REVIEW ARTICLE

Brown rice-speciﬁc c-oryzanol as a promisingprophylactic avenue to protect against diabetes
mellitus and obesity in humans
Hiroaki Masuzaki1* , Chisayo Kozuka1, Shiki Okamoto1, Masato Yonamine1, Hideaki Tanaka2, Michio Shimabukuro3
1

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology, Department of Medicine, Graduate School of Medicine, University of the Ryukyus, 2Tanaka Clinic,
Okinawa, and 3Department of Diabetes, Endocrinology and Metabolism, School of Medicine, Fukushima Medical University, Fukushima, Japan

Keywordsc-Oryzanol, Brown rice, Obesity
disease*Correspondence
Hiroaki Masuzaki
Tel.: +81-98-895-1146
Fax: +81-98-895-1415
E-mail address:
hiroaki@med.u-ryukyu.ac.jp
J Diabetes Investig 2018
doi: 10.1111/jdi.12892

ABSTRACT
Chronic overconsumption of animal fats causes a variety of health problems, including
diabetes mellitus and obesity. Underlying molecular mechanisms encompass leptin resistance, a decrease in rewarding effects of physical activities, xanthine oxidase-induced
oxidative stress in vasculature and peripheral tissue, impaired activation of incretin signaling, deviation in food preference, and dysbiosis of gut microbiota. Based on our clinicalobservation that daily intake of brown rice effectively ameliorates bodyweight gain,
impaired glucose tolerance/insulin resistance and dependence on fatty foods in obese,
prediabetes men, a line of research on brown rice (rice bran)-derived c-oryzanol in miceexperiments, cultured cells and human clinical trials is underway in our laboratory. Our
works in mice showed that c-oryzanol, an ester mixture of ferulic acid and several kindsof phytosterols, acts as a molecular chaperone, thereby attenuating the strong preference
for animal fats through suppression of endoplasmic reticulum stress in the hypothalamus.
In pancreatic islets from both high-fat diet-induced and streptozotocin-induced diabetic
mice, c-oryzanol ameliorates endoplasmic reticulum stress and protects b-cells against
apoptosis. Noticeably, c-oryzanol also acts as a potent inhibitor against deoxyribonucleic
acid methyltransferases in the brain reward system (striatum) in mice, thereby attenuating,at least partly, the preference for a high-fat diet through the epigenetic modulation of striatal dopamine D2 receptor. Because dopamine D2 receptor signaling in the brain reward
system is considerably attenuated in obese humans and rodents, c-oryzanol might represent a unique property to ameliorate both hedonic and metabolic dysregulation of feeding behavior, highlighting a promising prophylactic avenue to protect against metabolic
derangement.

INTRODUCTION
It has been well highlighted that chronic and excessive intake
of animal-derived fats causes a variety of metabolic hazards,
including obesity, diabetes mellitus, dyslipidemia, atherosclerotic
diseases and cognitive impairment (Figure 1). Some underlying
mechanisms consist of defects in circadian organization andresultant disorders of physiological output1, exaggerated oxidative stress through the enzyme xanthine oxidase2, so-called lipotoxicity in a variety of organs3, hyperphagia caused by leptin
insensitivity in the brain hypothalamus4, and a decrease in
Received 27 June 2018; accepted 4 July 2018

rewarding effects of locomotion via hyperleptinemia throughdopamine neurons in the midbrain5.
Chronic and excessive intake of animal-derived fats drastically attenuates the action of leptin to the brain, a hormone
secreted from adipocytes (also known as leptin resistance),
thereby leading to difﬁculties in bodyweight reduction. In thebrain, the arcuate nucleus in the hypothalamus is one of themain control centers for appetite regulation through input of avariety of hormones and the autonomic nerve system (alsoknown as a regulatory system of metabolic hunger)6. Noticeably, excessive intake of animal fats provokes microglial inﬂammation and cellular stresses, such as endoplasmic reticulumª 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution andreproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Addiction

Cognitive impairment–+

ExerciseNicotine
Obesity
Internet
Diabetes
Traditional
Japanese foods
Animal fats

Gambling
Cream
Cakes

Game
BBQ

Alcohol

Foie gras
Junk foods
Lard/Beef tallow Egg yolk

CheeseButterNarcotics

Figure 1 | Cognitive impairment and addictive behavior, two major factors of brain dysfunction in a super aging society. Chronic and excessive
intake of animal fat-rich diets causes a variety of metabolic hazards, including diabetes mellitus and obesity. Furthermore, an animal fat-rich dietapparently increases the risk for cognitive impairment and addiction to fatty foods.

