Plant-Derived Hydroxycinnamate Derivatives, Insulin Sensitivity, and Adiponectin: Implications of Diabetes Control

14CHAPTER

Plant-Derived Hydroxycinnamate
Derivatives, Insulin Sensitivity, and
Adiponectin: Implications for Diabetes
Control

H. Ushio*,†, K. Ohara*,†, R. Nagasaka*, M. Hori†

ÃTokyo University of Marine Science and Technology, Tokyo, Japan
†University of Tokyo, Tokyo, Japan

1. INTRODUCTION

Hydroxycinnamate derivatives, observed ubiquitously in plants, have some physiolog-
ical functions. Curcumin, 1,7-bis(4-hydroxy 3-methoxy phenyl)-1,6- heptadione-
3,5-dione (Figure 14.1 here), a major active hydroxycinnamate derivative of turmeric
in curry, is an inhibitor of nuclear factor (NF)-kB (Singh and Aggarwal, 1995) and also
shows antioxidant activity (Ruby et al., 1995). The physiological functions of curcu-
min and its analogs have been extensively investigated. Caffeic acid phenethyl ester
(CAPE, (E)-phenethyl 3-(3,4-dihydroxyphenyl)acrylate), an active component of
propolis from honeybee hives, is also derived from plant metabolites (Park et al.,
2002) and acts as an NF-kB inhibitor (Natarajan et al., 1996) and antioxidant as well
(Russo et al., 2002).

The metabolic syndrome represents a cluster of metabolic risk factors, including
central obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension for
type 2 diabetes mellitus and cardiovascular diseases. In order to discuss the antidiabetic
uses of plant-derived hydroxycinnamate derivatives, we should start from their diverse
properties including the antioxidative and anti-inflammatory functions. Many studies
have recently identified the therapeutic abilities of hydroxycinnamate derivatives from
plants both in vitro and in vivo. This chapter discusses the potential applications of hydro-
xycinnamate derivatives for diabetes control: curcumin and CAPE, which have been
exclusively investigated in the past decade, and g-oryzanol, based on our recent
findings.

Bioactive Food as Dietary Interventions for Diabetes # 2013 Elsevier Inc.
http://dx.doi.org/10.1016/B978-0-12-397153-1.00014-7
All rights reserved. 145

146 H. Ushio et al.

H3CO OO OCH3 HO O
HO Curcumin OH HO O

R CAPE

R

H3CO O H3CO O
HO O HO O

R R
Cycloartenyl ferulate Sitosteryl ferulate

24-Methylenecycloartanyl ferulate Campesteryl ferulate

Figure 14.1 Chemical structures of hydroxycinnamate derivatives and related compounds.

Plant-Derived Hydroxycinnamate Derivatives, Insulin Sensitivity, and Adiponectin: Implications for Diabetes Control 147

2. CURCUMIN

Curcumin possesses antioxidant, anti-inflammatory, anticancer, and cardioprotective ac-
tivities. The physiological effects of curcumin have been shown to be mediated by tran-
scription factors such as NF-kB, PPARg, and STAT; enzymes such as COX-2, iNOS,
and MAPK; inflammatory cytokines such as TNFa, IL-1, IL-6, and MCP-1; and growth
factors such as EGF and HGF (Goel et al., 2008). Nanji et al. (2003) demonstrated that
curcumin prevented alcohol-induced liver disease via NF-kB pathways. Curcumin also
has anticarcinogenic effects to inhibit both tumor initiation induced by benzo(a)pyrene
and 7,12-dimethylbenz(a)anthracene and promotion induced by phorbol esters (Huang
et al., 1995), and it has already been subjected to clinical trials for the treatment of various
human cancers (Goel et al., 2008). The natural and synthetic analogs of curcumin also
showed anti-Alzheimer, antioxidant, antiangiogenic, antimalarial, antitubercular, antic-
arcinogenic, anti-HIV, anti-inflammatory, antiandrogenic, antimutagenic, and COX
inhibitory activities (Agrawal and Mishra, 2010).

