J. Biol. Macromol., 9(2) 39-48 (2009)

Review
Diet and Metabolic Syndrome
Satomi Akagiri*, Yuji Naito, and Toshikazu Yoshikawa
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine,
Kyoto 602-8566, Japan
Received March 4, 2009; Accepted April 11, 2009
Recent change in lifestyle, including physical inactivity and unhealthy diets, are likely tohave played an important role in global epidemic of obesity, type2 diabetes mellitus (T2DM),
and the metabolic syndrome (MetS). Implementation of a healthy lifestyle, with an increase inphysical activity and reduction of body weight, based on the regulation of calories and fat
intake, are the basis for the prevention and treatment of lifestyle related disease. This review
highlights some recent advances in the understanding of metabolic and molecular mechanisms
concerning the effect of diet and focuses on the prevention and/or improvement ofdyslipidemia, insulin resistance, impaired glucose homeostasis, obesity, T2DM and MetS in
experimental rodent models, with some extension to humans.
Keywords: metabolic syndrome, obesity, nutrition , diet
Introduction
Diet is cornerstone of lifestyle related disease
prevention. Calorie-enriched diet and lack of
exercise are causing a worldwide surge ofobesity [1, 2]. The metabolic syndrome (MetS)
is a cluster of metabolic disorders, namely
dyslipidemia, hypertension, obesity and glucose
intolerance. MetS is highly prevalent conditions,affecting between one in six and one in three
adults in most developed countries, and asimilar proportion in the urban areas of many
developing countries. This condition has a big
public health importance because they areassociated with a markedly increased risk of
diabetes and cardiovascular disease (CVD),
thus contributing to the epidemic proportions ofthese diseases.
Obesity is a key aetiological factor indevelopment of MetS. Insulin resistance is thecore phenomenon. Co-occurrence is associatedwith a high risk of subsequent development oftype 2 diabetes mellitus (T2DM), CVD and*Corresponding author: tel., +81-75-251-5307;
e-mail, akagiri@koto.kpu-m.ac.jp

premature death [3]. It is obvious thatappropriate animals models are crucial forstudies on the pathogenesis and therapy of thiscomplex metabolic disorder, but it is less clear
how exactly to define the term “appropriate”.
From a scientific and an ethical point of view,
it is reasonable to require that not only thephenotype but also the pathogenesis of theanimal’s condition resembles the humandisease examined. Looking at the polygenic
nature of the human MetS, it seems that studies
examining monogenic [such as the ob/obmouse or Zucker-(fa/fa) fatty rat] or
pharmacologically induced (such as the goldthioglucose mouse model) obesity models must
be interpreted with care. The question ofwhether the results obtained arise from theobese phenotype or the model’s genetic/
pharmacological background is difficult toanswer completely.
In this review, we describe some recent
advances in the understanding of metabolic andmolecular mechanisms concerning the effect of
diet.

40

Diet and Metabolic Syndrome

Macronutrient and MetS
Fat - high fat
Approximately 60 years ago, Samuels
described that rats fed with a diet containing
70% energy as fat developed obesity andelevated basal and postprandial blood sugar
values [4, 5]. Such high fat (HF) diet effects,
noticed when the fat content is well above 30%
energy [6-9], have been subsequently specified
for different animal strains, fat types, and dietlengths.
Table shows the range of metabolic changes
described under different HF diets in studies
from the last 10 years, in which fat type, dietlength, and animal strain were stated. Diet withextreme fat contents (>60% energy) and diets
using chow-based HF diets were not included
because the physiological significance of theseresults must be questioned. Due to the scarcity
of studies using semi-purified, low-fat control
diets, it chose not to use this point as aninclusion criterion for the table.
Fat - fatty acid
A important action of n-3 fatty acids is thatthey could play a key role in the prevention andmanagement of several diseases such as
coronary heart disease, dyslipidemia, T2DM,
insulin resistance, hypertension and so on[10-12]. When added to the diet, the EPA and
DHA (poly unsaturated fatty acids: PUFAs)
present in fish or fish oil can alter themembrane phospholipid composition of thecells, impact eicosanoid synthesis and action,and regulate transcription factor activity andabundance. Recent studies suggest that n-3
fatty acids serve as important mediators of gene
expression, working via the peroxisome
proliferator-activatedreceptors(PPARs)controlling the expression of genes involved inlipid and glucose metabolism and adipogenesis[13].
Moreover, experimental studies have shownthat fish oil could down-regulate the hepatic
mRNA level of the sterol regulatory
element-binding protein-1 (SREBP-1), which
also controls several lipogenic genes [14-16].
Several studies have shown a consistent