(ER) stress and oxidant stress in the hypothalamus, paralyzing
the regulatory system of metabolic hunger, thus creating a condition where the brain cannot correctly judge the energy intake
appropriate for the body7. It is as if the brain is ‘hacked.’ Whenmice are fed animal fat-rich foods, activated microglia inﬁltrates
into the hypothalamus within a couple of days8. Subsequently,
hypothalamic damage and immune cell migration is aggravated,
resulting in the condition of chronic inﬂammation8. It is
intriguing, however, to note that microglial inﬂammation occurring in the hypothalamus of mice associated with excess animal
fat intake is drastically improved by daily exercise on a regularbasis9.
The mechanistic similarity between the addiction to animalfats and that to narcotics, nicotine, alcohol, gaming and gambling is of great interest10. Among various types of dependence,a plausible mechanism where the intake of stimulants increases
would be similar to that where the recognition threshold of thebrain reward system gradually increases, and consequently, thebrain cannot obtain the same satisfaction and pleasure as
before. Experimentally, in obese mice housed on a high animal
fat diet, the level that the brain reward system can respond toanimal fat gradually rises, reminiscent of the case of dependence on cocaine and heroin11. It is therefore possible to speculate that the mice fall into a vicious cycle where no matter how
much they eat, they cannot be satisﬁed. In rat experiments
using narcotics, nicotine and alcohol, when these addictive substances were forcibly blocked, the robust dependence rapidly
disappears within 3 days. However, the dependence on animalfats was not improved even 2 weeks after the diet was
2

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removed, suggesting that animal fat is more addictive thannarcotics11.

ROLE OF HYPOTHALAMIC ER STRESS IN DEPENDENCE
ON ANIMAL FATS
When wild-type C57/B6 mice are food-deprived for 24 h andgiven both high carbohydrate and high animal fat foods placedside-by-side, they choose preferentially high carbohydrate foodin order to avoid protracted hypoglycemia12. In contrast, in asimilar experiment using mice with high animal fat dietinduced obesity, obese mice still chose high animal fat food.
Such a phenomenon can be explained by the notion that themice became unable to judge how many calories they need andwhich food they should choose under the chronic excess intake
of animal fat.
From a series of mouse experiments by the authors’ researchgroup, it was clariﬁed that exaggerated ER stress in the
hypothalamus strongly impacts on the preference for animal
fats13. For example, mice were allowed to choose between standard laboratory chow and high animal fat food, and then mice
were dosed with 4-phenyl butyric acid that functions as amolecular chaperone (also known as an ER stress reliever).
Consequently, the proportion of mice choosing high animal fat
foods was signiﬁcantly decreased, and the metabolic phenotype
in obesity and hyperglycemia was concomitantly alleviated13.
These results raise the possibility that a vicious cycle is formed
in which the excess intake of animal fat increases ER stress inthe hypothalamus, and in turn, the exaggerated ER stress further strengthens the preference for animal fat13.

