFD-fed control (134 ± 28 mg/dl
100 mg/kg CGA or DMSO (car- vs. 204 ± 43 mg/dl)
rier solution) as control per week
Insulin tolerance CGA maintained glucose sensitivity
and improved diet-induced hyper-
insulinemia
Body weight Obese mice received intraperi- 6 weeks CGA blocked the progress of diet
toneal injection of 100 mg/kg induced obesity significantly but
CGA, twice weekly or DMSO did not affect body weight in obese
(control) mice
Cheong et al. [37] Glucose intolerance 30 Male C57BL6 mice (6–8 weeks (n  = 10/group) No significant differences between
old) Normal diet (ND) groups regarding glucose Intoler-
ance and insulin resistance
Insulin resistance High-fat diet (HFD) 12 weeks GCE did not improve HFD-induced
Obesity improvement HFD + GCE (70% CGA) obesity
Tunnicliffe et al. [77] Blood glucose Male Sprague–Dawley rats Standard diet with or without CGA 180 min CGA decreased blood glucose
(120 mg/kg) significantly
Plasma insulin No significant changes in plasma
GIP insulin and GLP-1
GLP-1 CGA blunted plasma GIP response
up to 180 min postprandially
Van Dijk et al. [70] Blood glucose 15 Overweight men 270 ml water containing In the CGA and trigonelline treated
Blood insulin 12 g decaffeinated coffee group early glucose and insulin
responses decreased during glu-
1 g chlorogenic acid
cose tolerance test
500 mg trigonelline 2 h
Placebo (1 g mannitol)
Johnston et al. [73] Plasma glucose Nine healthy adults 400 mL water containing 25 g In the caffeinated coffee group
glucose (control) glucose and Insulin concentrations
Plasma insulin 400 mL water containing 25 g tended to be increase after 30 min
glucose + caffeinated coffee compared the other groups
GIP
(2.5 mmol CGA/L)
GLP-1 400 mL water containing 25 g 3 h Glucose and insulin decreased in
glucose + decaffeinated coffee decaffeinated coffee group after
(2.5 mmol CGA/L) 30 min GIP decreased in treated
groups
GLP-1 increased 0–120 min post-
prandially in decaffeinated coffee
group compared with the control

13

Table 2  (continued)
Reference
13
Olthof et al. [78]
Shin et al. [81]
Herling et al. [82]
Simon et al. [83]
Lecoultre et al. [86]
HFr high-fructose diet, HGP hepatic glucose production, HFD high-fat diet, FBS Fasting Blood Glucose, GIP Plasma glucose-dependent insulinotropic peptide, GLP-1 glucagon-like peptide-1,
THC Tetrahydrocurcumin, STZ streptozotocin
Relevant outcome
GIP
GLP-1
Retinal vascular leakage in the
diabetic retinopathy
Blood glucose
Glucose-6-phosphatase activity
Blood glucose
Glucose-6-phosphatase activity
Hepatic insulin sensitivity
Hepatic glucose production
Type of subjects (animal/human)
15 Overweight men
Male Sprague–Dawley rats
Male Wistar rats
Male adult Wistar rats
Ten healthy subjects
Treatments
270 ml water containing
12 g decaffeinated coffee
1 g chlorogenic acid
500 mg trigonelline
Placebo (1 g mannitol)
Control
STZ
STZ + CGA(10 mg/kg)
STZ + CGA (20 mg/kg)
10, 30 and 50 mg/kg/h S 4048
intravenously
Control
50 mg/kg/h S 3483 intravenously
Control
High-fructose diet
Caffeinated coffee (9% CGA) + HFr 14 days
Decaffeinated coffee (9%
CGA) + HFr
Decaffeinated coffee (3%
CGA) + HFr
Control, diet without fructose sup-
plementation
Duration Main results
No significant differences in GLP-
and GIP-secretion pattern with
placebo
2 h
14 days CGA treatment effectively preserved
the vascular leakage
5 h In the treated group blood glucose
decreased dose dependently with a
corresponding increase in hepatic
glucose-6-phosphate
8.5 h In the S 3483 treated rats Glc-6-Pase
activity increased significantly
Blood glucose concentrations
decrease during the first 90 min of
infusion
HFr significantly increased HGP by
16 ± 3%
In all three coffee treated groups
HGP decreased significantly
Eur J Nutr
Eur J Nutr
olism deficits and dyslipidaemia in L ­ eprdb/dbmice primar-
ily by activating AMPK. Numerous beneficial impressions
of CGA on glucose metabolism have been considered in
previous studies with the probability of modified systemic
glucose control [78]. One of the primary mechanisms for
inverse associations between CGA and T2DM is inhibi-
tion of the glucose-6-phosphate system and subsequently
delayed glucose absorption in the intestine [71, 79, 80].
Moreover, CGA diminishes blood glucose levels by directly
inhibiting glucose-6-phosphatase (G6Pase) activity with
relevant effects of hepatic gluconeogenesis [81].
CGA has been viewed as having a positive effects on
glucose metabolism regulation [45, 82, 83], glucose tol-
erance, and insulin resistance in Zucker (ƒa/ƒa) rats, thus
indicating a possible role for CGA as a compound of inter-
est for reducing the risk of developing T2DM [45, 82, 84].
Ma et al. [82] studied the effect of CGA on insulin resist-
ance in C57BL/6 mice. They intraperitoneally admin-
istered mices with 100  mg/kg CGA for 21  weeks. CGA
maintained glucose sensitivity and improved diet-induced
hyperinsulinemia in compared with control group. In a ran-
domized crossover study separated by a three-day washout
period, Tunnicliffe and colleagues [85] found no effects on
glucagon-like peptide-1 (GLP-1) secretion in rats fed with
CGA, while plasma glucose-dependent insulinotropic pep-
tide (GIP) response was decelerated. They concluded that
CGA treatment could have beneficial impacts on blood
glucose response, with adjustments observed in GIP lev-
els. The findings of Cheong et al. also suggest that mice fed
with green coffee bean extract rich in CGA did not have a
better glucose tolerance and insulin resistance than that of
the controls [38].
Johnston [19] reported that the consumption of cof-
fee rich in CGA stimulates the secretion of GLP-1, which
is known to augment insulin secretion after oral glucose
consumption in healthy volunteers. Olthof et  al. [86] also
reported that the acute ingestion of CGA did not affect
GLP-1 and GIP responses during OGTT in overweight
men.
CGA and obesity
Obesity, as one of the main risk factors of cardiovascular
disease, has become a worldwide serious health concern
[87]. Due to high expenditure for medicinal weight loss
interventions, the public opinion is gradually switching
to nutraceuticals (functional foods) as alternatives and
one of the most controversial weight-loss supplements
is GCE. The evidence suggested that the consumption of
coffee is inversely associated with weight gain [88]. This
beneficial effect has been attributed to caffeine and CGA
[20, 89]. The results from two prospective cohort stud-
ies showed that caffeinated and decaffeinated coffee were
both independently associated with body weight loss,
which is suggestive of a positive effect of non-caffeine
compounds of coffee on weight reduction [88, 90].
The interaction between CGA and body weight, body
mass index (BMI) and percent body fat is ambiguous.
Recently, Narita et al. reported that CGA and its metabo-
lite, CA, may decrease caloric input via inhibiting amyl-
ase in  vitro [91]. As mentioned previously, CGA dem-
onstrates a significant improvement in glucose tolerance
that might be a consequence of reduction in BMI and its
effects on body weight [84]. The respective glucose dep-
rivation might be indicative of the decline in BMI and
fat content [45, 92]. Flanagan et  al. revealed the other
putative mechanism to be related to the effects on adi-
pocyte metabolism that—via enhanced lipolytic activity
in the adipocyte tissue—may explain weight reduction
[93]. There were 11 studies that examined the association
between CGAs consumption and obesity (Table  3). Six
were on animal models and five on humans.
In animals, CGA has been reported to influence body
weight, probably by inhibiting hepatic triglyceride accu-
mulation [94]. In keeping with the previously discussed
findings of Huang et  al. [49], CGA can suppress body
weight gain but did not show any changes in food intake.
Similar results were also observed in other studies [52,
54]. In 2009, Tanaka et al. revealed the lipolytic activity
of GCE in SD rats. To this end, 4-week-old SD rats were
orally treated with GCE (diet containing 1% GCE) rich in
caffeine (10%) and CGA (27%) for 4 weeks. In the GCE-
treated rats, the activity of hepatic fatty acid oxidative
enzymes significantly increased compared to the control
group, while fatty acid synthetic enzymes decreased sig-
nificantly [95]. However, the lipolytic activity observed
in Tanaka’s study could be attributed to caffeine. Other
studies demonstrated that caffeine may reduce obesity
by stimulating catecholamine (important regulators of
lipolysis) secretion [96]. Current evidence corroborates
the beneficial effects of CGA on body weight in diet-
induced obese rats through modulating PPARα [49].
Other investigators also concluded that non-caffeine com-
pounds in coffee may be responsible for its anti-obesity
activity. Song et al. [97] reported that decaffeinated GCE
significantly reduces visceral fat-pad accumulation in
the mouse model of obesity, possibly due to attenuating
genes involved in adipogenesis and inflammation in the
white adipose tissue. Furthermore, Cho et al. observed a
similar response to body weight in high-fat diet-induced
obese mice; they suggested that CGA mediates its anti-
obesity effect through the adjustment of obesity-related
hormones and adipokine levels and by upregulating fatty
acid oxidation in the liver and downregulating fatty acid
and cholesterol biosynthesis [98].
13


