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Benefits of Weight Reduction on

Cardiovascular Disease Risk Factors

Hae Yon Kim

The Graduate School

Yonsei University

Department of Food and Nutrition

Benefits of Weight Reduction on Cardiovascular

Disease Risk Factors

A Dissertation

Submitted to the Department of Food and Nutrition

and the Graduate School of Yonsei University

in partial fulfillment of the

requirements for the degree of

Doctor of Philosophy

Hae Yon Kim

January 2003

This certifies that the dissertation of

Hae Yon Kim is approved.

Thesis Supervisor: Jong Ho Lee

Thesis Committee Member: Kyung Hee Sohn

Thesis Committee Member: Yang Cha Lee-Kim

Thesis Committee Member: Yangsoo Jang

Thesis Committee Member: Nam Sik Chung

The Graduate School

Yonsei University

January 2003

ACKNOWLEDGEMENTS

Many persons have contributed to the effort leading to this

dissertation. Special thanks go to my major professor, Dr. Jong Ho Lee, for her

guidance and encouragement. I would like to express my appreciation to Dr.

Kyung Hee Sohn, Yang Cha Lee-Kim, Yangsoo Jang and Nam Sik Chung for

their valuable advice, suggestions, and service on the advisory committee.

I also wish to thank the professors in the department of food and

nutrition, Dr. Ilsun Yang, Sun Yoon, Tong Kyung Kwak and Taesun Park for

their academic insights and valuable information.

Sincere thanks are extended to Rev. Sooyoung Ok and Ms. Darlene

Wood for their interest and pray.

I would like to thank the members in the clinical nutrition laboratory,

Ohyeon, Jisook, Jiyoung, Sujung, Jaejung, Yeojin, Hana, Sunhee, Hyejin, Yejung

and Boram for their assistance and cooperation. Special thanks go to Soohyun

for her assistance with sharing valuable time and efforts.

I want to give thanks to my friends, Jongkeum, Myunghee, Ryung,

and Yesoon for their love and encouragement.

Very special thanks go to my mother, Junghee Lee, my brother

Taeyoon, my sisters, Haerim and Haeree, and my sister-in-law, Euree Lee, for

their interest and love.

Ultimate thanks must go to my husband, Jin Bae Park and sons,

Jonghoon and Haeun for their love, interest, assistance, encouragement, and

support throughout my study.

I am very thankful to the Lord for His love and guidance throughout

my life.

To the memory of my father,

Young Song Kim

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Table of Contents

List of Figures …………………………………………………………………………… iv

List of Tables …………………………………………………………………………… v

Abbreviations and Acronyms ……………………………………………………… viii

ABSTRACT ……………………………………………………………………………… ix

1. INTRODUCTION …………………………………………………………………… 1

2. LITERATURE REVIEW ……………………………………………………………… 3

2.1. Obesity and its Growth in Population ……………………………………… 3

2.2. Obesity Related Health Risks ………………………………………………… 6

2.3. Obesity Related Cardiovascular Disease Risk Factors …………………… 10

2.3.1. Anthropometric Indices …………………………………………………… 10

2.3.2. Hypertension ………………………………………………………………… 11

2.3.3. Lipid Profile ………………………………………………………………… 13

2.3.4. Endothelial Dysfunction …………………………………………………… 14

2.4. Obesity Related Protein ……………………………………………………… 17

2.5. Menopause-related Change …………………………………………………… 18

2.6. Food Intake Reducing Substances …………………………………………… 20

2.6.1. Hydroxy Citric Acid (HCA) ……………………………………………… 20

2.6.2. Chitosan ……………………………………………………………………… 20

3. SUBJECTS and METHODS ………………………………………………………… 22

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3.1. Subjects …………………………………………………………………………… 22

