HEALTH AND NUTRITION NEWSNo. 14
December 15, 2005

Table of Contents
Prefatory Note
National Institute of Health and Nutrition as a brain of dietitians in Japan……………………Eiji Oshino

CURRENT RESEARCH PROJECTSInvestigation of a new biological function of nutrient: Vitamin D…….. ……..……….……Jun Yamauchi

THOUGHTS ON HEALTH AND NUTRITION RESEARCH
About “Dietary Survey”…

...….…………………………......…..................................... Nobuo Yoshiike

RESEARCH FINDINGS
6-O-carboxypropyl-α-tocorienol has an anti-carcinogenic effect against lung adenocarcinoma
cells……………………………………………………………………..………………………Tomohiro Yano
Abnormalities in the amounts of elements and heme biosynthesis-related substrates in IDA patients.
…..…… Masao Kondo
An alcohol intake ≥ 300g/week is associated with significantly greater annual BP increase in Japanese
men……………………………………………………………………………………..……Katsushi Yoshita
Energy expenditure by intravenous administration of glucagons like peptide-1.…….Toshimasa Osaka© National Institute of Health and Nutrition

Prefatory Note

National Institute of Health and Nutrition as a brain of
dietitians in Japan
Eiji Oshino, MSc. RD.
Director of Nutrition Section, Ishikawa Prefectural Central Hospital

So far, the researches and those outcomes at
the National Institute of and Health and Nutrition(NIHN) have been regarded as unreachable forthe dietitians working in the local provinces.
However, looking at the research outcomes
where energy expenditures of general Japanese
were actually measured using the doubly labeledwater method, and also at the cited references foreach nutrient, we can see that more than tens of
thousands of articles were reviewed to establish
the energy requirements in the recently published“Dietary Reference Intakes (DRIs) for Japanese2005”. I think, this is exactly the practice of“Human nutrition based on scientific evidence”.
Besides, targeting the nutrition administrative
staffs from all over the country, two open
seminars titled [Application of “DRIs for Japanese2005”: Meal planning at the specific facilities forfeeding and importance of administrative support]
were held in Tokyo and Osaka in May 2005. In
addition, under the joint-hosting of NIHN and theJapan Dietetic Association, several training
programs were organized in various parts of thecountry, for which the staffs in charge of DRIs
have been working hard even in the weekend too.
In particular, with the application of the DRIs,
the registered dietitians are no longer obliged tostick at the theory and recommended values, andthat can plan and provide the meals at ones’ own
judgments, based on the results of assessment
for each patient. This is quite encouraging for the
dietitians, indeed. I am happy that the skills ofregistered dietitians are now highly evaluated,
and at the same time, I feel a great responsibility.
We, nutritionists, are often asked about“supplement” at the dietary guidance. In most of
the cases, it is actually difficult to answer to thosequestions promptly using the scientific evidences,while affluent information on health/supplements

have been spread around by the mass media.
So, we find that the NIHN website of “Information
system on safety and effectiveness for healthfoods” is useful to search/confirm the answers.
Mass media can provide the information tomore than tens of millions of peoples at once. On
the other hand, nutritionists can answer to thequestions individually only, which sometimes
makes me feel rather empty.
Yet, it is also important for the nutritionists toacquire the trusts from the patients by answering
questions appropriately. We also utilize the“Starling News” of the NIHN, for the informationon the latest researches in the world and also forthe literature search for the surveys/researches.
We learnt the goals of Dr. Watanabe, the new
Director-General of NIHN, from this newsletter“Health and Nutrition News”, where he says that
the NIHN should accumulate not only basic
researches on health and nutrition, but also thescientific knowledge on the control of life-style
related diseases, and on the Health Frontier Plan.
So, we expect that the NIHN will enhance theresearch/projects, with the emphasis on “Healthpromotion” and “clinical nutrition”.
I think that these recent research activities of
NIHN reflect the spirits of the founder, Dr. Tadasu
Saeki, to use the science in the practical activities,
and also conversely to investigate the practicalactivities scientifically, in accordance with thechanging social needs in the different times.
The existence of NIHN becomes closer than
before, and that it is really indispensable for the
dietitians. In particular, the NIHN website and“Health and Nutrition News” are really useful forthe dietitians working in the local provinces.
Lastly, I strongly hope that the NIHN will keep
supporting the activities of dietitians, based on thescientific evidences.
2