Table 3  Summary of animal and human studies that assessing the effects of CGA on obesity
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main results

13
Shimoda et al. Body weight Male ddy mice Mice consumed a standard diet containing GCE reduced visceral fat content and body-
[94] weight
Visceral fats GCE (0.5% or 1%)
Caffeine (0.05% and 0.1%) 14 days CGA and Caffeine showed a tendency to reduc-
tion of visceral fat and body weight
CGA (0.15% and 0.3%)
Placebo (orlistat)
Tanaka et al. [95] Body weight Male, 4-week-old Sprague–Dawley rats Control diet GCE-rich diet decreased significantly body-
Food intake GCE–rich diet (27% CGA and 10.0%caffeine) weight gain and white adipose tissue weight
compared to control
Adipose tissue weight 4 weeks No significant differences in food intake
between two groups
Song et al. [97] Body weight 48 male C57BL/6Nmice (n = 8/group) Body weight gain decreased dose-dependently
Food intake Normal control group (chow diet) in GCE groups and CQA-treated group
Blood glucose HFD control group In all treated groups plasma lipids, glucose, and
Blood insulin HFD containing, 0.1, 0.3, and 0.9%decaffein- 11 weeks insulin levels improved, instead of 0.1% GCE
ated GCE
Lipid profile HFD containing 0.15% CQA No significant differences in food intake
between all groups
Cho et al. [98] Body weight 32 male 4-week-old ICR mice (n = 8/group) Both treatment groups significantlydecreased,
Food intake Normal body weight, visceral fat mass, plasma leptin
and insulin levels and improved plasma lipid
Plasma lipid HFD control
compared to the HFD control group
Plasma leptin HFD-caffeic acid (0.2 g/kg diet) 8 weeks CGA-treated group increased plasma adiponec-
Plasma adiponectin HFD -chlorogenic acid (0.2 g/kg diet) tin level compared to HFD control group
Huang et al. [47] Body weight 40 male Sprague–Dawley rats (n = 10/group) 5-CQA suppressed increases of bodyweight
Visceral fats Normal control group (chow diet) induced by HFD, visceral fat-pad weight and
serum lipid levels dose-dependently
Lipid profile HFD control group 12 weeks
HFD with low-dose 5-CQA (20 mg/ kg)
HFD with high-dose 5-CQA (90 mg/ kg)
Dellalibera et al. Body weight 50 overweightvolunteers Control group (placebo)+low calorie diet 8 weeks Significant reduction in body weight intreat-
[99] ment group compared to control
BMI Treated group (CGA supplement) )+lowcalo- Muscle Mass/Fat Mass ratio increasedsignifi-
Muscle mass/fat mass rie diet cantly in CGA- treated group
ratio
Bakuradze et al. Body weight 33 Healthyvolunteers Consumption of 750ml coffee rich in green 12 weeks Body weight, body fat decreasedsignificantly
[100] BMI orroast bean constituents (CGA 580 mg/l)
for 8weeks wash out phase
Body composition
Eur J Nutr
 Eur J Nutr

On the other hand, some studies [40, 50, 56] failed to

12 weeks Body weight decreased significantly intreatment

observe any significant effect of CGAs and GCE on body
12 weeks No significant changes in body weight andan-

In CGA-treated group body weight, BMIde-

tioxidant status following consumptionof

Waist circumference and abdominal fatde-

weight in a diet-induced animal model of obesity.
A limited number of human studies with CGA have been

creased significantly in both groups

reported so far. Thom reported that following 12 weeks

group compared to the control

of rich-CGA coffee intake (200 mg/day) in 30 overweight
subjects, the mean body weight significantly decreased
compared to the placebo (5.4 vs. 1.7  Kg) [20]. Favour-
creased significantly
able effects of CGA on body weight in healthy overweight
CGA-rich coffee

adults have also been observed in another study with a sim-

ilar design, where GCE rich in CGA significantly decreased
Duration Main results

weight (by 5 kg) compared with placebo (2.45 kg) [99].