relationship between plasma fatty acidcomposition and insulin resistance. A
prospective cohort study has investigated theinteraction between serum fatty acidcomposition and the development of impaired
fasting glycemia or T2DM in cohort of
middle-aged normoglycemic men [17]. It was
found that at baseline the proportions of serum
esterified and non-esterified saturated fatty
acids (SFA) were increased and PUFA weredecreased in men who after 4 years developed
impaired fasting glycemia or T2DM.
This finding is also in line with recent
epidemiological evidence from the Nurses’
Health Study, which shows that a higher intake
of saturated fat and a low polyunsaturated fat:saturated fat are related to increased CVD risk
among women with T2DM [18].
This study also estimates that replacement of
5% energy from saturated fat with equivalentenergy from carbohydrates or mono unsaturated
fatty acids (MUFA) is associated with 22 and
37% lower risk of CVD respectively. Thesefindings suggest that replacement of SFA by
MUFA may be more effective at reducing CVD
risk than low-fat high-carbohydrate diets. Thus,
several studies suggest a casual relationshipbetween dietary fatty acid composition andinsulin resistance. In comparison with thenumber of studies that have determined therelationship between dietary fatty acidcomposition and CVD risk factors, in particularlipoprotein metabolism, there are relatively few
that have used insulin sensitivity as the primarymetabolic end point.
Dietary fatty acids play an integral role in thepathogenesis and prevention of the MetS.
Given the increasing prevalence of obesity a
key objective should be to reduce the impact ofmodifiable risk factors, within the context ofthe obese phenotype. Whilst there is evidence
to suggest that high-saturated-fat diets havedeleterious effects on the MetS, there is a
paucity of information in relation to the mosteffective fatty acid intervention therapy. In
addition, future research will have to takeaccount of an individual’s.