Current Research Projects
Investigation of a new physiological function of nutrients: Vitamin D
Jun Yamauchi
Division of Applied Food Researchcell strains that activate a kind of protein kinase in
response to VD were obtained (Fig. 2) (Ref. 1).
Further analyses will be bringing us to explore theidentity of membrane VDR.
Well, for what purpose does membrane
VDR-mediated non-genomic actions exist, then?
As we mentioned earlier, most of thephysiological functions of VD can be explained bygenomic effects. Yet, we hypothesize thatgenomic actions may work together with
non-genomic ones. Now, let me take the effects
for promoting calcium absorption as an example,
as it is the most important physiological functionsof VD. Calcium is absorbed in small intestine, and
it is said that the absorption can be promoted bygenomic effect of VD, as it increases theexpression of genes; e.g. calcium channel (forinduction of calcium into the cells) and calcium
binding protein (that functions for cellular calcium
transportation). In fact, however, it is likely thatthe calcium absorption occurs before gene
expression. So, we suppose that non-genomic
response would occur just after the addition of
VD, followed by genomic effects (Fig. 1). Since
this is a hypothesis, we have to explore theidentity of membrane VDR first, so as to confirm
it.
Recently, it has been reported that membraneand nuclear VDR might be the same molecule.
The relationship of “genomic” vs. “non-genomic”
of VD, therefore, seems still veiled in mystery.

We have been working on the researches related
to the functions of nutrients. Here, we would liketo explain about our studies on a newphysiological function in vitamin D, member of thelipid-soluble vitamins.
The precursors of vitamin D go through various
processes, and eventually are hydrated in liverand kidney to be an active form of vitamin D (VD).
In the target cells, VD passes through the cell
membrane and binds to the nuclear VD receptor(VDR). This nuclear VDR-VD complex would
regulates gene expression by binding to a specificsite of genomic DNA on the target gene promoter.
This is a so-called “genomic” effect of VD. It is
well acknowledged that there are many studies
on physiological function of VD, most of which
can be explained by genomic effect. In addition,
VD is known by its “non-genomic” effect as well.
This means that the effects are, literally, notmediated by gene expression. The main
characteristics is that, in the target cells, VD binds
to VDR on the cell surface membrane (membrane
VDR), and activates some protein kinase, leading
to a rapid cellular signal transduction. Therefore,
the effects of VD can be observed relatively
quickly (Fig. 1). Experimentally, the effects would
appear in a couple of seconds or minutes when
the culture cells are used. On the other hand,even using similar experiments, it takes at least a
few hours for the expression of genomic effects.
This phenomenon has been recognized since
before. However, the mechanism of non-genomic
effects of VD is still unclear, as the identity ofmembrane VDR is unknown.
So, we are trying to identify the membrane VDR
using the molecular biological method. Currently,

Ref.1) Yamauchi J. The establishment of HeLa cell demonstrating
rapid mitogen activated protein kinase phosphorylation in responseto 1α, 25-dihydroxyvitamin D3 by stable transfection of chickskeletal muscle cDNA library. Biosci. Biotechnol. Biochem., in press

Control

Protein kinase

Cell A

Cell B

Cell C

membrane VDR

Calcium channel
Calcium binding protein

genomic DNA

nuclear VDR

Fig. 2. VD Induced Phosphorylation of ERK in Selected HeLa
Cells. The selected HeLa cell lines of A, B, C, and control
were treated with or without VD for 1 min. The extracts wererun on 4-12 % SDS-polyacrylamide gels. Western blot analysis
was carried out using pERK1/2 and tERK1/2 antibodies.

Fig. 1. A model of the physiological functions of vitamin D in
calcium absorption. Thick full lines show genomic effects
and dotted lines show hypothetical non-genomic effects.