Bakuradze et  al. also found that the intake of high-
antioxidant coffee enriched with both green or roast bean
constituents (CGA, 580  mg/l) significantly reduces body
5 weeks

weight along with a significant decrease in oxidative dam-

age [100]. In a meta-analysis performed including three tri-
als, Onakpoya noted that an average weight reduction was
reasonable (2.5 kg) and that the outcomes were encourag-
Consumption of 100 ml green coffee rich
Consumption of 600 ml light roast coffee

Consumption of 600 ml dark roast coffee

5 cups coffee rich in CGA (200 mg/day)

Consumption of 100 ml black coffee for
richin CGA (4.5 mmol/L) for 4 weeks

ing [25]. In contrast to this data, Watanabe et al. showed in

a placebo-controlled, randomized clinical trial performed
in mildly hypertension subjects that CGA did not modify
the BMI but significantly decreased blood pressure, sug-
(0.05mmol/L) for 4 weeks

One week wash out phase

gesting that CGA may be an effective and safe therapy

4 weeks wash out phase

for patients with mild hypertension [30]. In another rand-

inCGA for 2 weeks

5 cups normal coffee

omized intervention performed in 30 healthy volunteers,

GCE green coffee bean extract, CGA chlorogenic acid, HFD high-fat diet, CQA 5-caffeoylquinic acid
(n = 15/group)

it was found that CGA-rich coffee (CGA: 4.5 mmol/L) did

Treatments

not modify body weight [101]; however, it should be noted

2weeks

that the study period was too short (4 weeks) in comparison

to other previous studies. Vinson et al. observed a dramatic
weight loss compared with previous investigations, i.e. 8 kg
or more than 10% of the body weight. It should be noted
that the article was retracted in October 2014, because the
Type of subjects (animal/human)

US-based sponsors could not confirm the validity of the

study which was performed in India [92]. Finally, in a ran-
30 Overweightvolunteers

domized pilot crossover study involving 20 healthy subjects

33 Healthyvolunteers

18 Healthyvolunteers

who consumed green coffee rich in CGA or black coffee

for 2 weeks, coffee rich in CGA had a significant effect on
BMI and abdominal fat [34].
These encouraging results from animal and human stud-
ies could help explain the epidemiological evidence that
long-term consumption of decaffeinated coffee is effective
in lowering body weight, albeit as yet limited and incom-
Body composition
Antioxidant status
Relevant outcome

plete. For example, no studies of the influence of CGAs

Anthropometry

intake on thermogenesis, thermic effect of food, appetite

Body weight
Body weight

and satiety have been conducted.

Cancers and CGA
Table 3  (continued)

Revuelta-Iniesta
Kotyczka et al.

Early in-vitro observations suggest that cellular damage

et al.[31]

Thom [14]

caused by reactive oxygen species (ROS) is related to the

Reference

[101]

incidence of a number of diseases, including coronary

heart disease, diabetes and cancers [102, 103]. CGA, as an

13


Table 4  Summary of animal and human studies that assessing the effects of CGA on cancers
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main results

13
Mori et al. [112] Incidence of total large intestinal 98 Syrian golden hamsters MAM-asetate (by injection 20 mg/ Both incidence of total large intestinal
tumours bw) + normal diet tumours and adenocarcinomas signifi-
cantly decreased in CGA-treated group
Incidence of large intestinal adenocar- MAM-asetate + CGA-rich diet 24 weeks The numbers of hyperplastic liver cell
cinomas CGA-rich diet (%25) foci in MAM-asetate rich in CGA
group significantly decreased com-
Numbers of hyperplastic liver cell foci No treatment
pared with the MAM acetate group
Matsunag et al. [114] Carcinogen-induced large bowel 150 Male F344 rats AOM (by injection 15 mg/bw) + nor- CGA showed a chemopreventive ability
carcinogenesis mal diet against colon carcinogenesis in rats
CGA-rich diet (250 ppm for 5 weeks)
AOM + CGA-rich diet 32 weeks
CGA-rich diet (250 ppm for 32 weeks)
No treatment (control)
Tanaka et al. [115] Incidences of tongue neoplasms 118 Male 4-week-old F344 rats 4-NQO (20 p.p.m. dissolved at water 32 weeks The incidences of tongue neoplasms and
for 5 weeks) preneoplastic lesions (hyperplasia and
4-NQO + CA (500 p.p.m for 7 weeks) dysplasia) significantly reduced in all
phenolic-treated groups by 32 weeks
4-NQO + EA (400 p.p.m for 7 weeks)
Preneoplastic lesions (hyperplasia and 4-NQO + CGA (250 p.p.m for CA, EA, CGA and FA inhibited the
dysplasia) 7 weeks) tongue carcinogenesis induced by
4-NQO + FA (500 p.p.m for 7 weeks) 4-NQO
CA (500 p.p.m for 7 weeks)
EA (400 p.p.m for 7 weeks)
CGA (250 p.p.m for 7 weeks)
FA (500 p.p.m for 7 weeks)
No treatment
Eur J Nutr
 Table 4  (continued)
Reference Relevant outcome
Tanaka et al. [116] The numbers of hyperplastic liver
cell foci and the incidence of colon
tumours
The incidence of altered hepatocellular Experiment 3: male ACI/N rats
The number of hepatocellular foci
Incidences of liver tumours and hepa-
tocellular foci
Shimizu et al. [118] Incidences of adenomatous hyperpla- 78 Male 5-week-old F344 rats
sia
Incidences of glandular stomach
carcinoma
Boettler et al. [119] ARE-dependent transcription
Volz et al. [120] Transcription of Nrf2/ARE Pathway
MAM methylazoxymethanol, CA caffeic acid, EA ellagic acid, CGA chlorogenic acid, FA ferulic acid, 4-NQO 4-nitroquinoline-l-ojdde, FAA N-2-fluorenylacetamide, MNU N-methyl-N-nitrosou-
rea, NMP N-methylpyridinium, ARE antioxidantresponse element
13
Type of subjects (animal/human)
Experiment 1: Male and female
Syrian golden hamsters
Experiment 2: Female ACI/N rats MAM + CGA-rich diet (0.025%) for
Experiment 4: rats
27 healthy volenteers
29 healthy volunteers
Treatments
MAM acetate alone (control)
24 weeks
FAA alone (control)
FAA + reserpine (weekly injections of
1 µg/g bw) for 10 weeks
FAA alone (control)
FAA + polyprenoic acid (40 mg/kg bw,
3 times/week) for 13 weeks
Aminopyrine (0.01%of diet) and
sodium nitrite (0.01% of diet)
(control)
Aminopyrine and sodium nitrite + cof-
fee solution as a drinking water
MNU alone (control)
MNU + CGA (500 ppm in diet for
22 weeks)
MNU + CGA (4250 ppm in diet for
22 weeks)
CGA (500 ppm for 36 weeks)
No treatment
2 weeks wash out phase
Consumption of 500 ml coffee rich in
CGA (4.5 mmol/L) for 4 weeks
2 weeks wash out phase
Consumption of 500 ml coffee rich in
NMP for 4 weeks
4 weeks wash out phase
Consumption of 750 ml green and
roasted coffee rich in CGA for
4 weeks
4 weeks wash out phase
Duration Main results
Eur J Nutr
The numbers of hyperplastic liver
cell foci and the incidence of colon
tumours were significantly lower in
CGA-treated group than control
The incidence of altered hepatocellular
foci in reserpin-treated group was
significantly lower than control
24 weeks
The number of hepatocellular foci in
treatment group was significantly
smaller than control
Incidences of liver tumours and hepa-
tocellular in treatment group were
significantly lower than control
36 weeks The incidences of adenomatous hyper-
plasia in second treatment group was
significantly lower than control
The incidences of glandular stomach
carcinoma in third treatment group
was significantly lower than control
12 weeks Both treatment group modulated ARE-
dependent transcription
12 weeks CGA-rich coffee increased Nrf2 tran-
scription significantly
However, pattern of genes showed sub-
stantial variations interindividually