Curcumin also has diverse physiological functions in energy metabolism and diabetic
symptoms. The antidiabetic effects of curcumin are partly due to a reduction in hepatic
glucose production caused by activation of AMP-activated protein kinase (AMPK) and
inhibition of glucose 6-phosphatase (G6Pase) activity and phosphoenolpyruvate carbox-
ykinase (PEPCK) activity (Fujiwara et al., 2008). Pari and Murugan (2007) revealed that
oral administration of tetrahydrocurcumin (THC) to diabetic rats reduced the levels of
blood glucose and plasma glycoproteins and increased the level of plasma insulin. Kim
et al. (2009) found that curcumin and THC had no effect on basal or insulin-stimulated
glucose uptake in L6 muscle cells stably expressing myc-tagged GLUT4, and that cur-
cuminoids increased the phosphorylation of AMPK and its downstream target acetyl-
CoA carboxylase (ACC) in H4IIE rat hepatoma and Hep3B human hepatoma cells.
They concluded that AMPK-mediated suppression of hepatic gluconeogenesis may be
a partial mechanism for the serum glucose-lowering effects of curcumin. Curcumin also
increases glucose uptake in rat L6 myotubes via the mitogen-activated protein kinase
kinase (MEK)3/6-p38 mitogen-activated protein kinase (MAPK) signaling pathways
(Kim et al., 2009). Jain et al. (2009) demonstrated that the effects of high serum glucose
in diabetes on lipid peroxidation, inflammation-related cytokines such as IL-6, IL-8,
MCP-1, and TNF-a secretion were diminished by curcumin in cultured U937 mono-
cytes and streptozotocin (STZ)-induced diabetic rat models. Activation of muscarinic
M-1 cholinergic receptors (M1-mAChR) by curcumin increased GLUT4 expression
and glucose utilization through PLC-PI3-kinase pathway in skeletal muscle isolated from
Wistar rats (Cheng et al., 2009).

Several studies have demonstrated that macrophage infiltration of white adipose tissue
and the resulting adipose tissue inflammation could be responsible for the development of
type 2 diabetes. The anti-inflammatory effects of curcumin as stated above would then

148 H. Ushio et al.

suppress the macrophage-inducing inflammation of adipose tissue. The spice-derived
components containing curcumin downregulated obesity-induced inflammatory re-
sponses by suppressing adipose tissue macrophage accumulation or activation and inhi-
biting the release of a macrophage-recruiting cytokine, monocyte chemoattractant
protein-1 (MCP-1) from adipocytes (Woo et al., 2007). We have recently demonstrated
that curcumin enhanced the adiponectin secretion of 3T3-L1 adipocyte probably due to
NF-kB inactivation (Ohara et al., 2009). Curcumin also suppresses adipogenesis of 3T3-
L1 cells via Wnt/beta-catenin signaling pathways (Ahn et al., 2010). Weisberg et al.
(2008) demonstrated that dietary curcumin reduced macrophage infiltration into white
adipose tissue, increased adiponectin secretion, and decreased hepatic NF-kB activity and
hepatic inflammation, improving diabetes in high-fat-diet-induced obese and leptin-
deficient mice.

3. CAPE

CAPE also possesses antioxidative and anti-inflammatory functions as curcumin. Chen and
Ho (1997) demonstrated that the addition of CAPE to oil products significantly extended
the induction time of lipid oxidation. Hishikawa et al. (2005) stated that oral CAPE sup-
plementation attenuated the atherosclerotic process in apoEÀ/À mice, probably via direct
inhibition of NF-kB in the lesion and reduction of systemic oxidative stress.

Celik and Erdogan (2008) stated that CAPE treatment reversed the diabetic-induced
oxidative stress in rat brains and reduced levels of inflammatory cytokines such as TNFa
in diabetic rat brain. These anti-inflammatory properties of CAPE occurred partially via
NF-kB cascade inactivation by CAPE. Jung et al. (2008) suggested that CAPE suppressed
inflammatory response in the LPS-induced inflammatory mice and attenuated the intra-
venous LPS-induced increase in plasma TNFa and IL-1b levels via inhibition of LPS-
induced NF-kB activation. Wang et al. (2010) estimated the activity of CAPE as a
cytoprotective agent and demonstrated that the induction of HO-1 played a more
important role in the cytoprotective activity of CAPE derivatives than their direct anti-
oxidant activity in a human umbilical vein endothelial cell model.