3Thoughts on Health and Nutrition Research
About “Dietary survey”…
Nobuo Yoshiike
Division of Health and Nutrition Monitoring“nutritional

In our Division, we have been working on theassessment” has been greatly emphasized indevelopment of more precise measurements andvarious activities for improving the diets andimprovement of skills of the survey teamnutritional conditions of the populations. There

members for the dietary intake survey (one of theare diversified target populations and approaches

components in the National Health and Nutrition

for the “nutritional assessment”. Of which, dietary

Survey), especially during the past 5-6 years.

survey is known to be the most important as a

Having the cooperation and comments from thestart point of a series of assessments, because it

survey team members who have been actively

examines and evaluates quantitatively “what andinvolved in the data collection, we repeatedly

how much an individual (in the personal healthconducted the pretest of methodologies at theservice) or population of a community (in public

local level. This process helps us to keep thehealth service) would eat”, Many nutrition experts“sense” acquired through practical work, so that

like

been

we can avoid following an academic theory only.

conducting “dietary survey” in both practical and

There still remain quite a lot of things to be done

academic fields. Most of all, the National Healthon the dietary survey; research, development ofand Nutrition Survey has a history of about 60

methodologies, skill improvement and education

years.

at the registered dietitian training schools. Of

In the field of “Nutritional Epidemiology” which

which, a particular attention should be paid on theaims to explore the associations between the

education, as I heard that the education/training

amountandare still inadequate in some of the schools foroccurrence of diseases, many countries haveregistered dietitian. Here, let me bring an example

attempted

of medical education again. If one has never seen

Recently,

the

the

importanceregisteredof

habitualtodietitians

nutrient

develop

the

of

have

intakes

self-recording

questionnaire applicable in a large-scaled survey

patients(e.g. Food Frequency Questionnaire). Japan has

supposed to provide the lectures on pathognomy.

also achieved a significant progress in thisLikewise, I expect that the research andresearch field. On the other hand, for theeducation on the dietary survey will be greatly

semi-weighed recording method or recall one, thedeveloped, if the experienced registered dietitians

types and amounts of food items taken on a

are actively involved, At the NIHN, we aim tocertain day (mostly on the previous day) should

enhancebe precisely examined, and thus, various skills

collaboration with the active dietitians/nutritionists.

are required to the survey teams (e.g. interviews,
checking, recoding, data entry and analyses,interpretation etc.). Actually, it is quite difficult forthe persons who have not actually implemented
the survey to images the types/level of required
skills. These skills are never explained enough inthe textbooks, and none of them can be acquired
in a short term, like the pathognomy in the
medical education.
4