effective electrophilic trapping agent, has beneficial effects
against diseases whose pathogenesis involves increased
oxidative stress and oxidative damage [102, 104].
CGA shows vigorous action on lipid peroxidation [105],
for instance 8-hydroxydeoxyguanosine is configured via
this inhibitor [106]. In this respect, Hoelzl et  al. reported
the consumption of coffee containing high levels of CGA
decreasing 8-isoprostaglandin F2α and 3-nitrotyrosine by
15.3 and 16.1%, respectively, thus offering a protective
effect of CGA against the damage mediated by free radicals
[107]. Aforementioned results were confirmed by another
experiment in which the prevention of oxidative DNA
damage caused by two types of coffee was compared. The
maximum protection was seen after intervention in CGA-
rich coffee compared with N-methylpyridinium-rich coffee
[108]. Several phenolic compounds are known to possess
an effective inhibitory action on polycyclic aromatic hydro-
carbons mutagenesis and carcinogenesis [109, 110]. Mori
et al. tested the effects of dietary CGA on methylazoxym-
ethanol (MAM) acetate-induced colon carcinogenesis in
Syrian golden hamsters. They reported that the number of
hyperplastic liver cell foci were significantly smaller in the
intervention group than in the controls; this suggests that
CGA might inhibit MAM acetate-induced carcinogenesis
[111].
Similarly, Morishita et al. were able to show an inverted
CGA effect on configuration of azoxymethane (AOM)-
induced aberrant crypt foci (AFC) in the rat colon [112].
These results were confirmed by another experiment which
suggested that CGA has chemopreventive capability against
colon carcinogenesis in rats [113]. Tanaka et  al. reported
that CGA inhibits 4-nitroquinoline-1-oxide-induced oral
carcinogenesis in rats [114] and hepatocarcinogenesis in
hamsters [115]. Huang et al. demonstrated that the inhibi-
tory effect of CGA on tumour promotion in the mouse
skin was less effective than curcumin [116]. CGA mark-
edly suppressed N-methyl-N-nitrosourea-induced glandu-
lar stomach carcinogenesis in male F344 rats, suggesting
chemopreventive effects of CGA on rat glandular stom-
ach carcinogenesis and implying a promising factor for
human stomach cancer prevention [117]. One important
mechanism for protecting cells and tissues from carcino-
genesis and carcinogenic metabolites is the activation of
the Nrf2/ARE pathway [118]. The same group reported
the beneficial effects of coffee rich in chlorogenic acid on
DNA integrity in another study [119] (Table  4). A more
recent pilot human intervention study found that following
14-weeks of high-CGA coffee intake in 29 healthy subjects,
Nrf2 transcription significantly increased peripheral blood
lymphocytes [120]. Although the current animal data on
CGAs are promising, beneficial effects of CGAs on human
cancer have not been studied extensively. The relationship
between CGAs consumption and cancer was investigated in
13
Eur J Nutr
11 studies (Table 4) including sevenanimal models and four
humans.
CGA and brain health
There were 13 studies that examined the association
between CGAs consumption and brain health (Table  5).
Ten were on animal models and three on humans.
Behavioural effects of CGA
While considerable in vitro evidence verifies the effects of
CGA on brain health, several pre-clinical studies also sup-
port this hypothesis. Han et al. [121] assessed the ability of
a diet rich in CGA to counteract the age-related deteriora-
tion in senescence-accelerated-prone mice (SAMP). At the
age of 3  months, they performed the Morris water maze
(MWM) test for evaluating learning and memory in mice
who received CGA in drinking water (6.7  mg/kg/day) for
1  month. The CGA-treated mice exhibited a reduction in
escape latency time compared to the control.
Converging results comes from animal models of cog-
nitive impairment which make use of CGA-enriched diets.
Kown et  al. [21] reported the neuroprotective effects of
CGA on scopolamine-induced learning and memory
impairments in mice and Jang et al. [122] found that instant
decaffeinated coffee rich in CGA protects animals from
learning and memory impairments caused by scopolamine
via cholinergic and antioxidative mechanisms. As shown in
previous studies, nitric oxide synthase (nNOS) is necessary
for normal learning and memory processes [123] and Tu
et  al. reported that CGA improves the kinic acid-induced
memory impairments in mice through the protection of
nNOS positive neurons in the hippocampus [123]. Bouayed
et al. examined the anxiolytic effect of CGA in mouse mod-
els of anxiety using the light/dark test, the elevated plus
maze and the free exploratory test. They concluded that
CGA (20  mg/kg) induced a decrease in anxiety-related
behaviour, with results similar in the diazepam (1 mg/kg)-
treated mice [124]. It is noticeable that except for Jang’s
study all studies used CGA directly (Table  5). Lapchak
et  al. assessed the effects of CGA on behavioural impair-
ment linked with embolic strokes in a rabbit small clot
embolic stroke model (RSCEM). Rabbits received 50 mg/
kg CGA 5 min, 1 and 3 h following embolic strokes. Com-
pared to control animals, CGA-treated rabbits exhibited a
significant increase in behavioural function at 5 and 60 min
post-embolization. In addition, a synergistic effect of the
combination of thrombolytic tissue plasminogen activator
(tPA) with CGA was shown just 3h following embolization
[22].
Although CGA has various physiological effects, its
actions on the central nervous system remain controversial
 Table 5  Summary of animal and human studies that assessing the effects of CGA on brain health
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main results
Eur J Nutr