3.2. Materials and Methods ………………………………………………………… 24

3.2.1. Anthropometric Measurements and Fat Distribution Assessment

………………………………………………………………………………… 24

3.2.2. Diet and Physical Activity Assay ……………………………………… 25

3.2.3. Metabolic Studies ………………………………………………………… 25

3.2.3.1. Glucose Tolerance Test ……………………………………………… 26

3.2.3.2. Serum Lipid Profiles and Leptin ……………………………………26

3.2.3.3. Plasma C-reactive Protein(CRP) …………………………………… 27

3.2.3.4. Plasma Total Antioxidant Status (TAS) ……………………………27

3.2.4 Statistical analysis ………………………………………………………… 28

4. RESULTS ……………………………………………………………………………… 30

4.1. Total Calorie Intake and Energy Expenditure ………………………………30

4.2. Clinical Characteristics of Subjects …………………………………………… 30

4.3. Serum Lipid Profiles of Subjects ………………………………………………33

4.4. Serum Glucose, Insulin, and Free Fatty Acid Concentrations of

Subjects …………………………………………………………………………… 34

4.5. Fat and Muscle Area at Different Levels of the Body of Subjects …… 35

4.6. Leptin, TAS and CRP values of Subjects ……………………………………38

4.7. Correlations between Body Compositions and Correlations between Body

Compositions and Metabolic Profiles …………………………………………39

4.8. Comparison of Parameters of Subjects in Menopausal Status ……………47

4.8.1. Comparison of Anthropometric and Metabolic Parameters between

Pre- and Post-menopausal Subjects before Study …………………… 47

4.8.2. Comparison of Clinical Characteristics, TCI and TEE in Different

Menopause Status of Case Group ……………………………………… 51

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4.8.3. Comparison of Serum Lipid Profile in Different Menopausal Status of

Case Group ………………………………………………………………… 53

4.8.4. Comparison of Serum Glucose, Insulin and Free Fatty Acid in

Different Menopausal Status of Case Group ………………………… 54

4.8.5. Comparison of Fat and Muscle Area at Different Levels of Body

in Different Menopausal Status of Case Group ………………………55

4.8.6. Comparison of Leptin, TAS and CRP values in Different Menopausal

Status of Case Group ………………………………………………………57

4.8.7. Correlations between Menopause Transition and Body Compositions,

and Correlations between Menopause Transition and Metabolic

Profiles …………………………………………………………………………58

5. DISCUSSION ……………………………………………………………………………60

REFERENCES ………………………………………………………………………………66

ABSTRACT(Korean) ………………………………………………………………………82

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List of Figures

Figure 1. The public health impact of obesity ……………………………………7

Figure 2. Comparison visceral fat and subcutaneous fat area at L1 and L4

levels in each group before and after study …………………………36

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List of Tables

Table 1. Clinical characteristics of subjects: Control and Case ………………22

Table 2. Supplement facts in 450mg of a capsule ………………………………23

Table 3. Total calorie intake and total energy expenditure in each group

before and after study ……………………………………………………31

Table 4. Clinical characteristics in each group before and after study ………32

Table 5. Serum lipid profiles in each group before and after study …………33

Table 6. Concentrations of serum glucose, insulin and free fatty acid

concentrations in each group during the oral glucose tolerance test

before and after study ………………………………………………………34

Table 7. Fat and muscle area at different levels of the body in each group

before and after study ……………………………………………………35

Table 8. Leptin, TAS and CRP values in each group before and after

study ……………………………………………………………………………38

Table 9. Correlation between body compositions of all subject before

study ……………………………………………………………………………41

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Table 10. Correlation between body composition and metabolic profiles

of all the subjects before study …………………………………………42

Table 11. Correlation between the decreased weight and body composition

changes ………………………………………………………………………43

Table 12. Correlation between body composition changes and metabolic profiles

………………………………………………………………………………… 44

Table 13. Correlation between body compositions of all the subjects after

study …………………………………………………………………………45

Table 14. Correlation between body composition and metabolic profiles of

all the subjects after study ………………………………………………46

Table 15. Differences in clinical characteristics between pre- and

post-menopausal participants before study …………………………………………48

Table 16. Differences in serum lipid profiles, glucose, insulin and free fatty

acid concentrations between pre- and post-menopausal participants

before study …………………………………………………………………49

Table 17. Differences in fat and muscle area at different levels of the body

between pre- and post-menopausal participants before study ………50

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Table 18. Differences in Leptin, TAS and CRP values between pre- and