S. Akagiri et al.

41

Table. Effects of HF diets in rodent.
Rodent type
rats
rats
rats
rats
rats
rats
rats
rats
rats
rats
rats
mice
mice
mice
rats
Serum glucose
rats
rats
rats
rats
rats
rats
rats
mice
rats
Seru insulin
rats
rats
rats
rats
rats
rats
rats
rats
rats
rats
mice
mice
Serum triglycerides rats
rats
rats
rats
rats
rats
Serum fatty acids rats
rats
rats
rats
rats
rats
rats
mice
rats
Leptinmice
mice
Adiponectin
mice
mice
Resistin* Seven percent fish oil.
WeightEnergypercentage Length (days) Effect (%)
from fat
Wistar
Lard
60
120
+15
Wistar
Lard
58
42
+10
WistarSafflower oil
59
21
NC
WistarSafflower oil
60
300
+28
WistarFish oil
48*
28
NC
Lewis
Coconut fat
40
70
+16
Lewis
Olive oil
40
70
+8
Lewis
Safflower oil
40
70
+19
Lewis
Fish oil40
70+21
Fischer
Fish oil45
28-8Long Evans
Butter43
75+10Balb/c J
Milk fat
42
136+11C57BL/6
Coconut fat
42
105
+8
C57BL/6
Corn oil42
105+11
Wistar
Lard
58
42
+14
WistarSafflower oil
59
21
+11
WistarSafflower oil
45
14
+15
WistarSafflower oil
60
300
NC
WistarSafflower oil
58
28
+26
WistarFish oil58
28+24
WistarFish oil48*
28
NC
Fischer
Fish oil
45
28-5C57BL/6
Milk fat
42
50+11
Wistar
Lard
25
21
+81
Wistar
Lard
60
120
-18
Wistar
Lard
58
42
NC
WistarSafflower oil
59
21
+20
WistarSafflower oil
60
300
+170
WistarSafflower oil
45
14
+85
WistarSafflower oil
58
28
+95
WistarFish oil58
28+80
WistarFish oil48*
28-45
Fischer
Fish oil45
28-50
Long Evans
Butter
43
75
+35
129S1
Lard
45
98
+100
C57BL/6
Milk fat
42
50+510
Wistar
Lard
58
42
+90
WistarSafflower oil
60
300
-25
Lewis
Coconut fat
40
70
+175
Lewis
Olive oil
40
70
+190
Lewis
Safflower oil
40
70
NC
Lewis
Fish oil40
70-35
Wistar
Lard
58
42
+100
Wistar
Lard
60
120
-41
WistarSafflower oil
60
300
-30
Lewis
Coconut fat
40
70
+87
Lewis
Olive oil
40
70
+112
Lewis
Safflower oil
40
70
+19
Lewis
Fish oil
40
70
+9
129S1
Lard
45
98
NC
Long Evans
Butter
43
75+66
C57BL/6
Milk fat
42
50
+1560
129S1
Lard
45
98
-11
129/Sv-C57BL6 Lard
40
105
-5
C57BL/6
Milk fat
42
136+50
StrainFat type42Diet and Metabolic Syndrome

Carbohydrate
Fructose (a simple sugar found in honey,
fruit and table sugar (sucrose)) may cause
obesity via several different mechanisms.
First, Havel et al. [19] conducted a clinicalstudy that found that fructose may not cause thelevel of satiety equivalent to that of a
glucose-basedmeal.
Specifically,thedifferences in the effect of fructose and glucose
consumption (consumed beverages with 3
meals) on ad libitum food intake and hunger
rating were observed on the day after the
exposure to the sweetened beverages. The
mechanism was related to the inability offructose to acutely stimulate insulin and leptin,
and to inhibit ghrelin, all factors that are known
to affect the satiety center in the central nervous
system.
Yudkin [20] also argued that sweetness offructose (or sucrose) often makes food more
platable, and, indeed, the food industry has
capitalized on this by frequently adding
high-fructose corn syrup or sugar to normallynon-sweetened foods (such as crackers) toenhance the taste. This may stimulate more
food intake. Furthermore, mice fed fructosesweetened water gain more weight than domice given the same calories as starch, whichsuggests that fructose may also slow the basal
metabolic rate [21]. One unique aspect offructose is that it is the only sugar that raises
uric acid concentrations, and this can be shownin both human [22] and rodents [23]. Fructose
enters hepatocytes and other cells (including
tubular cells, adipocytes, and intestinal
epithelial cells), where it is completely
metabolized by fructokinase with theconsumption of ATP; unlike in glucose
metabolism, there no negative regulatory
mechanism to prevent the depletion of ATP.
As consequence, lactic acid and uric acid are
generated in the process, and uric acidconcentrations may rise by 1-4 mg/dL after theingestion of large fructose-based meal [24].
Although the rise in uric acid concentrations
has historically been viewed as simply apotential risk factor for inducing gout, recent