Han et al. [121] Neuroprotective effects of CGA on 20 Male SAMP8 and SAMR1 mice SAMP8 mice control group 4 weeks 3,5-di-O-CQA improved spatial
spatial learning and memory 3,5-di-O-CQA-treated SAMP8 mice learning and memory on SAMP8
orally received CGA (6.7 mg/kg / mice
day) in drinking weter
Age matched SAMR1 mice normal
aging control
Kwon et al. [122] Neuroprotective effects of CGA on Male 4-week-old ICR mice 1 h before Y-maze, passive 4 days In the 6 and 9 mg/kg CGA-treated
scopolamine-induced learning and avoidance and MWM test mice groups the impairment of short-
memory impairments received term memory and escape latencies
in the Y-maze test significantly
improved
0 mg/kg CGA in distilled water Consumption of 9 mg/kg CGA in the
3 mg/kg CGA in distilled water passive avoidance test significantly
reversed cognitive impairments
6 mg/kg CGA in distilled water
9 mg/kg CGA in distilled water
Jang et al. [123] Scopolamine-induced memory Rat 1 h before Y-maze, passive 13 days Instant decaffeinated coffee rich
impairments avoidance and MWM test mice in CGA prevented Scopolamine-
received induced memory impairment in rats
Orally administration of120 or
240 mg/kg instant decaffein-
ated coffee rich in CGA in 1 ml
distilled water for 6 days in the
MWM test, 5 days in the Y-maze
and 2 days in the passive avoid-
ance
Tu et al. [124] Kainic acid-induced memory Mice Two daily intragastric administra- 35 days CGA-treated group had milder
impairment tions of 1 ml CGA or saline memory impairments compared to
control group
Bouayed et al. [125] Anxiolytic effect of chlorogenic Male 9-week-old Swiss albino mice 30 min before each test mice 20 mg/kg CGA decreased anxiety-
acid (OF1) received related behaviours
2, 10, 20, 40 mg/kg CGA or 1 mg/
kg diazepam in saline for light/
dark choice test
20 mg/kg CGA 0r 1 mg/kg diaz- 45 min
epam in saline for free exploratory
test
20 mg/kg CGA 0r 1 mg/kg diaze-
pam or 5 mg/kg flumazenil + CGA
or diazepam + flumazenil for
elevated plus maze test
1 mg/kg Diazepam in saline

13
Control (saline)

Table 5  (continued)
Reference Relevant outcome
13
Lapchak et al. [127] Behavioural deficits associated with RSCEM rabbit
embolic strokes
Stefanello et al. [136] Brain disorders (impaired memory Male wistar rats
and anxiety) promoted by diabetes
mellitus
Ho et al. [137] Brain energy metabolism dysfunc-
tion promoted by high-fat diet
Shen et al. [140] Brain protection from oxidative
damage
Lee et al. [141] Brain damage and edema promoted
by cerebral ischemia
Type of subjects (animal/human)
Female C57B6SJL mice
Rat
Sprague–Dawley rats
Treatments
Intravenous injection of 50 mg/kg
CGA at 5 min, 1 h or 3 h post-
embolization
Injection of 3.3 mg/kg tPA at 1 h or
3 h post-embolization
50 mg/kg CGA + 3.3 mg/kg tPA 3 h
post-embolization
(n = 10/group)
Control (water)
5 mg/kg CGA
15 mg/kg caffeine
0.5 g/kg coffee
Diabetic rats (water)
Diabetic rats + 5 mg/kg CGA
Diabetic rats + 15 mg/kg caffeine
Diabetic rats + 0.5 g/kg coffee
(n = 10/group)
HFD
HFD +
CGA-rich supplement (40–45%)
Normal diet
Normal diet +
CGA-rich supplement
Intraperitoneal injection of 100 mg/
kg/day of CGA or saline
Oxidative damage induced by injec-
tion of 20 mg/kg methotrexate
Sham group
Vehicle-treated group
Intraperitoneal injection of 3, 10,
and 30 mg/kg CGA-treated group
Duration Main results
3 h CGA injected at 5 min post-emboli-
zation increased behavioural func-
tion significantly
CGA injected at 1 h post-emboliza-
tion increased the P 50 value
CGA + tPA injected at 3 h post-
embolization increased behavioural
function
29 days CGA improved memory and
decreased anxiety promoted by
diabetes mellitus
20 weeks CGA-rich supplement improved brain
mitochondrial energy metabolism
dysfunction promoted by high-fat
diet
24 days CGA attenuated induced oxidative
damage
2 h CGA reduced infarct volume and sen-
sory-motor functional deficits at 0 h
and 2 h after middle cerebral artery
occlusion dose-dependently
CGA reduced brain water content and
Evans blue extravasation
Eur J Nutr
 Table 5  (continued)
Reference Relevant outcome Type of subjects (animal/human) Treatments Duration Main results
Eur J Nutr