Park and Min (2006) suggested that CAPE prevented diabetes-induced decreases in
IGF-I and IGF-II proteins and gene expression in liver, heart, and kidney in STZ-
induced diabetic rats. Lee et al. (2007) demonstrated that CAPE enhanced Akt, AMPK,
and glucose uptake in differentiated L6 rat myoblast cells and that CAPE upregulated
insulin-mediated Akt activation. Celik et al. (2009) suggested that CAPE would show
significant potential as an antidiabetic agent by suppressing hepatic glucose output via
inducing mRNA expression of glucokinase and pyruvate kinase, while inhibiting
PEPCK in STZ-induced diabetic rats. They also demonstrated that CAPE reduced
the gene expressions of inflammatory cytokines, such as TNF-a and IFN-g, and iNOS
in diabetic rat brain. We have demonstrated that CAPE enhanced adiponectin secretion

Plant-Derived Hydroxycinnamate Derivatives, Insulin Sensitivity, and Adiponectin: Implications for Diabetes Control 149

from 3T3-L1 adipocyte (Ohara et al., 2009). Treatment of 3T3-L1 with CAPE reduced
the mRNA levels of PPARg and CCAAT/enhancer-binding protein alpha (C/EBPa),
suppressing 3T3-L1 differentiation to adipocytes (Juman et al., 2010).

4. g-ORYZANOL

Crop bran-derived g-oryzanol, including cycloartenyl ferulate, 24-methylene cycloarta-
nyl ferulate, campesteryl ferulate, and beta-sitosteryl ferulate, has highly antioxidant po-
tency against the oxidative damage of biological molecules. We have recently
demonstrated that CAF significantly reduced the production of ROS in H2O2-induced
NIH 3T3 fibroblast cells (Islam et al., 2009). We also suggested that oral administration of
trans-ferulic acid and g-oryzanol markedly decreased serum activities of plasma aspartate
aminotransferase and alanine aminotransferase and hepatic lipid hydroperoxide and thio-
barbituric acid reactive substance (TBARS) levels in mice with ethanol-induced liver in-
jury (Chotimarkorn and Ushio, 2008). The antioxidant activity of g-oryzanol is shown to
be similar to that of nonesterified ferulic acid, indicating that the ferulic acid moiety
would be responsible for the antioxidant properties as stated by Nystro¨m et al. (2005).
We have however found that not only the ferulic acid moiety but also the sterol moiety
showed ROS-scavenging action in living cell systems, even though the sterol moiety had
no antioxidant activity in cell-free assay systems (Islam et al., 2009). The biomedical im-
portance of phytosteryl ferulates should be explained from the view of the chemical anti-
oxidation by the ferulic acid moiety and the inhibition of ROS production by the sterol
moiety in living cells as discussed in Islam et al. (2011).

Akihisa et al. (2000) reported that rice bran oil markedly prevents inflammatory ac-
tivity in inflammation of mouse ear induced by 12-O-tetradecanoylphorbol-13-acetate
(TPA). We then investigated the effect of g-oryzanol on NF-kB activity in RAW264.7
macrophage cells, indicating that phytosteryl ferulates significantly reduced iNOS ex-
pression and NO production in activated macrophages by inhibiting NF-kB activation
(Nagasaka et al., 2007). We have further demonstrated that g-oryzanol, CAF, and ferulic
acid improved colonic inflammation in dextran sulfate sodium-induced colitis in mice.
From the results of an in vivo colitis model and RAW264.7 macrophages in vitro, we have
concluded that g-oryzanol significantly inhibited IkB-a degradation levels, resulting in
the inhibition of NF-kB nuclear translocation and the amelioration of inflammation.

Several studies on rice bran phytosteryl ferulates suggested that they showed the antic-
arcinogenic activity in the colon (Raicht et al., 1980). Kong et al. (2009) demonstrated
that the anticancer activity of CAF was mediated through the elevated death receptor
expressions, depletion of antiapoptotic Bcl-2, upregulation of pro-apoptotic Bak, and
the release of cytochrome c from mitochondria into the cytosol in human colorectal ad-
enocarcinoma SW480 cell lines. CAF and 24-mCAF also exhibited moderate cytotox-
icity against human breast adenocarcinoma MCF-7 cells (Luo et al., 2005). Rice bran

150 H. Ushio et al.

sitosterol ferulate, CAF, and 24-mCAF inhibited phorbor ester-induced tumor-
promotion in 7,-12-dimethylbenz[a]anthracene-initiated mice (Yasukawa et al.,
1998). It is still ambiguous whether these anticancer effects of phytosteryl ferulates
and the related compounds are responsible for antioxidant and/or NF-kB-inhibitory
properties.