post-menopausal participants before study ……………………………50

Table 19. Clinical characteristics, total calorie intake and total energy

expenditure of the case group subjects in different menopausal

status of the case group ……………………………………………………52

Table 20. Serum lipid profiles of the case group subjects in different

menopausal status of the case group ……………………………………53

Table 21. Serum glucose, insulin and free fatty acid concentrations during the

oral glucose tolerance test in different menopausal status of the case

group ……………………………………………………………………………54

Table 22. Fat and muscle area at different levels of the body in different

menopausal status of the case group ……………………………………55

Table 23. Leptin, TAS and CRP values of the case group in different

menopausal status ………………………………………………………… 57

Table 24. Correlation in body composition and metabolic profile with

menopausal status ………………………………………………………… 59

Table 25. Correlation in changes of body composition and metabolic profile

with menopausal status ……………………………………………………59

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Abbreviations and Acronyms

BMI: body mass index

CAD: coronary artery disease

CHD: coronary heart disease

CRP: C-reactive protein

CT : computerized tomography

CVD: cardiovascular disease

DBP: diastolic blood pressure

FFA: free fatty acid

HCA: hydroxy citric acid

HDL: high-density lipoprotein

HOMA: homeostasis model assessment

IRS: insulin resistance syndrome

L1 : 1st lumber vertebra

L4 : 4th

lumber vertebra

LBM: lean body mass

LDL: low-density lipoprotein

OGTT: oral glucose tolerance test

SBP: systolic blood pressure

TAS: total antioxidant status

TCI: total calorie intake

TEE: total energy expenditure

TG : triglyceride

WC: waist circumference

WHR: waist to hip ratio

- ix -

ABSTRACT

Benefits of Weight Reduction

on Cardiovascular Disease

Hae Yon Kim

Department of Food and Nutrition

The Graduate School

Yonsei University

The incidence of obesity in the world has been increasing and poses a

significant health problem. High mortality has been reported in overweight

people with cardiovascular disease(CVD) being the most common cause of

death.

In this study, seventy-one overweighted healthy middle aged women

were recruited and divided into 2 groups with Control(n=37) and Case

group(n=34). The control group took the substances with dextrin for 8 weeks.

The case group took chitosan and hydroxycitric acid(HCA), which are known

to reduce fat absorption and fat absorption and fat intake, to induce the

weight loss for 8 weeks.

The case group had significant weight reduction(1.9kg, p<0.001). Body

fat %, BMI, waist circumference and hip circumference were significantly

reduced(p<0.001). Abdominal fat was decreased significantly at L1(p<0.01) and

L4(p<0.001) vertebrae. Calf fat was also significantly decreased(p<0.01). Among

the metabolic profiles, the concentrations of triglyceride, fasting glucose, and

C-reactive protein(CRP) concentrations were significantly reduced(p<0.05).

Leptin, the product of the obesity gene, was significantly decreased(p<0.01).

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The influence of menopausal status on the weight reduction was

assessed. Before study, post-menopausal women(n=41) had significant difference

in systolic blood pressure, total cholesterol, and LDL cholesterol compared with

pre-menopausal women(n=30, p<0.01). Atherogenic index, and response area of

glucose and free fatty acid during glucose tolerance test were significantly

different between pre- and post-menopausal status(p<0.05). The

post-menopausal women had significantly more abdominal fat(visceral fat) than

the pre-menopausal women despite their similar weight and body fat %

between two groups(p<0.01). After the 8 week program, the effect of the

weight reduction depends on the menopause status. Pre-(n=10) and

post-menopausal(n=14) women showed significant reduction in weight, BMI,

body fat %, and hip circumference with the significant total calorie intake

reduction(p<0.01). But the significant reduction of waist circumference was

shown only in the post-menopausal women(p<0.01). Only post-menopausal

women had significant reduction in abdominal fat(p<0.01). Calf fat was

significantly decreased in the post-menopause group(p<0.01). Triglyceride &

fasting glucose level and its response area of the fasting glucose were

significantly decreased only in the post-menopause(p<0.05). Atherogenic index

and HDL to tatal cholesterol ratio were significantly decreased only in the

pre-menopausal women(p<0.1). Leptin and CRP level were significantly reduced

in post-menopausal women(p<0.05). More effects of weight reduction on the

cardiovascular(CV) risk factors were found in the post-menopausal women who

had more CV risk factors.

In view of a correlation study, all the participant had significant

inter-relation between anthropometric variables(p<0.01). Leptin, insulin, blood

pressure, insulin resistance and insulin sensitivity had significant relation with

weight and abdominal fat amount(p<0.01). Decreased weight was significantly

related with BMI, hip circumference and visceral fat at L4 vertebra(p<0.01).