for

the

medicalpractice,researches

in

s/he

this

is

field,

notinLatest Research
6-O-carboxypropyl-α-tocorienol has an anti-carcinogenic effect against lungadenocarcinoma cells
Tomohiro Yano (Division of Applied Food Research)
Vitamin E, as represented by α-tocopherol, is well known as lipid-soluble antioxidants. It has been reported
that the antioxidant effects of Vitamin E could reduce the risk of lifestyle-related diseases. Similarly, the resultsof past epidemiological studies and animal experiments explored the effects of Vitamin E to reduce the risk ofsome kinds of cancer. On the other hand, however, it has been also explored that Vitamin E radicals, which
are produced when Vitamin E exerted the antioxidant effects, could promote the development of cancer.
Similarly, several studies of cell cultures reported that it is not α-tocopherol itself that has the inhibitory effects
against cancer cell proliferation, but some derivatives to block the antioxidant property of α-tocopherol
through ester bond. It is therefore presumed that anticancer activity of Vitamin E is attributed to the structureof non-antioxidant property.
It is known that, generally, tocotrienols posses more potential anticancer properties than tocopherols,possibly due to the difference of the side chain between tocopherols (saturated phytyl chain) and tocotrienols(unsaturated farnesyl chain). Studies have shown that, through this farnesyl chain, tocotrienols could
suppress the biosynthesis of cholesterol, inactivate the functions of Ras family (one of the oncogene groups),
and finally inhibit the proliferation of cancer cells. Tocotrienols are, however, unstable in the body and are notexpected to exert the anticancer activity continually, partly due to their antioxidant property. We therefore
synthesized a new stable ether derivative, 6-O-carboxypropyl-α-tocotrienol (T3E) to block the antioxidant
property through ether bond, and compared the anti-carcinogenic effect of this derivative with that of
α-tocorienol, using malignant lung adenocarcinoma cells with a ras gene mutation (A549 cells).
In this study, the ether derivatibe of α-tocotrienol, T3E, showed cytotoxicity against A549 cells at lower
pharmacologic concentrations than α-tocorienol or 6-O-carboxypropyl-α-tocopherol (TE), while it had nocytotoxic effect against non-tumorigenic cells under the same treatment conditions. Therefore, we supposethat T3E could be a safe anticancer property as it works on the cancer cells relatively selectively. Our further
analyses of T3E cytotoxicity showed that, by inactivation of ras family molecules and inhibition ofsurvival-growth signal transduction pathway, T3E would accumulate the cells in the G1-phase of cell-cycle
and subsequently induce apoptosis. In addition, the degradation of T3E was not observed even using several
enzymes; hence, it was confirmed stable in the body as well. In conclusion, our study succeeded inenhancing the anticancer potential of α-tocotrienol, by blocking its antioxidant activity through ether bond.

Induction of cytotoxicity in human lung adenocarcinoma cells
6-O-carboxypropyl-α-tocotrienol, a redox-silent derivative of α-tocotrienol.

byInternational Journal of Cancer. 2005;115:839-846.
Yano Y1), Satoh H2), Fukumoto K2), Kumadaki I3), Ichikawa T4), Yamada K2), Hagiwara K2) and Yano T2)
1)

Department of Biochemistry, Osaka City University Medical School, Osaka, Japan2)

Department of Food Science Research for Health, National Institute of Health and Nutrition, Tokyo, Japan.

3)

Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan

4)

School of Nutritional Sciences, Nagoya University of Arts and Sciences, Aichi, Japan

Abstract:
Tocotrienols are one of the most potent anticancer agents of all natural compounds and theanticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of
tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage
and reinforce the anticancer activity in tocotrienols, we synthesized a redox-silent analogue of α-tocotrienol(T3), 6-O-carboxypropyl-α-tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent
against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed
cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in adose-dependent manner (0-40 μM), whereas T3 and a redox-silent analogue of α-tocopherol (T),
6-O-carboxypropyl-α-tocopherol (TE), showed much less cytotoxicity in cells within 40 μM. T3E cytotoxicity
was based on the accumulation of cells in the G1-phase of the cell-cycle and the subsequent induction of
apoptosis. Similar to this event, 24-hr treatment of A549 cells with 40 μM T3E caused the inhibition of Ras
farnesylation, and a marked decrease in the levels of cyclin D required for G1/S progression in the cell-cycle
and Bcl-xL, a key anti-apoptotic molecule. Moreover, the T3E-dependent inhibition of RhoA
geranyl-geranylation is an inducing factor for the occurrence of apoptosis in A549 cells. Our results suggestthat T3E suppresses Ras and RhoA prenylation, leading to negative growth control against A549 cells. In
conclusion, a redox-silent analogue of T3, T3E may be a new candidate as an anticancer agent against lungadenocarcinoma showing poor prognosis based on the mutation of ras genes.
5Latest Research
Abnormalities in the amounts
substrates in IDA patients.

ofelements

and

heme

biosynthesis-related

Masao Kondo (Division of Applied Nutrition)