It is generally accepted that NF-kB-related inflammation has an important role in the
late phase of allergy. g-Oryzanol may therefore have a potent antiallergic effect in the case
of allergy by inhibiting NF-kB action. We have recently found that CAF and g-oryzanol
diminished the dinitrophenyl (DNP)-human serum albumin-induced passive cutaneous
anaphylaxis reaction in the dorsal skin of rats (Oka et al., 2010). CAF and g-oryzanol also
reduced the degranulation in mouse monoclonal anti-DNP antibody (DNP-IgE)-
sensitized RBL-2H3 mast cells stimulated with anti-DNP-HAS. On the other hand,
an antioxidant, ferulic acid, which does not have the sterol chemical structure of
CAF, did not alter mast cell degranulation, suggesting that the antiallergic function of
CAF is not due to antioxidant ability. Further investigations on the ameliorative effects
of g-oryzanol in allergy using animal models are required.

Dyslipidemia is one major risk factor of cardiovascular disease. Rice bran oil has a
cholesterol-lowering effect. Several reports suggest that rice bran oil and its major com-
ponents (polyunsaturated fatty acids, triterpene alcohols, phytosterols, a-tocopherol, and
tocotrienols) improve the plasma lipid profiles of mammals by reducing total serum
cholesterol and triglyceride concentration while increasing high-density lipoprotein cho-
lesterol (HDL-C) (Cicero and Gaddi, 2001). Seetharamaiah and Chandrasekhara (1989)
reported that the administration of a diet containing 10% rice bran oil significantly
reduced total serum cholesterol levels, free esterified, and low- and very-low-density
lipoprotein cholesterols (LDL-C and VLDL-C). Treatment of chronic schizophrenic
patients with dyslipidemia with gamma-oryzanol (100 mg, 3 times daily for 16 weeks)
significantly reduced LDC-C and total cholesterol levels without changing HDL-C
levels (Nicolosi et al., 1991). Sasaki et al. (1990) also demonstrated that the intake of rice
bran oil by using it as the cooking oil for 50 days significantly decreased lipid peroxides,
triglycerides, LDL-C, and VLDL-C in human blood. Most interestingly, the study of
co-administration of gamma-oryzanol, vitamin E, and niacin in dyslipidemic human
volunteers showed an improvement in serum lipid profiles, ROS, and total antioxidant
capacities (Accinni et al., 2006). There is an exact evidence that g-oryzanol reduces
serum non-HDL-C levels possibly through increased fecal excretion of cholesterol
and its metabolites (Rong et al., 1997).

Adiponectin is secreted from adipose tissue, exists in the circulation, and has been
postulated to play an important role in the modulation of glucose and lipid metabolisms
in insulin-sensitive tissues such as liver and skeletal muscle (Kadowaki et al., 2006).
Plasma adiponectin levels are reduced in the obese and insulin-resistant state or metabolic
syndromes (Saely et al., 2007), suggesting that adiponectin is a novel target molecule that

Plant-Derived Hydroxycinnamate Derivatives, Insulin Sensitivity, and Adiponectin: Implications for Diabetes Control 151

ameliorates type 2 diabetes. We have recently demonstrated that exposure to inflammatory
cytokines dramatically reduced adiponectin secretion in mouse 3T3-L1 adipocytes and that
g-oryzanol enhanced adiponectin secretion in 3T3-L1 adipocytes (Ohara et al., 2009). We
also found that g-oryzanol upregulated adiponectin secretion by activating peroxisomal
proliferator-activated receptor gamma (PPARg) through the inhibition of NF-kB activity.
It is noteworthy that g-oryzanol increased adiponectin secretion only under the NF-kB
activation state by inflammatory cytokines, although other hydroxycinnamic acid deriva-
tives such as curcumin and CAPE upregulated adiponectin secretion even in the resting
state. The oral administration of animal fats such as beef tallow and palmitate decreased
plasma adiponectin level in mice and g-oryzanol recovered the adiponectin level into
the normal level (Nagasaka et al., 2011). In this case, HOMA-insulin-resistant index
was markedly improved by gamma-oryzanol administration (Figure 14.2 here, unpub-
lished data). g-Oryzanol would probably suppress dietary fat-induced infiltration and ac-
tivation of macrophage, factors partly responsible for diabetes development as described
above. Further investigations are required for understanding the mechanisms.