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Insignificant relation was found between decreased weight and metabolic

profiles. After the program, the relation between body compositions and the

relation between body compositions and metabolic profiles were similar to the

relations before program. Menopause transition was significantly related with

abdominal fat and total cholesterol(p<0.01).

In this study, significant changes were found in several CVD risk

factors with diet-induced small weight reduction in the short-term duration. In

addition, menopause transition was an important factor for the cardiovascular

disease.

key words: obesity/cardiovascular disease/weight reduction/abdominal fat/

anthropometric variables/ metabolic profiles/ menopause transition

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1. INTRODUCTION

Obesity is now so common within the world's population that it is

beginning to replace undernutrition and infectious diseases as the most

significant contributor to ill health[1]. Sedentary lifestyle and overconsumption

of energy-dense foods are responsible for the increased prevalence of

obesity[2,3]. Worldwide, around 250 million people are obese, and obesity

prevalence will be increasing rapidly in both industrialized countries and

nonindustrialized countries[1].

The two most important risk factors for mortality in the industrialized

countries are cardiovascular disease(CVD) and cancer. CVD is a major cause of

mortality and disability[4]. CVD is a leading disease to cause death in our

country[5]. Costs for survivors of heart disease are enormous because of blood

pressure-lowering drugs, antithrombotics and diuretics. The direct costs

(personal health care, other professional services, and drugs) of obesity are

now estimated to be around 7% of total health care costs in the United

State[6] and around 1% ~ 5% in Europe[7]. Narabro calculated that

approximately 10% of the total costs of productivity due to sick leave and

work disability might be attributable to obesity-related diseases[8].

The linear relationship between body mass index(BMI) and the

incidence of CVD and the J-shaped relationship between BMI and rate of

mortality, which remained after the exclusion of probands with history of

cancer, have been in some studies[9,10]. With the exception of smoking, the

prevalence of risk factors associated with the development of atherosclerosis

increased in a statistically significant fashion with increasing body weight.

Hence, it is possible that the apparently independent influence of obesity on

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the incidence of CVD is related to the distribution and severity of

atherosclerotic lesions[11]. Weight was a relatively potent risk factor for total

CVD in women[9]. Obesity is a risk factor for increased blood pressure and

unfavorable lipid profile decreased high-density lipoprotein(HDL) cholesterol

level and increased low-density lipoprotein(LDL) cholesterol and triglyceride

levels and for CVD. Specially, an increase in abdominal obesity is associated

with hyperinsulinemia, dyslipidemia and CVD[12]. C-reactive protein(CRP) has

been also proposed as an independent risk factor for CVD and has been

positively associated with body weight and body fatness[13]. Therefore

reductions in body fat and changes in regional body composition will impact a

composite of cardiovascular(CV) risk factors. In this study, substances with

chitosan and hydroxycitric acid(HCA) causing reduction of fat absorption and

food intake was used to examine the effects of a weight loss. It was

hypothesized that weight loss would have beneficial effects on blood lipid

profiles, insulin level and regional body composition, and would induce a

reduction in CRP levels related to adiposity measures.

The purpose of this study was to examine the effects of weight

reduction on CV risk factors with the body fat, fat distribution, lipid profile

and circulating CRP levels in healthy middle aged women.

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2. LITERATURE REVIEW

2.1. Obesity and its Growth in Population

Obesity and its antithesis, starvation, have always been part of the

human condition, and for most of human history have been seen as

resulting simply from availability of food, or acts of will related to

attainment of desired body shape. Although this view persists in some

quaters to this day, the last 5 years of the millennium have witnessed

a dramatic increase in our understanding of the biology of regulated

energy balance and body weight. In 1997, the World Health

Organization(WHO) reported overweight and obesity to be an

escalating epidemic with health consequences that are now well

recognized. Obesity is associated with five of the ten leading causes of

death in industrialized countries[1].

Obesity is the result of both genetic and environmental factors.