Reyes-Izquierdo et al. [133] Blood levels of BDNF 25 Healthy volunteers Whole coffee fruit concentrate
powder(100 mg)
Green coffee caffeine powder
(100 mg)
Green coffee bean extract powder
(100 mg)
Grape seed extract powder (100 mg)
Placebo (silica oxide)
Cropley et al. [134] Mood and cognition 39 healthy older volunteers High CGA (521 mg and 11 mg caf- 2 h
feine) Decaf
Regular CGA (224 mg and 5 mg
caffeine) Decaf
Caffeinated coffee (224 mg CGA
and 167 mg caffeine)
Placebo (0 mg CGA and 0 mg
caffeine)
One week wash out phase
Camfield et al. [135] Mood and cognition 60 Healthy older adults 540 mg CGA administered as a
300 ml normal hot coffee drink
6 g Decaffeinated green blend
coffee administered as a 300 ml
normal hot coffee drink
6 g Maltodextrin placebo admin-
istered as a 300 ml normal hot
coffee drink
2 h Consumption of green coffee caffeine
Powder and grape seed extract
powder increased levels of plasma
BDNF by 31%, whereas whole
coffee fruit concentrate powder
increased it by 143%
Decaffeinated coffee high in chlo-
rogenic acid also to a lesser extent
improved some mood and behav-
ioural measures in compared with
the regular decaffeinated coffee
2 h Decaffeinated green blend coffee
improved sustained attention, deci-
sion time and alertness relative to
placebo
Both treatments group improved
symptoms of headache

3,5-di-O-CQA 3,5-di-O-caffeoylquinic acid, SAMP senescence-accelerated-prone mice, MWM Morris water maze, RSCEM rabbit small clot embolic stroke model, tPA thrombolytic tissue
plasminogen activator, P 50 value or the amount of microclots that produce neurologic dysfunction in 50% of a group of animals, HFD high-fat diet, BDNF blood levels of brain-derived neuro-
trophic factor