Chronic stress, including psychological and physical stresses, is found to be linked with
metabolic syndrome, and is believed to be an important risk factor for the development of
metabolic syndrome (Chandola et al., 2006). We have then investigated the influence of
immobilization stress on plasma adiponectin levels in mice. Plasma adiponectin levels were
markedly reduced by immobilization stress and g-oryzanol significantly increased the
plasma adiponectin levels under immobilization stress (Ohara et al., 2011). This recuper-
ating effect of g-oryzanol on hypoadiponectinemia in immobilized mice is also thought to
be partially due to the direct upregulation of adiponectin secretion from adipocytes via sup-
pression of NF-kB activation (Nagasaka et al., 2007; Ohara et al., 2009).

4

**

3

HOMA-IR 2

1

0 Control γ-Oryzanol

Figure 14.2 Effects of oral administration of g-oryzanol on HOMA-IR in index high-calorie-induced
type 2 diabetes model mice.

152 H. Ushio et al.

5. CONCLUSION
In this chapter, plant-derived hydroxycinnamate derivatives, namely, curcumin, CAPE, and
g-oryzanol, have been discussed. These compounds are analogous to each other in sharing
the antioxidant activity and the downregulatory function of NF-kB pathways (Figure 14.3).
We can find similar structures in these three compounds, namely hydroxycinnamate moi-
eties, such as caffeic and ferulic acids (Figure 14.1). These structures participate in the

Figure 14.3 Hypothetic scheme for targets of hydroxycinnamate derivatives.

Plant-Derived Hydroxycinnamate Derivatives, Insulin Sensitivity, and Adiponectin: Implications for Diabetes Control 153

antioxidant activity, but other structures also might contribute to the antioxidative defense
systems in living cells, as discussed above. In addition, the downregulatory function of
NF-kB pathways would be also considered to arise partly from the hydroxycinnamate moi-
eties. However, g-oryzanol showed the activation of adiponectin secretion from 3T3-L1
adipocyte only in the inflammatory state, but curcumin and CAPE enhanced the secretion
even in the steady state as stated above (Ohara et al., 2009). In addition, curcumin inhibits
IkBa degradation at or before the phosphorylation of IkBa and consequently downregulates
the signal transduction pathway of NF-kB activation (Singh and Aggarwal, 1995), while
CAPE suppresses NF-kB activation not by inhibiting the IkBa degradation but by suppres-
sing the interaction of NF-kB proteins with the DNA (Natarajan et al., 1996). Therefore,
suppressing modes and/or points of the hydroxycinnamate derivatives in NF-kB pathways
were probably different from one another. Our computer simulation for ligand docking
using Sybyl 8.0 with Surflex Dock in an NF-kB-IkB complex (PDB 1O3Y) conferred
higher docking scores of 6.03 on CAF, one component of g-oryzanol, and 5.94 on curcumin
compared to 4.87 on CAPE (Figure 14.4, unpublished data). It is reminiscent to us that the

Figure 14.4 Putative three-dimensional structure of an NF-kB p65 (PDB 1O3Y) complex with IkB and
cycloartenyl ferulate. The ligand docking on p65 and IkB was performed using Sybyl 8.0 with Surflex
Dock.

154 H. Ushio et al.

stabilization of the NF-kB- IkB complex by ligands might participate in the inhibition of
IkB degradation and the downregulation of NF-kB signaling pathways. Further analyses
about the signaling pathways and the structure/activity relationships of hydroxycinnamate
derivatives are needed to fully understand their physiological functions and therapeutic
potentials against diabetes. Because the intracellular signaling pathways via protein kinases
such as MAPK and AMPK are also important in insulin-sensitive cellular responses
(Figure 14.3), further analyses of g-oryzanol functions are required. In addition, the potential
function of rice bran and g-oryzanol should be estimated in more clinical trials, as in the case
of curcumin and CAPE.

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