Iron deficiency (ID) is one of the most frequent nutrition disorders among humans. WHO has estimated that 4 to 5
billion people, approximately 80% of the world’s population, suffer from ID. Moreover, about 2 billion are anemic
attributable mainly to ID. Thus, ID is an extremely common disease not only in developing countries but also indeveloped countries, particularly among children, reproductive-age women and elderly people. Poor nutrition is themain cause of ID in developing countries, whereas unbalanced diets would contribute to ID in developed countries.
Iron in the form of heme, which is chelated with protoporphyrin, is involved in vital biochemical reactions such as
oxygen transport and stock, drug metabolism, energy production, intercellular signaling and elimination of active
enzymes. Therefore, the symptoms of ID can appear all over the body such as weariness, irritation, depression,
headaches, reduced physical capacity and working efficiency, reduced immunity, paleness, alopecia and brittle nail.
Additionally, prolonged ID ultimately suppresses erythropoiesis, leading to iron deficiency anemia (IDA). Due to its
significant effects on human health, many studies have been done with respect to the diagnosis, treatment andpathogenic mechanism of ID. Yet, few studies investigated the elements other than iron.
In this study, Zinc-protoporphyrin (ZP) content and the enzymatic activity of both δ-aminolevulinate dehydratase(ALAD) and porphobilinogen deaminase (PBGD) were significantly higher in IDA subjects (12 women aged 23-38
years were diagnosed as IDA by blood test) than in age-matched healthy controls (Table 1). This result is possibly due
that; since heme can not be produced due to a lack of iron (a substrate of heme synthetase), consequently, these
enzyme activities increased under the de-repression mechanism induced by the reduction of heme contents. In
particular, ZP is increasingly drawing attention as an index for IDA, and rapid automatic measuring instruments havebeen developed in other developed countries. Next, the concentrations of trace elements in typical IDA patients were
determined by an inductively coupled plasma mass spectrometer (ICM-MS). Figure 1 shows that the amounts of K,
Mn, Fe, Se and Rb in IDA subjects were significantly lower than those of healthy ones. On the other hand, the mean
Mo and Ba levels were three-fold and six-fold higher in IDA subjects, respectively. So far, no study has reported thatthe decrease in iron content could affect the concentration of various other elements in IDA patients, hence this study
explored an important finding for the prevention and treatment of IDA. For example, since a K deficiency affects themineral balance in humans and, an Mn and Se deficiency affects the bodies’ ability to deal with oxidative stress in vivo,
the supplementation of
IDA (n=12)
Control (n=15)
these minerals, in addition
Hematocrit (%)
to iron, is necessary for Hemoglobin (g/dl)
theprevention
and Coproporphyrintreatment of IDA. So, we Free protophyrin FP :believe, the importance of Zn-protophyrin: ZP
ZP/FPoverall mineral balance in Total porphyrins
one’s
body
will
be ALAD activity
emphasized in the future PBGD activity
argument on prevention
Table 1. Hematologic data and heme synthesis Fig 1. Relative levels of the elements in the bloodand treatment of ID.
of IDA subjects, compared to the healthy controls
enzymes and intermediates of patients with IDA

Iron deficiency anemia: elements and heme biosynthetic system in blood.
Porphyrins. 2005;14(2): 99-104
Kondo M1), Miyamoto H2), Aiba N1), Mori M3) and Urata G1).
1) Laboratory of Nutritional Biochemistry, National Institute of Health and Nutrition, Tokyo, Japan
2) Chiba City Institute of Heath and Environment, Chiba, Japan
3) Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan

Abstract:
Iron deficiency anemia (IDA) is one of the diseases of worldwide interest. However, almost no research efforts havebeen made so far on changes in blood trace elements in patients with IDA for the purpose of prevention and treatmentof this particular type of anemia, and found out abnormalities in amount of elements in blood of IDA patient’s.
Eleven female patients with IDA aged 23~38 and healthy females within the same age range as the patients were
employed in this study. Upon obtaining informed consent from these subjects beforehand a heparinized whole blood
sample was obtained from each of the subjects and analyzed for blood elements, enzyme activities of heme-synthetic
pathway and porphyrins.
In patients with IDA, zinc protoporphyrin, δ-aminolevulinate dehydratase activity and porphobilinogen deaminase
activity were 180.1±133.8µg/dlRBC, 3.83±0.82µmol PBG/mlRBC/h and 35.0±6.30nmol URO/mlRBC/h respectively
and were significantly higher than the control value (p<0.01). Concentrations of 23 elements (Li, Al, Ca, Fe, K, Cu, Mg,
Ti, V, Cr, Mn, Ni, Zn, Ga, As, Se, Rb, Sr, Mo, Sn, Sb, Ba, Pb) were determined by an inductively coupled plasma mass
spectrometer or an inductively coupled plasma atomic emission spectrometer. The average concentrations of Fe, K,
Mn, Se and Rb in the patients were significantly lower than the corresponding control values (p<0.01).
These results suggest that the trace elements play a very important role in the prevention and treatment of IDA.