13

[125, 126]. Ohnishi et al. reported that CGA increased the
activity of spontaneous locomotor activity in mice [127].
Brain-derived neurotrophic factor (BDNF), as a member of
the nerve growth factor-related family, is involved in devel-
opment and function of the central nervous system [128,
129]. It is known that diabetes mellitus linked to brain mod-
ifications may contribute to cognitive impairment [130]. In
this context, Ho et  al. found that dietary supplementation
with decaffeinated green coffee enhanced the dysfunction
of brain energy metabolism in a HFD mouse model [131].
Recently, Stefanello et al. have also reported the beneficial
effects of CGA on brain disorders promoted by diabetes.
After 29  days of intake of a diet containing either CGA
(5 mg/kg), caffeine (15 mg/kg), coffee (0.5 mg/kg) or pla-
cebo, a significant decrease in anxiety and improvement
in memory was observed in induced diabetic rats receiv-
ing CGA-rich diet compared with the other groups [130].
In a recent pilot study, Reyes-Izquierdo et al. examined the
effects of polyphenol-rich natural products on plasma lev-
els of BDNF in healthy subjects. Volunteers were randomly
divided into five groups (n = 5 per group) and received a
100  mg dose of one of the following food supplements:
whole coffee fruit concentrate powder (WCFC), green cof-
fee caffeine powder, GCE powder, green seed extract pow-
der, or placebo (silica oxide). The collected data revealed
that among the substances tested, WCFC significantly
increased plasma BDNF by about 143%. Since WCFC
has a CGA content, it was thought that it might have trig-
gered the increase in BDNF blood levels. Consequently, in
a follow-up study, five participants received CGA (50 mg),
WCFC (100  mg) or placebo. CGA did not increase the
plasma level of BDNF significantly. Further clinical experi-
ments in a larger population are needed to acknowledge the
outcomes of this pilot study [132].
Cropley examined the immediate effects of decaffein-
ated coffee enriched with CGA (521 mg) and decaffeinated
coffee with regular CGA content (224 mg) on brain func-
tion in 39 healthy older volunteers. Compared to the regu-
lar decaffeinated coffee group, the CGA-rich coffee group,
exhibited decreased headaches and mental fatigue and
increased alertness [133]. Most recently, Camfield et  al.
conducted a randomized placebo-controlled trial with 60
healthy participants aged over 50 years, who consumed 6 g
of decaffeinated green coffee blend or 540 mg pure.
CGA or placebo and completed cognitive and mood tests
at baseline, 40 min and 120 min post dosing. Cognitive and
mood functions were assessed by the Rapid Visual Infor-
mation Processing (RVIP), the Jensen box decision/reaction
time test, serial subtraction and N-Back working memory
test. The symptoms of headache significantly improved in
both groups at 120 min compared to the placebo. In addi-
tion, a decrease in jitteriness was observed in both groups
at 40 min after application compared to placebo. In terms
13
Eur J Nutr
of cognitive function, CGA did not induce any significant
improvements. In contrast, decaffeinated green coffee blend
significantly improved sustained attention, reaction time
performance and alertness compared with the placebo.
These observations suggest that CGA, the major compound
of green blend coffee, could be a principle but not the only
compound responsible for positive cognitive and mood
effects [134].
Neuroprotective effects
Various evidences suggest that oxidative damage and neu-
ronal dysfunction contribute to the pathogenesis of neuro-
degenerative diseases, such as Alzheimer’s disease, Parkin-
son’s disease and mental disorders [130]. CGA is known
for its antioxidant activities which are linked to free radi-
cal scavenging quality [11]. It has been shown that CGA
and their metabolites are present in brain tissue [131].
Kwon et  al. investigated the effects of CGA on scopola-
mine-induced amnesia in mice. The results showed that
CGA significantly modified the impairment of short-term
memory in the Y-maze test, reversed cognitive impair-
ments and increased latency time in the target quadrant
in a dose-related fashion [21]. Shen et  al. [135] reported
that CGA (100  mg/kg/day) decreased the oxidative dam-
age in rat brain cerebellum exposed to the methotrexate
(20 mg/kg). They found that CGA pre-treatment attenuated
lipopolysaccharide (LPS)-induced IL-1β and tumour necro-
sis factor alpha (TNF-α) release in the substantia nigra,
thereby pointing to the neuroprotective effects of CGA on
pro-inflammatory cytokine-mediated neurodegenerative
disease.
Lee et al. [136] intraperitoneally administered rats with
3, 10, and 30 mg/kg CGA, immediately and 2 h after mid-
dle cerebral artery occlusion. In CGA-treated rats, reduced
infarct volume, sensory-motor functional impairments,
brain water content and Evans blue extravasation were
noted compared to the control group. CGA also improved
lipid peroxidation as well as matrix metalloproteinase
expression and activity. The evidence for its neuroprotec-
tive properties is also supported by results of in vitro exper-
iments [137–139].
While numerous studies have been conducted to deter-
mine the effects of coffee on the human nervous system
and cognition with the main focus on caffeine, few clini-
cal studies have been dedicated to CGA (the most abundant
coffee polyphenol) specifically; however, the outcomes are
promising albeit as yet inconclusive. The majority of stud-
ies have investigated the acute effects of CGAs and two
recent human studies were performed in elder population.
Further researches should evaluate the neuroprotective
effects of CGAs over extended periods of exposure and in
different age population groups.
Eur J Nutr
Other health effects
19 animal studies investigated the other health benefits
of CGAs.
Effects of CGA on inflammation and pain
Despite various biological activities of CGA being
associated with an antioxidant action, it is also able
to change physiological and/or pathological condi-
tions through anti-inflammatory mechanisms [17]. The
inflammatory reaction is orchestrated and influenced by
a large range of cytokines and chemokines and reduction
of these markers should decrease the degree of overall
inflammation [140].
The beneficial effects of CGA on inflammation were
observed in animal studies [17, 140, 141]. This finding
is in agreement with the results of in  vitro experiments
which showed that CGA is able to strongly inhibit the
production of TNF-α and interleukin 6 (IL-6) by periph-
eral blood mononuclear cells [142]. Chauhan et al. [141]
reported the antiarthritic activity of CGA (40 mg/kg) in
male Wistar rats through elevation of IL-10 and IL-4
and suppression of IL-2, IL-12.
Oedema is considered one of the main signs of an
acute inflammation. Dos Santos et al. [17] observed that
CGA inhibited oedema formation and pain following the
inflammatory reaction in carrageenan-induced inflam-
mation and formalin-induced pain models. A favourable
effect of CGA on inflammatory pain has also been found
in another animal study, where GCE extract displayed a
considerable anti-inflammatory action by alleviating paw
oedema and formalin-induced pain [140]. These results
imply that a CGA-rich fraction from medicinal plants
demonstrates anti-inflammatory and analgesic activities
in animal pain models [143–145].
CGA also appear to have beneficial effects on neuro-
pathic pain. Bagdas et  al. [146] reported the beneficial
effects of acute (50, 100 and 200  mg/kg) and chronic
(100  mg/kg for 14  days) intraperitoneal administration
of CGA in neuropathic pain. Similarly, a more recent
study investigated the effects of intrathecally adminis-
tered CGA on mechanical, thermal and cold hyperalge-
sia in an animal neuropathic pain model. It was found
that CGA ameliorates mechanical and cold hyperalge-
sia, suggesting that CGA may represent a novel treat-
ment approach for neuropathic pain [147]. Very recently,
Qu et al. [148] proposed that the use of CGA may exert
analgesic action by modulating acid-sensing ion chan-
nels (ASICS) in rat dorsal root ganglion neurons.
CGA and hepatic health
Several studies have shown the beneficial impacts of coffee
on liver disease. However, the results are controversial and
the mechanism underlying this effect is yet to be clarified
[149, 150]. As mentioned previously, CGA has both anti-
oxidant and anti-inflammatory potential; it therefore seems
conceivable that the positive effects observed after decaf-
feinated coffee ingestion might be due to CGA.
Hepatic injury may result from many different causes,
including viral hepatitis, iron overload, obesity, and exces-
sive alcohol consumption. CGA has been shown to be
effective against carbon tetrachloride (CCL4)—liver injury
in an in vitro assay [151]. Wang et al. [152] reported anti-
hepatitis-B virus activity of coffee rich in CGA in  vitro
and in animal models. Furthermore, CGA inhibited iron-
induced lipid peroxidation by forming a chelate with iron
[153].
The hepatoprotective impacts of CGA were investigated
in animal models with normal and pathological liver injury.
Kapil et  al. [154] analyzed the effects of CGA extracted
from the leaves of Anthocephalus cadamba (a tree with
medicinal value for various disorders) on the liver against
oxidative injury by CCL4. CGA (100  mg/kg bw/day) was
administered intraperitoneally in mice for 8 days. The mice
exhibited significant reversal in lipid peroxidation and gen-
erated cellular antioxidant defence modification. These
results revealed that the hepatoprotective activity of CGA
might be caused by its antioxidative action. Xu et al. [155]
administered intraperitoneal CGA to C57BL/6 J mice (liver
injury due to lipopolysaccharide) at a dose of 50  mg/kg/
day. In treated mice, the expression of TNF-α was mark-
edly inhibited, suggesting a positive effect of CGA on
acute liver injury through its anti-inflammatory action. The
results of two recent studies by Xu et al. [156] and Koriem
et al. [157] also support the protective role of CGA in ani-
mal models of liver injury through its antioxidant capac-
ity. In contrast, Akashi et  al. [158] investigated the effi-
cacy of a diet enriched with coffee-derived compounds for
counteracting (LPS)/D-GalN-induced acute liver injury in
rats and did not find any beneficial effects of a CGA-rich
diet. One possible explanation might be the differences in
experimental methods, especially the use of different toxic
compounds.
Finally, Yun et  al. examined the effects of CGA on
hepatic ischemia/reperfusion (I/R) injury in rats. In CGA-
treated rats, the levels of serum TNF-α, inducible nitric
oxide synthase and cyclooxygenase-2 protein was sig-
nificantly reduced and hepatic histology was improved,
suggesting a positive effect of CGA on I/R-induced liver
injury. This effect is probably associated with an inflam-
matory response inhibition and antioxidant defence sys-
tems modification [159]. The findings of Shi et  al. [160]
13