studies suggest that this may be a key
mechanism to explain how fructose causes
cardiovascular disease. In addition, it also
provides a mechanism to explain why rodents
are relatively resistant to effects of fructose.
Rodents are resistant to fructose because they
synthesize vitamin C, have low uric acidconcentrations, and have good endothelial
function [25]. If uric acid concentrations areraised [26] or if low doses are prolonged [27],then insulin resistance is readily induced.
Micronutrient and MetS
Magnesium
Micronutrient plays a central role inmetabolism and in maintaining tissue function.
Recently, biochemical function and effects oftrace elements in preventing or treating diseases
were extensively studied. Magnesium plays anessential role in wide range of fundamental
cellular reactions and it not surprising that anincreasing number of clinical disorders havebeen found to be associated with magnesium
deficiency [28, 29].
Large epidemiological studies indicate thatlower dietary magnesium and lower serum
magnesium are associated with insulin
resistance [30, 31]. Low-magnesium serum
levels are strongly related to elevated serum
concentrations of both TNF-α and C-reactive
protein (CRP) suggesting that magnesium
deficiency may also be involved in thedevelopmentof
low-grade
chronic
inflammatory syndrome including metabolic
disorders.
Other studies show the association of lowserum magnesium and TNF-α in obese [32]and nonalcoholic steatohepatitis (NASH)
subjects [33].
A way to investigate the pathogenesis of
metabolic syndrome is the use of appropriate
animal model. Of particular interest is the factthat high-fructose diet induces a metabolic
syndrome
includinginsulinresistance,
hypertension and dyslipidemia in the rat [34,35].

S. Akagiri et al.

Recent findings also indicate the implicationof inflammation and oxidative stress in thismodel and show the aggravating effect ofmagnesium deficiency on the development of
insulin resistance [36, 37]. The proinflammatory effect of magnesium deficiency
may contribute to other aspects of metabolic
syndrome such as hyperlipidemia, bloodpressure elevation, endothelial dysfunctions
and thrombotic tendency.
Calcium
One hypothesis postulates that dietarycalcium plays a critical role in the regulation ofenergy metabolism.
Studies in cell culture and in rodent models
like the agouti mouse demonstrated a key rolefor intracellular Ca2+ in the regulation of
adipocyte metabolism. Increased dietarycalcium reduces vitamin D activity andintracellular Ca2+ influx, decreasing fatty acidsynthesis and increasing lipolysis, leading todecreased triglyceride stores.
Furthermore, decreased vitamin D activity may
up-regulate the expression of uncoupling
protein 2 (UCP2) and this may contribute to theincreased thermogenesis observed with highcalcium diets [38]. Calcium increases also
faecal fat excretion, presumably by formationof insoluble calcium-fatty acid soaps or bybinding of bile acids that impair the formationof micelles [39].
In addition to dietary calcium other dairyderived bioactive compounds may contribute to
the augmented effect of whole dairy food intake
vs. calcium supplementation alone [40].
Preliminary data suggest that this additional
activity lies in the whey fraction [41].
Vitamin D
It is now known that insufficient serum
vitamin D alters metabolite function causing
perturbation of many cellular functions,
including that of the endocrine pancreas [42].
Recently, there has been a resurgence ofhypovitaminosis D in many populations [43].
In parallel, there has been a world-wide
increase in obesity [44]. Links between
hypovitaminosis D and obesity have been