6

Latest Research
An alcohol intake ≥ 300g/week is associated with significantly greater annual BP
increase in Japanese men.
Katsushi Yoshita (Division of Health and Nutrition Monitoring)
Hypertension is one of the most important risk factors for cardiovascular diseases, and its prevention andtreatment are of international importance. It has been well recognized that hypertension is strongly associatedwith one’s daily lifestyle, including heavy alcohol intake. Most of the past epidemiological studies on the alcohol
intake and blood pressure (BP) were either cross-sectional or short-term intervention studies. On the other hand,
there were only a few longitudinal studies, most of which examined the long-term effects of alcohol consumption
on BP using the onset of hypertension as the endpoint. Yet, little is know about year-long BP increases within thenormal range. We, therefore, examined the association of alcohol consumption with BP change over sevenconsecutive years (1994-2001) in a large adult male population. The study population consisted of male workers
at a factory aged 20-59 years. Firstly, detailed baseline data were obtained by a self-reporting questionnaire,
which include work-related factors (type of work, shift work, working hours, work intensity, physical/mental stressat work) and lifestyle-related factors (diets, frequency of intake of major food items, alcohol intake, smoking,physical activity levels). BP was measured for all the workers annually at the regular medical examination. Data
analyses were performed, taking the changes in systolic and diastolic BP during 7 years as an outcome variable.
For which, the recently developed multivariate analysis called “generalized estimating equation (GEE) method”
was used to exclude the effects of possible confounders (e.g. work-related or lifestyle-related factors).
The baseline systolic BP (SBP) of drinkers consuming ≥ 300g alcohol per week was 5.21mmHg higher thannon-drinkers, after adjustment for baseline age and weight in each year. Annual SBP increase was 0.44mmHg
greater in drinkers consuming ≥300g/week than in non-drinkers, hence the increase of 3.08mmHg in total during
the 7 years’ follow-up period. Next, the SBP data were analyzed with adjustment for work-or lifestyle-related
factors, in addition to age and weight. Then, the baseline SBP was 4.97mmHg higher in drinkers consuming≥ 300g/week, with 0.33mmHg greater annual increase, compared to non-drinkers. In addition, even for drinkers
consuming ≥ 200g/week, the baseline SBP was significantly higher than non-drinkers. Likewise, the diastolic BP(DBP) data were analyzed with adjustment for age and weight, where the baseline DBP of drinkers consuming≥ 300g/week was 4.16mmHg higher, with 0.19mmHg greater annual increase, compared to non-drinkers.
In conclusion, this study showed that alcohol intake ≥ 300g/week would significantly influence not only thebaseline BP, but also the subsequent BP increase for a long-term in Japanese men. This trend was observed
even after the adjustment for various confounders by the multivariate analyses. In Japan, the drinking unit of gou
is generally used to express the amount of alcohol intake (1 gou=180ml of sake). So, alcohol intake ≥ 300g/weekcorresponds to the intake ≥ 13 gou of sake per week. We must note, therefore, that the BP could increase evenwith fewer amounts than “14-21 gou/week”, which is generally known to be the amount at risk of hypertension.
It is believed that primary prevention of cardiovascular diseases can be accomplished through interventions
conducted widely within the general population, with the objective of achieving a downward shift in the
distribution of BP. Our findings of BP increase within the normal range with high alcohol intake would suggest thepossibility of suppressing the age-related increase in BP the in general population. We therefore believe that our
results provide important evidence for planning the primary prevention measures of hypertension in the future.