ª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, LtdREVIEW ARTICLE
c-Oryzanol as a novel avenue against diabetes

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c-ORYZANOL FUNCTIONS AS A ER STRESS RELIEVER
IN THE HYPOTHALAMUS
Brown rice (rice bran) is highlighted as a natural complete diet,which abundantly contains a variety of vitamins, minerals, antioxidizing substances, trace elements, proteins, lipids and dietaryﬁbers (carbohydrates)14. Brown rice is also characterized as a
low glycemic index food, inhibiting postprandial hyperglycemia15. Noticeably, the Chinese character for ‘bran’ includes
a part that means ‘health.’ In contrast, the Chinese character
connecting ‘white’ and ‘rice’ means ‘nothing remains.’ From theresults of a cross-over interventional trial using brown rice formale patients with metabolic syndrome living in Okinawa Prefecture, Japan, named the BRAVO study, a series of metabolically-beneﬁcial beneﬁts to dysfunction of vascular endothelium,
liver steatosis, overweight, and furthermore, to the dependence
on animal fat-rich diets, such as junk foods and fast foods,
were shown16.
Based on the notion that Okinawan people of senior age arefond of eating brown rice, the authors’ research group focused
their attention on c-oryzanol, a functional component speciﬁcally and abundantly contained in brown rice (rice bran)17. It
was clariﬁed by a line of mouse and cellular experiments inwhich c-oryzanol functions as a molecular chaperone that promotes protein folding and decreases ER stress, which considerably increases in the hypothalamus by the chronic, excessive
intake of animal fats, thereby attenuating the dependence on

animal fats, and improving fuel dyshomeostasis and insulin
resistance13.
Because the scientiﬁc name of rice is Oryza sativa, c-oryzanol exactly symbolizes the main component of rice oil. c-Oryzanol was ﬁrst extracted from brown rice by two
Japanese researchers, Dr Tsuchiya and Dr Kaneko. Structurally,
c-oryzanol is a ferulic acid ester compound of several kinds oftriterpene alcohol and phytosterol (Figure 2)17. When orally
dosed in mouse experiments, a part of c-oryzanol passes
through the blood–brain barrier, keeping its ester binding as itis, and is distributed in the brain in considerably high concentrations18. It is well documented that C57/B6 mice show astrong preference for animal fats, as do humans12. In an experimental paradigm where a part of the carbohydrates of bothstandard laboratory chow and animal fat-rich diets was substituted with brown rice powder or white rice powder with thesame calories, only the mice of the group in which carbohydrates were substituted with brown rice had a signiﬁcantly
decreased preference for an animal fat diet (~20%)13. Consequently, the obesity and fuel dysmetabolism in mice weremarkedly improved. Such a result can be reproduced by anexperiment where a part of the carbohydrates of both standard
laboratory chow and animal fat-rich diets is substituted with coryzanol7.
Using a HEK293 cell line, the authors showed that c-oryzanol signiﬁcantly suppresses the transcriptional activity in the

γ-Oryzanol, one of the major bioactive components
specifically and abundantly in brown rice

γ-Oryzanol is a mixture of ferulic acid esters with several kinds of phytosterols.
An extremely similar structure
4-PBA(a potent ER stress eraser)O
HO

Ferulic acid
O
H3CO

HO

H3CO

O
O

O

HO

HO

O
H3CO

O
O

H3CO
HO

O
O

H3CO

O

HO

As the scientific name of rice is Oryza Sativa,
γ-oryzanol means a ‘rice-derived cooking oil’.

Figure 2 | Structure and biochemical properties of c-oryzanol. c-Oryzanol is a functional component specifically and abundantly contained inbrown rice. Structurally, c-oryzanol is a ferulic acid ester compound of several kinds of triterpene alcohol and phytosterol. Chemical properties of coryzanol are beneficial for its stable central action. The structure is resistant to esterase, and robust against heat, pressure and acidic environment.
4-PBA, 4-phenyl butyric acid; ER, endoplasmic reticulum.

ª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd

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ER stress responsive element that is induced by tunicamycin13.
Furthermore, experiments using a fetal mouse brain-derived
nerve cell primary culture veriﬁed that c-oryzanol remarkably
suppresses the gene expression of ER stress-related molecules
induced by tunicamycin13. Taken together, we conﬁrmed thatc-oryzanol surely functions as a chaperone in a viable cellsystem.