Obesity is defined medically as a state of increased body weight, more

specifically adipose tissue, of sufficient magnitude to produce adverse

health consequences. Obesity is most often defined by the body mass

index(BMI), a mathematical formula that is highly correlated with body

fat. Most variation in weight for persons of same height is due to fat

mass. Body mass index is weight in kilograms divided by height in

metre squared(kg/㎡). A graded classification of overweight and

obesity using BMI values provides valuable information about

increasing body fatness. It allows meaningful comparisons of weight

status within and between populations and the identification of

individuals or community level and for evaluating the effectiveness of

- 4 -

such interventions because it is thought to be independent of age and

reference population. It is important to appreciate that, owing to

differences in body proportions, BMI may not correspond to the same

degree of fatness across different populations. The practice of using a

single BMI standard assumes that the BMI is independent of variables

such as age, sex, ethnicity, and level of physical activity[14]. But the

heritage results are consistent with published data showing the need to

consider age and gender. The relation between BMI and fat % is not

independent of gender and age[15]. In the elderly group, obese BMI

values were higher compared with middle-aged subjects[16].

The WHO and National Institutes of Health(NIH) cut off BMI

values of 25 and 30kg/㎡ to delineate overweight and obesity were

defined because of the general trends in the relationships between BMI

and morbidity and mortality rates[15], Ethnic difference in body

composition exists, a study of 5153 chinese subjects aged 18-90yrs

(median age 50.7yrs) examining BMI values corresponding to different

percentiles of body fat (measured by impedance) concluded that

overweight should be defined as ≥23kg/㎡ rather than 25kg/㎡, and

obesity ≥26kg/㎡ rather than 30kg/㎡[16]. In the United States, people

with a BMI between 25 and 30 are categorized as overweight, and

those with an index above 30 are categorized as obese[17]. In

Asia-Pacific Guide for obesity, obesity is defined with a BMI over

25[18].

Obesity is a widespread phenomenon in industrialized countries,

but it is relatively complex and surprisingly little is known about it, in

spite of the large body of research which has been and continues to

be dedicated to the subject. Direct and indirect costs attributable to

obesity in the United States have been estimated at $99.2 billion U.S.

- 5 -

dollars[19].

The most recent data from the United States, derived from the

third National Health and Nutrition Examination Survey(1988-94),

shows 20% of US men and 25% of US women are obese[20]. In

England and Wales, the most recent health survey has confirmed an

increase in the prevalence of obesity in adults from 6% in men and

8% in women in 1980 to 17% of men and 20% of women in 1997[18].

In South Asia, a marked rise is being seen in all populations, and in

Japan and China, a pronounced increase in the prevalence of

overweight and obesity has been observed during the past two

decades[21]. Obesity is now more prevalent in Malaysia than

undernutrition in both urban and rural communities, but the most

striking figures come from the Pacific region. In urban Samoa the

prevalence of obesity is estimated as greater than 75% of adult women

and 60% of adult men[22]. High prevalence rates also occur in the

Middle East. In the United Arab Emirates obesity is recognized as a

major public-health problem that may be important in the increasing

occurrence of other chronic diseases[23].

In Korea, National Health and Nutrition Examination Survey in

1998 shows 2.4% of obesity and 23.9% of overweight[1]. The prevalence

of obesity is 25.97% of men and 26.52% of women with the

Asia-Pacific Guide. Increasing energy intake and decreasing energy

expenditure with the changing of diet and lifestyle is increasing the

population of overweight and obesity.

The propensity for obesity must have been in our midst for a long

time, only to emerge recently on a large scale as a result of changes

in the environment, in particular the availability and composition of

food and reduced requirement for physical exertion.

- 6 -

2.2. Obesity Related Health Risks

Persons who are overweight or obese are at increased risk for

high blood pressure, type 2 diabetes, coronary heart disease, stroke,

gallbladder disease, osteoarthritis, sleep apnea, respiratory problems

and some type of cancer(Fig 1).

There is a close relationship between BMI and the incidence of

several chronic conditions caused by excess fat. Their incidence

increases with BMI. Starting at a BMI of 22kg/㎡, an increase in

body weight equivalent to 1 BMI unit(kg/㎡) was related to a 4% to

5% increase in coronary heart disease(CHD) mortality. In other words,

an increase in body weight of 1kg increased the risk of CHD

mortality by 1% to 5%[24]. Waist circumference correlates with

measures of risk for CHD such as hypertention or blood lipid levels.

The choice of cut-off points on the waist circumference continuum

involves a trade-off between sensitivity and specificity similar to that

for BMI.