Relationship of alcohol consumption to 7-year blood pressure change in Japanese men
Journal of Hypertension. 2005;23:1485-90
Yoshita K1) 2), Miura K1), Morikawa Y1), Ishizaki M3) Kido T4), Naruse Y5), Soyama Y1), Suwazono Y6),
Nogawa K6) and Nakagawa H1).
1) Department of Epidemiology and Public Health, Kanazawa Medical University, Ishikawa, Japan.
2) Division of Health and Nutrition Monitoring, National Institute of Health and Nutrition, Tokyo, Japan.
3) Department of Social and Environmental Medicine, Kanazawa Medical University, Ishikawa, Japan
4) Department of Community Health Nursing, School of Health Sciences, Kanazawa University, Ishikawa, Japan
5) Department of Community and Gerontology Nursing, Toyama Medical and Pharmaceutical University, Toyama, Japan
6) Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

Abstract: OBJECTIVE: To determine the association of alcohol consumption with years-long blood pressure(BP) change, as well as baseline BP, adjusted for potential confounders. DESIGN: A prospective cohort study.
SETTING: A metal-products factory in Toyama, Japan. PARTICIPANTS: A total of 3900 men aged 20-59 years.
MAIN OUTCOME MEASURES: BP was measured annually for 7 years after the baseline examination. The
generalized estimating equation method was used to analyze the relationship of alcohol consumption tobaseline BP and average annual BP change, adjusting for age, yearly weight, work-related factors, and lifestylefactors, including the frequency of intake of 22 food groups. RESULTS: The baseline systolic BP after
multivariate adjustment was 3.9 and 5.0 mmHg higher in drinkers consuming 200-299 and ≥ 300 g alcohol/week,
respectively, than in non-drinkers (P < 0.001). The annual increase in systolic BP was 0.44 mmHg greater indrinkers consuming ≥ 300 g/week than in non-drinkers after adjustment for age and weight change (P < 0.001),
where the increase over 7 years was estimated to be 3.08 mmHg greater. Even after being adjusted for thefrequency of intake of 22 food groups, drinkers consuming ≥ 300 g/week showed a 0.33 mmHg greater annual
increase in systolic BP than non-drinkers (P = 0.022). Baseline diastolic BP was significantly associated withalcohol consumption, but annual BP change was not. CONCLUSIONS: An alcohol intake ≥ 300 g/week was
associated with significantly greater annual BP increase, and baseline BP was significantly higher in drinkers
consuming ≥ 200 g/week. It is necessary to limit alcohol intake to less than 200 g/week to prevent hypertension.
7