c-ORYZANOL IMPROVES DYSFUNCTION OF
PANCREATIC ISLETS ASSOCIATED WITH
GLUCOLIPOTOXICITY
In mouse experiments, our research team showed that c-oryzanol improves dysfunction of pancreatic islets associated withglucolipotoxicity through enhancing glucose-stimulated insulin
secretion (GSIS) and also inhibiting the excessive secretion of
glucan18. We clariﬁed that such a metabolically beneﬁcial effectof c-oryzanol on pancreatic islets is explained by the following
two molecular mechanisms. First, c-oryzanol functions as achaperone and alleviates the exaggerated ER stress in pancreatic
islets (Figure 3)18. Second, at both transcription and translationlevels, c-oryzanol inhibits the dopamine type 2 receptor (D2R)
signaling in pancreatic islets, which is augmented by animal
fat-rich diets19.
It has been shown that augmented signaling of D2R in pancreatic islets inhibits GSIS and resultantly elevates the blood
glucose level20. However, to date, detailed molecular mechanisms are not fully elucidated. In this context, the authors’ ﬁnding that excess intake of animal fat does increase D2R signaling
locally in pancreatic islets would exemplify a novel facet of
metabolic hazard caused by overconsumption of animal fats19.
Furthermore, we showed that c-oryzanol acts directly on islets
and enhances GSIS through the activation of the cyclic adenosine monophosphate/protein kinase A pathway. Elevatedexpression levels of molecules involved in D2R signaling in
islets from high animal fat diet-fed mice are normalized by oral
administration of c-oryzanol. Experiments with ribonucleic acidinterference against D2R and D2R ligands also suggest thatc-oryzanol suppresses D2R signaling and augments GSIS. The
unexpected role of c-oryzanol on D2R signaling in pancreatic
islets might shed light on a natural food-based novel antidiabetic approach in humans.
c-ORYZANOL AS A EPIGENETIC CONTROLLER IN THE
BRAIN REWARD SYSTEM
The signal of the brain reward system is conveyed by dopamine neurons. Clinically, an apparent decrease in D2R activity
in the striatum, one of the key nuclei in the brain reward system, is shown in obese people who abuse cocaine10,21,22. In
accordance with this notion, functional magnetic resonanceimaging shows that postprandial activation of the striatum, as
evidenced by an increase in blood ﬂow, is markedly diminishedin obese people23. These ﬁndings indicate that obese people
cannot appropriately accept the reward signal in the brain during meals.
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As a molecular mechanism responsible for the decrease in
the D2R signal of the brain reward system accompanied by the
addiction to animal fat-rich foods, epigenetic modiﬁcations,such as deoxyribonucleic acid (DNA) hypermethylation in the
promoter region (CpG island) of the D2R gene, would be suggested10,24. For example, regarding the mechanism whereby visceral fat tends to accumulate in the excess of animal fat-richdiets, the expression level of peroxisome proliferator-activatedreceptor-c (PPARc), a master transcriptional factor that controls the accumulation of subcutaneous fat depots, has beenshown to decrease in mice on a high-fat diet, where DNA
hypermethylation in the promoter region of PPARc gene isalso involved25. It is therefore tempting to speculate that excess
intake of animal fats inactivates a variety of genes involved inmetabolic and endocrine homeostasis.
Recently, the authors showed that c-oryzanol acts on thebrain reward system in obese mice fed an animal fat-rich diet,and changes ‘the brain that cannot be satisﬁed’ to ‘the brainthat can be satisﬁed’ as an epigenome controller26. In striatumfrom mice fed an animal fat-rich diet, the expression level of
D2R was signiﬁcantly decreased through the considerable
increase in DNA methylation of its promoter region. First,
pharmacological inhibition of DNA methyltransferases by 5aza-20 -deoxycytidine in mice normalized the expression level of
D2R in striatum with a concomitant decrease in the DNA
methylation of its promoter region. In this experimental setting,the preference for an animal fat-rich diet was signiﬁcantly
decreased in 5-aza-20 -deoxycytidine-treated mice. Second, oral
administration of c-oryzanol also decreased the expression of
DNA methyltransferases, thereby decreasing the DNA methylation in the promoter region of D2R and concomitantly restoring the expression level of D2R in striatum. Consistent with aseries of in vivo ﬁndings, enzymatic in vitro assays also showedthat c-oryzanol inhibited the activity of DNA methyltransferases26.
Together with our previous research in mice showing thatc-oryzanol attenuates the preference for an animal fat-rich dietthrough hypothalamic regulation of ER stress, c-oryzanol also
represents a unique property to ameliorate both hedonic andmetabolic dysregulation of feeding behavior (Figure 4). Because
overeating in obese individuals shares, at least partly, common
mechanisms with addiction to alcohol, nicotine and narcotics10,
a natural food-based approach toward the brain reward system
is anticipated to safely treat obesity. In this paradigm, c-oryzanol is a promising anti-obesity candidate with a distinct property of epigenetic modulator.