43

reported when obesity is defined using bodymass index [45, 46] and waist circumference[47]. Large waist, a surrogate for abdominal
obesity, is the key marker required formetabolic syndrome as defined by International
Diabetes Federation (IDF) [48].
Evidence indicates that patients with diabetes
have hypovitaminosis D and persons at risk fordiabetes or metabolic syndrome have inadequate
serum concentrations of vitamin D [49].
Food factors and MetS
Dietary fiber
Several foods or food factors may contributeto the beneficial effects, by affecting insulin
sensitivity, body weight, blood pressure andlipid levels, and possibly others.
A high dietary fiber intake is emphasized in therecommendations of most MetS and nutritional
associations.
Consumption of soluble dietary fiber reduces
postprandial
glucoseresponses
after
carbohydrate-rich meals, as well as lowering
total and LDL cholesterol levels [50]. These
effects are likely explained the viscous and/or
gel-forming properties of soluble dietary fiber,
which thereby slow gastric emptying andmacronutrient absorption from the gut.
Colonic fermentation of naturally available
high fiber foods can also be mainly attributed tosoluble dietary fiber, whereas no difference
between soluble and insoluble dietary fiber
consumption on the regulation of body weight
has been observed. However, it is not soluble
dietary fiber, but mainly the consumption of
insoluble cereal dietary fiber and whole grains,that is consistently associated with reduced riskof T2DM in large prospective cohort studies[51, 52].
Recent research indicates that dietary fiber
consumption contributes to a number of
unexpected metabolic effects independent fromchanges in body weight, which include
improvement of insulin sensitivity, modulationof secretion of certain gut hormones, andeffects on various MetS.

44

Diet and Metabolic Syndrome

Figure 1. Histological images of white
adipocytes at 8-weeks treatment. a) Basal diet,b) High fat diet, c) High fat diet + astaxanthin.

Tea catechin
Tea catechins reduce serum cholesterol
concentrations and suppress postprandial
hypertriacylglycerolemia
inexperimental
rodents and humans. These effects are mainly
ascribed to the gallate esters of catechins,(-)-epicatechin gallate, and (-)-epigallocatechingallate.
During pasteurization of tea drinks, tea
catechins are epimerized to so-called
heat-treated tea catechins such as (-)-catechingallate, and (-)-gallocatechin gallate. Both tea
catechins and heat-treated tea catechins withthe galloyl moiety lowerd intestinal absorptionof cholesterol by inhibiting micellar solubilityof cholesterol.
Since they inhibited pancreatic lipase in vitro
and slowed down lymphatic absorption of
triacylglycerols after the feeding of catechinpreparations causes suppression of postprandial
hypertriacylglycerolemia. It has been reported
that tea catechins and heat-treated tea catechinswith galloly moiety suppress deposition ofvisceral fat in rodents and humans [53-61].
Astaxanthin
Astaxanthin is a carotenoid in red pigment innature and contained in salmon, shrimp, crab,
krill, Phaffia yeast, and Haematococcus algae[62, 63]. It is a powerful antioxidant and hasvarious actions such as anti-inflammation [64],anti-hypertension[65],
anti-diabetic
nephropathy [66], anti-muscle damage [67],and anti-cancer [68]. Several reports
investigated the effects of astaxanthin
supplementation in obese mice fed a HF diet.
Astaxanthin inhibited the increases in bodyweight and weight of adipose tissue that result
feeding a HF diet. In addition, astaxanthin
reduced liver weight, triglyceride, and plasma
triglyceride, total cholesterol [69-71].
We found that size of adipocytes in white
adipose tissue was increased by >200% in HF
diet mice compared with no treatment mice andfound that astaxanthin inhibited the increase insize of adipocytes as shown in Figure 1 [71].
This result suggested that astaxanthin might beeffective to prevention of obesity.
Astaxanthin is ingestible with marine
products of the salmon etc. However, it is avery breakable carotenoid. Recently, the mass
production of astaxanthin became possible byimproving technique culturing and extraction of
Haematococcus algae. The supplement canefficiently intake of astaxanthin.
Kampo (Oriental Herbal Medicine)
In management of MetS, kampo medicine(oriental herbal medicine) is an excellent
representativeinalternative
andcomplementary medicines with a complete
theory system and substantial herb remedies.
Obesityisprescribed
Daisaikoto,
Saikokaryukotuboreito,
Tokakujiokito,
Daionotanpito,
Bofutsushosan,
Tudosan,
Kumibinroto, Boiogito, and so on [72].
Generally, obesity falls into two board
categories depending on its cause. In western
medicine, obesity is classified into two types
characterized by either visceral or subcutaneous
fat accumulation. On the other hand, in kampo
medicine, obesity is classified into the “robust
constitution” type and the “asthenic
constitution” type.
In western medicine, the obesity causing
MetS is of the visceral fat accumulation type,corresponding to the “robust constitution” typein kampo medicine. Of the above kampoprescriptions, Daisaikoto and Bofutsushosan
are used for the high physical energy typeobesity, i.e. obesity of the “robust constitution”