Latest Research
Energy expenditure by intravenous administration of glucagons like peptide-1
Toshimasa Osaka (Division of Human Nutrition)
Various hormones are released from the digestive system after a meal, to facilitate digestion and absorption offoods, as well as to process the absorbed nutrients. Glucagon-like peptide-1 (GLP-1) is one of these hormones,
which is secreted from the mucosa of the ileum and colon in response to nutrient ingestion.
GLP-1 stimulates the pancreas to promote glucose-dependent insulin secretion, which works for the uptake ofnutrients like glucose by the cells. Thus, promoted insulin secretion means that GLP-1 informs pancreas that
“Nutrients are going to circulate through the body now, so please release insulin to process them”. In addition,
GLP-1 has the function of slowing gastric emptying, by informing stomach that “Since intestine is now busy todigest and absorb the foods currently coming in, please keep the foods in stomach for a while”. Likewise,
another notable function is the inhibition of food intake, as GLP-1 would work as an endogenous satiety agent
who informs the brain that “There are lots of foods in the intestine, so it’s not necessary to take foods any more”.
It is generally recognized that one of the main meanings of having diets is to take in the energy source in our
body. Further more, it is also known that many of the hormones that are released postprandially to work as
satiety agents are also associated with energy metabolism. There have been several studies that examined theenergy expenditure with intravenous administration of GLP-1 for animals or human. Some human studies,
however, provided contradictory results as to whether GLP-1 has a stimulatory or inhibitory action on energy
expenditure; intravenous (iv) infusion of GLP-1 increased O2 consumption, an index of energy expenditure,
whereas it decreased meal-induced thermogenesis. We, therefore, examined the effects of GLP-1 on energy
expenditure as well as the mechanism of its response, using anesthetized rats. One of the reasons of using theanesthetized rats was that the GLP-1 induced alterations in feeding behavior could secondarily influence energy
expenditure. Besides, various surgical or pharmacological manipulations could be applied to the anesthetized
rats, so that the physiological functions of GLP-1 can be investigated in details.
In this study, iv administration of GLP-1 apparently increased the energy expenditure of urethane-anesthetized
rats. Even with one tenth amount of GLP-1 that causes inhibition of food intake, energy metabolism increased by
20% of the basal metabolic rate and colonic temperature increased by 0.2-0.3ºC. Promoted energy expenditure
by GLP-1, a satiety agent, means that “Since the energy source comes in now, let’s burn it so as not to beobese”.
In order to explore the physiological mechanisms underlying this thermogenic response, the effects of GLP-1
were investigated by administering transmission blocker of automatic nervous system or inhibitor of
β-adrenergic receptors or by the surgical resection of their organs. Accordingly, we found that the response wasmediated by the sympathoadrenal system and β-adrenergic receptors.
The sympathoadrenal system is controlled by the brain. We therefore investigated which part of brain would be
involved in the GLP-1-induced energy expenditure by partial alblation or transection of the brain. Decerebration
had no effect on the GLP-1-induced thermogenesis, suggesting that the forebrain is not essential for the
response. However, cervical spinal transection greatly attenuated the response, suggesting the criticalinvolvement of the lower brainstem.
While “satiety” or “hunger” is determined by the brain, signals that determine such sensations are ingested
nutrients in blood or hormones released from the gut. These signals would regulate nutrient digestion/absorption
and energy expenditure, as was observed in GLP-1.

Energy expenditure by intravenous administration of glucagon-like peptide-1 mediatedby the lower brainstem and sympathoadrenal system.
Peptides, 2005; 26:1623-1631
Osaka Ta), Endo M a)b), Yamakawa Ma)b) and Inoue Sa)b)a) Division of Human Nutrition, National Institute of Health and Nutrition, Tokyo, Japanb) Department of Nutrition and Physiology, Faculty of Home Economics, Kyoritsu Women’s University, Tokyo, Japan

Abstract: Glucagon-like peptide-1 (GLP-1) is released from the gut in response to nutrient ingestion. Intravenous(iv) administration of GLP-1 (50 pmol-20 nmol) elicited dose-dependent increases in the rate of whole-body O2
consumption (VO2), an index of energy expenditure, and heart rate of urethane-anesthetized rats. The body core(colonic) temperature increased up to 0.3 degrees C without accompanying alteration of tail skin temperature.
Intracerebroventricular (icv) administration of GLP-1 induced a slower and smaller increase in VO2 than theintravenous administration. The injection of glucagon-like peptide-2 (iv or icv) had no effect on VO2, bodytemperatures, or heart rate. Decerebration had no effect on the thermogenic responses induced by the iv
administration of GLP-1, suggesting that the forebrain is not essential for these responses. However, cervical spinal
transection greatly attenuated the responses, suggesting the critical involvement of the lower brainstem.
Adrenalectomy or pretreatment with an autonomic ganglion blocker, hexamethonium, or a β-adrenergic blocker,
propranolol, also significantly attenuated the thermogenic response. However, subdiaphragmatic vagotomy orceliac-superior mesenteric ganglionectomy had no effect. Rats made insulin-deficient by pretreatment withstreptozotocin also exhibited the normal thermogenic response to GLP-1. These results suggest the involvement of
the GLP-1 in postprandial energy expenditure, mediated by the lower brainstem and sympathoadrenal system.
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