APPROACH TOWARD THE PRACTICAL USE AND
SOCIAL IMPLEMENTATION OF c-ORYZANOLA series of approaches aiming at the practical use and social
implementation of c-oryzanol is underway. A fermented
brown rice beverage richly containing c-oryzanol, GENMAIORYZANO as the product name, has already been developed by the cross-ministerial Strategic Innovation Promotionª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, LtdREVIEW ARTICLE
c-Oryzanol as a novel avenue against diabetes

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γ-Oryzanol attenuates ER stress-induced apoptosis caused by high fat diets(a)

Mouse islets: immunohistochemistry
HFD-Veh
Chow(b)

Mouse isolated islets

HFD-Orz†

1
0.5
0Chow Veh Orz
HFD

**

1.5

†

1
0.5

Xbp1s mRNA/Rn18s(fold of Chow)

2
1.5

2

2

**
ERdj4 mRNA/Rn18s(fold of Chow)

Chop mRNA/Rn18s(fold of Chow)

2.5

**

1.5

†

1
0.5
0
Chow Veh Orz
HFD

0
Chow Veh Orz
HFD

Genes related to apoptosis
2

†
1
0.5
0

Chow Veh Orz
HFD

2

*
1.5

†

1
0.5
0

Chow Veh Orz
HFD

Dﬀb mRNA/Rn18s(fold of Chow)

1.5

2
*

B cI2 mRNA/Rn18s(fold of Chow)

Casp3 mRNA/Rn18s(fold of Chow)

PCNA

Cleaved caspase-3

Phospho-elF2α

Insulin

Genes related to ER stress

*

1.5

†

1
0.5
0

Chow Veh Orz
HFD(n = 6, * P < 0.05, ** P < 0.01 vs Chow , †P < 0.05 vs HFD-Veh)quoted from; Kozuka C, Masuzaki H, et al. Endocrinology 156: 1242-1250, 2015

Figure 3 | c-Oryzanol attenuates endoplasmic reticulum (ER) stress-induced apoptosis caused by high-fat diets. (a) Immunostaining images. (b)Messenger ribonucleic acid (mRNA) expression for ER stress-related genes (upper panel) and for apoptosis-related genes (lower panel). Levels ofmRNA expression for Chop, ERdj4, Xbp1s, Casp3, Bcl2 and Dffb in isolated pancreatic islets are shown by quantitative real-time polymerase chain
reaction and normalized with ribosomal 18S. Data are expressed as mean – standard error of the mean (n = 6 in each group), *P < 0.05,**P < 0.01 vs standard laboratory diet (Chow), †P < 0.05 vs high-fat diet plus vehicle-treated group (HFD-Veh). Bcl2, the BCL-2 families determine
the commitment of cells to apoptosis; Casp-3, caspase-3, sequential activation of caspases plays a central role in apoptosis; Chop, Chop is a C/EBP
homologous protein, also known as growth arrest- and deoxyribonucleic acid damage-inducible gene 153 (GADD153); Dffb, Dffb triggers both
deoxyribonucleic acid fragmentation and chromatin condensation during apoptosis; ERdj4, ERdj4 is a soluble endoplasmic reticulum DnaJ family
protein that interacts with endoplasmic reticulum-associated degradation machinery; HFD-Orz, high-fat diet plus c-oryzanol-treated group; PCNA,
proliferating cell nuclear antigen; Phospho-eIF2, phosphorylation of the eukaryotic initiation factor 2 a subunit; Xbp1s, Xbp1 is a transcription factor
that regulates the expression of genes in the cellular stress response. Reproduced with permission from Endocrinology 201518. Copyright and allrights reserved.