also suggest an improving effect of CGA on CCL4-induced
liver fibrosis in rats.
Despite promising findings in many animal studies, it is
unclear whether CGA could be an effective agent for liver
disease in humans.
CGA and gastrointestinal health
Some animal studies have revealed the effects of CGAs
on gastrointestinal health through its anti-inflammatory
properties. For instance, in an experimental model of
colitis when rats were given orally 2  mg/kg CGA for
4  days, the appearance of diarrhoea was greatly attenu-
ated. The authors suggested this to be a result of a reduc-
tion in pro-inflammatory cytokines and NF-KappaB
activation [161]. Similar results were achieved by Shin
et al. [162] when studying the effects of CGA on dextran
Fig. 2  Putative mechanisms of action of CGA and their effects on
physiological systems and on health. HMGR 3-hydroxy-3-methyl-
glutaryl coenzyme A reductase, PPAR-α peroxisome proliferator–
activated receptor-α, CPT carnitine palmitoyl transferase, AMPK
13
Eur J Nutr
sulfate sodium-induced (DSS) colitis in mice. Twenty
female C57BL/6 mice were divided into four groups
(n = 5/group): group1, normal mice; group2, DSS-
induced mice; group 3, the DSS-induced mice receiving
1  Mm CGA orally for 15  days; group 4, DSS-induced
mice receiving 1  Mm caffeic acid orally for 15  days.
Intestinal inflammatory impairment was induced by 3%
DSS for 8 days. In the CGA-treated group, diarrhoea, fae-
cal blood, DSS-induced body weight loss and shortening
of colon were significantly attenuated compared to the
other groups [162].
An intact intestinal barrier plays an important role in
gut-related disease. Ruan et  al. [163] recently evaluated
the effects of CGA on intestinal barrier function in weaned
rats challenged with LPS. They found that dietary supple-
mentation with CGA could mitigate the intestinal mucosal
inflammation through decreasing intestinal permeability
AMP‐activated protein kinase, GIP glucose-dependent insulinotropic
peptide, G-6-Pase glucose-6-phosphatase, ROS reactive oxygen spe-
cies
Eur J Nutr
and increasing intestinal expression of tight junction
proteins.
Only a few animal studies have so far specifically
addressed the gastrointestinal protective effect of CGA and
it has yet to be determined in humans.
Summary
CGA is a potent antioxidant and anti-inflammatory agent
and one of the main phenolic phytochemicals contained
in green coffee beans, which makes up 7–9% of coffee by
weight [164]. CGA is of special interest due to its wide
spectrum of potential health benefits, including anti-dia-
betic, anti-carcinogenic, anti-inflammatory and anti-bacte-
rial effects [98, 155, 160, 165–167]. On the other hand, it is
well established that ROS are involved in the pathogenesis
of most of these disorders. CGA possesses special proper-
ties, being able to battle oxidative stress by scavenging free
radicals, acting as a metal chelator, reducing lipid peroxida-
tion and inhibiting NAD(P)H oxidase activity [11]. The dif-
ferent pathways and their potential interaction in the gen-
eration of diseases are illustrated in Fig. 2.
It should be noted, however, that the assumed positive
effects of exogenous antioxidants such as CGA on health
may be able to counteract the health promoting effects, e.g.
of exercise through inhibition of the endogenous antioxi-
dant defence capacity [168]; therefore, the differential rules
under which CGA supplementation can be beneficial to
health still need to be explored.
Inflammation has been closely linked to oxidative
stress. Reactive oxygen is increasingly observed as a
main upstream agent in the signalling cascade involved in
inflammatory responses [169]. The inflammatory reaction
has been proposed to be interceded through the action of
inflammatory cytokines. For instance, TNF-α as a pivotal
pro-inflammatory cytokine involved in the initiation of the
inflammatory responses. In addition, TNF-α is responsible
for the induction of other pro-inflammatory cytokines, IL-1
and IL-6 [170]. Furthermore, it is believed that pro-inflam-
matory cytokines are involved in the pathology of chronic
diseases, such as diabetes, cancers and cardiovascular dis-
ease, to name but a few.
The literature has shown that CGA exerts its anti-inflam-
matory effects by inhibiting the production of some media-
tors such as TNF-α, IL-6 and IL-1β [101]. In accordance
with accumulating evidence for the anti-inflammatory
activities of CGA, Xu et al. [155] reported the hepatopro-
tective effects of CGA and Dos Santos et  al. reported the
antinociceptive impacts of CGA by inhibiting the expres-
sion of inflammatory mediators particularly, TNF-α.
The biological properties of CGA in addition to its
antioxidant effects have lately been the focus of attention
of many studies. It has been viewed as having positive
effects on glucose and lipid metabolism regulation by
inhibiting the activity of α-glucosidase, altering GIP con-
centrations [19], activating the AMPK [76], upregulating
the expression of hepatic PPAR-α [51], and inhibiting the
β-hydroxy-β-methyl glutaric acyl coenzyme A reductase
[171]. It is consequently postulated that CGA is able to
exert pivotal roles on glucose and lipid metabolism dis-
orders, e.g. diabetes, CVD, obesity, cancer, and hepatic
steatosis.
This data allows the depiction of some preliminary
pathways by which GCE and its main constituent, CGA,
act on different organ systems and clinical entities (s.
Fig. 2). However, while many of these pathways have been
explored in single experiments (in vitro, in  vivo in ani-
mals and humans, and clinically), a comprehensive and
comparative approach that compares the action of CGA
in different organ systems at the same time, and balances
its different actions is still lacking. It is therefore currently
unknown where—if at all—CGA will find a prime clini-
cal role in future treatments using such functional foods. It
is also likely that the proposed pathways are activated in a
concerted manner; however, the true cascade of physiologi-
cal effects induced by CGA consumption still needs to be
explored. Finally, comparisons of CGA with other “health
foods” (e.g. green tea extract) will need to explore its rela-
tive efficacy in therapy and prevention. To our knowledge,
this is the first review article that has systematically studied
the effects of CGAs on health.
Despite promising data on CGA, further gaps in knowl-
edge remain to be filled. For example, the side effects
(adverse events) of both short and long-term consumption
of CGA have not yet been investigated thoroughly. Only
a few interventional researches have explored exposure to
CGAs, in human whereas most data derive from animal
studies. Therefore, more research is needed to reach a deci-
sive approach for end-users (consumers and food indus-
tries) to eliminate these ambiguities.
The wide range of potential health benefits of CGA,
including its anti-diabetic, anti-carcinogenic, anti-inflam-
matory and anti-obesity impacts, may provide a non-
pharmacological and non-invasive approach for treatment
or prevention of some chronic diseases. In this study, the
effects of CGAs on different aspects of health by reviewing
the related literatures have been discussed.
Acknowledgements  Funding for this review was provided by the
Department of Internal Medicine VI: Psychosomatic Medicine and
Psychotherapy, University Hospital Tuebingen, Tuebingen, Germany.
Compliance with ethical standards 
Conflict of interest  On behalf of all authors, the corresponding au-
thor states that there is no conflict of interest.
13
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