S. Akagiri et al.

type, and several report suggesting that
Daisaikoto and Bufutsushosan have effects on“visceral fat accumulation type” obesity andvarious metabolic disorders such as abnormal
lipid metabolism, hyperinsulinemia, insulin
resistant,
hypertension
andperipheral
neuropathy [73, 74]. Studying the mechanisms
by Bofutsushosan caused less body fat
accumulation, we found increased white
adipose tissue uncoupling protein 1 (UCP-1)
mRNA levels (Figure 2) [75].
Recently, the Oriental Herbal medicine canbe easily obtained. However, choosing whatsuitable for the constitution should consult a
professional because it is difficult.
Intestine and MetS
Generally, target organs in metabolic
syndrome are liver, skeletal muscle, pancreaticbeta-cell, and adipose tissue.
Emerging research has focused on thephysiological processes associated with how
the intestine may exacerbate dyslipidemia in
obesity and insulin resistance.
The intestine is no longer considered apassive organ, but is involved in active
regulation of lipid absorption, intracellulartransport and metabolism, and has become
inextricably linked to whole body lipoprotein
metabolism. The significance of the intestine inlipid metabolism was highlighted with thediscovery of specific mucosal brush border
membrane transporters for cholesterol and long
chain fatty acids [76-79].
Conclusion
Until not so long ago, nutrition research
focused on single nutrient interventions.
Recognizing that nutrients are not consumed
individually but as combined constituents of avaried diet, efforts in this area have shifted to
the role of the overall diet, or dietary patterns.
That eating habits play a role in developmentof MetS has also been concluded from the
CARDIA study [80]. Fast-food frequency was
directly associated with changes in body weightand insulin resistance. New food-based dietary

45

Figure 2. UCP-1 mRNA expression levels of
the epididymis adipose tissue of mice fed basal
diet (BD), high-fat diet (HF), HF +bofutsushosan (HF+BOF), or HF + daisaikoto(HF+DAI). The data are expressed as themeans±SE of 5-6 mice.
recommendations by the American Heart
Association, with the objective of reducing risk
for CVD, promote an inclusionary approach.
Obviously several risk factors for CVD can be
reduced with diets that meet the current
recommended dietary guidelines.
The dietary approaches to stop hypertension(DASH) dietary pattern, which is rich in fruits,
vegetables and low-fat dairy products, has
become famous as a successful approach to
tackle several disorders of the MetS.
In several studies dairy consumption was
inversely associated with occurrence of one orseveral phases of the MetS. Several foods or
food factors may contribute to the beneficial
effects, by affecting insulin sensitivity, bodyweight, blood pressure and lipid levels, andpossibly others. The extent of the benefits is notclear yet. But even small effects are relevant if
additive and if exerted during a lifetime.
The fact that dairy consumption may
improve the bioavailability of folate and othersecondary plant components makes it plausiblethat the DASH dietary patterns is more
effective than the same diet without low-fat
dairy products. Dairy intake may be associatedwith other prudent eating habits or healthy
lifestyles. Medium-chain fatty acids may play a46Diet and Metabolic Syndromerole, as they affect spontaneous behavior suchthat food and thus energy intake is reduced[81].
In conclusion, most important word forprevent of the MetS is “balance”. Diet iscornerstone of lifestyle related disease
prevention.
Acknowledgements
This study was supported by a Grant for the
Research and Development Program for New
Bio-industry Initiatives from Bio-oriented
Technology Research Advancement Institution.
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Communicated by Masayuki Oda