Program, a Japanese national strategic project, collaboratingwith Aizu Tenpo Jozo K.K. Its practical use and social
implementation has been successful, and the product wascommended with the Food Action Nippon Award (FAN) of
the Ministry of Agriculture, Forestry and Fishery, Research
Development New Technology Excellence Award 2015. A
line of the accomplishment was also featured by Nature
SPOTLIGHT (page 19, issue of 30 March 2017). As a resultof the cross-over interventional trial with GENMAI ORYZANO for 40 middle-aged people with metabolic syndrome
in Okinawa, signiﬁcant improvement in metabolicª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd

derangement, dysbiosis of gut microbiota and related constipation, and robust preference for animal fats was observed(Yonamine et al. manuscript in preparation, 2018). Notably,such a line of a metabolically beneﬁcial impact of GENMAIORYZANO was signiﬁcantly exaggerated in the case of those
who did not habitually eat traditional Japanese foods or
those whose balance of gut microbiota was aggravated before
the trial.
Furthermore, our research team has succeeded in developinga novel delivery system that remarkably increases metabolicallybeneﬁcial effects of c-oryzanol by use of nanoparticle

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Habitual and excessive intake of animal fat-rich diets

Inflammation and ER stress: Hypothalamus

Epigenome dyscontrol: Brain reward system
Epigenetic enzyme :DNMTs

g-Oryzanol

ER stress
Microglial inflammation

Hypermethylation in the promotor
region of D2R
D2R
Regular feeding behavior

Break out of the dependency or addiction to animal fats
Quoted from; Kozuka C, Masuzaki H, et al. Diabetologia 60: 1502-1511, 2017

Figure 4 | c-Oryzanol ameliorates addictive behavior to animal fat-rich diets through hypothalamic and midbrain mechanisms. c-Oryzanol
attenuates the preference for animal fat-rich diet through hypothalamic regulation of endoplasmic reticulum (ER) stress. In contrast, c-oryzanol also
decreases the expression of deoxyribonucleic acid methyltransferases (DNMTs) in the brain reward system (striatum), thereby decreasing
deoxyribonucleic acid methylation in the promoter region of dopamine type 2 receptor (D2R) and concomitantly restoring the expression level of
D2R in striatum. In this paradigm, c-oryzanol is a promising anti-obesity candidate with a distinct property of epigenetic modulator.

Preference for animal fat-rich foods
ER stress in hypothalamus (Diabetes 2012)
Microglial inflammation (Drug Delivery 2017)
Epigenetic modulation of D2R in brain reward system(Diabetologia 2017)

γ-Oryzanol
O
H3CO
HO

Dysbiosis of gut microbiota

Fermentation products (SCFA)
Constipation(Drug Delivery 2017)O

Brown rice
GSIS
β cell apoptosis
ER stress in pancreatic islets (Endocrinology 2015)
D2R signaling in islets (British J Pharmacol 2015)

Figure 5 | Metabolically beneficial impact of c-oryzanol throughout the body. c-Oryzanol acts on the brain hypothalamus and reward system,
pancreatic islets, liver and adipose tissue, and gut microbiota with a unique and distinct property. D2R, dopamine type 2 receptor, ER stress,
endoplasmic reticulum stress; GSIS, glucose-stimulated insulin secretion; SCFA, short chain fatty acid.

technology in collaboration with SENTAN Pharma Inc. In fact,
toward the clinical application of c-oryzanol, extremely low
absorption efﬁciency from the intestine has been a difﬁcult
obstacle. Therefore, to overcome extremely low bioavailabilityof c-oryzanol with super high lipophilicity, we encapsulated
6

J Diabetes Investig Vol.  No.   2018c-oryzanol in polymer poly (DL-lactide-co-glycolide) nanoparticles (Nano-Orz), and evaluated its metabolically beneﬁcial
impact in genetically obese diabetic ob/ob mice, the best-known
most severe diabetic model in mice. Consequently, Nano-Orz
markedly ameliorated fuel dysmetabolism shown in ob/ob miceª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltdhttp://onlinelibrary.wiley.com/journal/jdi

with an unexpected magnitude (approximately 1,000-foldlower dose) compared with the regular c-oryzanol7. Surprisingly, such a conspicuous impact was achievable by its administration once every 2 weeks. Besides the excellent impact on
dysfunction of the hypothalamus and pancreatic islets, NanoOrz markedly decreased ER stress and inﬂammation in theliver and adipose tissue7.
Recent studies have highlighted that modulation of gut
microbiota by unreﬁned whole grains results in metabolicallybeneﬁcial changes in plasma levels of short chain fatty acids
through bacterial fermentation7. Notably, in most cases ofhuman and rodent obesity, the diversity of gut microbiota isdecreased, and the ratio of Firmicutes to Bacteroidetes is elevated27,28. We showed that Nano-Orz did decrease the Firmicutes-to-Bacteroidetes ratio, as well as a trend toward anincrease in plasma short chain fatty acids levels in mice. Taken
together, nanotechnology-based developments of functional
foods oriented toward c-oryzanol might shed light on the novel
approach to obesity in humans7.

PERSPECTIVE
Chronic and excessive intake of animal fats and the resultant
dependence on fatty foods complexly act on the onset andaggravation of type 2 diabetes mellitus and obesity in humans.
As we summarized in the present review, brown rice-derived
c-oryzanol can act on the brain hypothalamus and reward system, pancreatic islets, liver and adipose tissue, and gut microbiota with a unique and distinct property. Collectively,
c-oryzanol effectively acts against a line of metabolic hazards
provoked by chronic overconsumption of an animal fat-richdiet (Figure 5). In this paradigm, c-oryzanol is a promisinganti-obesity, antidiabetic target in academic, clinical and industrial ﬁelds (obtained intellectual properties are as follows. Japanese patents: No. 6098973 [2017], No. 6143215 [2017], No.
6281919 [2018], No. 6182540 [2017]; International patent
13F088-PCT-EP, ZL 201380067472.2 [China]).
Achieving a novel strategy to modify dietary habits throughfocusing on functional components derived from traditional
Japanese foods is highly anticipated. In this context, a series ofmetabolically beneﬁcial actions of c-oryzanol might shed lighton a novel, natural food-based preventive medicine for type 2
diabetes and obesity disease. Our research team is currently
investigating the potential beneﬁt of c-oryzanol in cognitive
impairment, physical inactivity, and addiction to alcohol, nicotine and dietary animal fats, all of which are often associatedwith type 2 diabetes and obesity.
ACKNOWLEDGMENTS
We are grateful to Professor Keiko Abe (Department of Applied
Biological Chemistry, Graduate School of Agricultural and Life
Sciences, The University of Tokyo, Tokyo, Japan) for invaluableadvice and continued support. We thank Chikako Noguchi,
Mamiko Hirata, Hoshino Kaneshiro, Tsugumi Uema and Ikuko
Asato for secretarial assistance, and also we acknowledgeª 2018 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd

REVIEW ARTICLE
c-Oryzanol as a novel avenue against diabetes

Tomoko Ikematsu, Ayano Kinjo, Yuko Murayama, Ikumi
Nomura and Chie Horiguchi for technical assistance. This work
was supported in part by Grants-in-Aid from the Japan Society
for the Promotion of Science (JSPS; KAKENHI; 15K19520 and
24591338), Council for Science, Technology and Innovation(CSTI, Japanese Government), Cross-ministerial Strategic Innovation Promotion Program (SIP, Japanese Government), ‘Technologies for Creating Next-Generation Agriculture, Forestry and
Fisheries’, New Energy and Industrial Technology Development
Organization (NEDO, Japanese Government), and a Grant fromthe Okinawa prefecture for promotion of advanced medicine(Okinawa Prefecture, Japan).

DISCLOSURE
The authors declare no conﬂict of interest.
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