Increasing body fatness is accompanied by profound changes in

physiological function. These changes are, to a certain extent,

dependent on the regional distribution of adipose tissue. Recent

studies have demonstrated a greater risk of chronic disease morbidity

and mortality with increasing level of abdominal, relative to gluteal or

femoral adiposity, which is often independent of the level of overall

obesity[25]. There are two types of obesity; one is visceral fat

dominant type (visceral type) and the other is subcutaneous fat

dominant type (subcutaneous type). There is evidence that deep

abdominal (or visceral) fat often comprising more hypertrophied fat

- 7 -

cells, os more metabolically active than other adipose tissue[26].

Generalized obesity results in alterations in total blood volume and

cardiac function, whereas the distribution of fat around the thoracic

cage and abdomen restricts respiratory excursion and alters respiratory

function. The intra-abdominal visceral deposition of adipose tissue,

which characterizes upper body obesity, is a major contributor to the

development of hypertension, elevated plasma insulin concentrations

and insulin resistance, diabetes milletus and hyperlipidemia. The

visceral fat depot is drained directly by the portal vein, resulting in

an increased free fatty acid(FFA) flux to the liver and consequent

overproduction of very low-density lipoproteins[12].

OB

ESIT

Y

Sex hormone imbalance

Increased free fatty acid

Mechanicalstress

Insulinresistance

Hypertension

Dyslipidemia

HormoneDependent tumors

Type 2 diabetesmellitus

Cardiovasculardiseases

Shortness of breath

Sleep apnea

Osteoarthritis

Low back pain

MO

RTALIT

YD

ISABIL

ITY

Respiratory disorders

Metabolic syndrome

Fig 1. The public health impact of obesity

- 8 -

Subcutaneous deposition of adipose tissue which is lower body obesity

rarely associated with those metabolic disorders.

In earlier, there were negative findings about relationship between

obesity and coronary atherosclerosis (and CHD). For example, results

of the Seven Countries Study revealed little correlation between body

weight and incidence of CHD[27]. Moreover, on the massive autopsy

study called "The Geographic Pathology of Atherosclerosis," edited by

Henry C. McGill, Jr, the relationship between body weight and

atherosclerosis was weak at best[28]. But the Framingham Heart Study

in the United States has consistently shown that increasing degrees of

obesity are accompanied by greater rates of CHD[29]. Obesity is not

defined as a single disease. Obesity induces several major risk factors,

which are hypertension, atherogenic dyslipidemia, insulin resistance, a

proinflammatory state, and a prothrombotic state. Seventy five percent

of hypertension can be directly attributed to obesity[30]. Atherogenic

dyslipidemia, or the lipid triad, consists of raised triglycerides, small

LDL particles, and low HDL cholesterol. Raised triglycerides

commonly reflect the presence of remnant lipoproteins, which are

widely believed to be atherogenic. Increased weight is a determinant

of higher levels of triglycerides, elevated LDL cholesterol, and low

HDL cholesterol.

The adult US population, whose combined prevalence of

overweight and obesity now exceeds 60%, is experiencing an

unprecedented exposure to obesity-related cardiovascular risk factors

and is expected to suffer the adverse clinical consequences in year to

come, and the prevalence of obesity in children is escalating

dramatically, presaging even greater medical harm in the decades to

come[19]. In our country, cardiovascular disease is the highest number

- 9 -

of death rate including hypertension, dyslipidemia and

hyperinsulinemia[5].

Overweight or obese individuals experience greatly elevated

morbidity and mortality from nearly all of the common cardiovascular

diseases (stroke, coronary heart disease, congestive heart failure,

cardiomyopathy, and possibly arrhythmia/sudden death)[30]. CVD

mortality is about three-fold higher among obese men and women,

and about 21 and 28% of CVD mortality in men and women,

respectively, could be attributed to being overweight[31,32]. Because

primary treatment and prevention of obesity often fail or are only

partially successful, it is anticipated that the future will bring

ever-increasing demands to treat the cardiovascular conditions

attributable to obesity. Reliable information on expected outcomes and

potential benefits, especially as it relate to cardiovascular disease risk,

may provide motivation and help set goals in weight management

program. Thus, to develop rational therapeutic approaches and to find

the weight loss effect on cardiovascular diseases, we need to

understand the basic biology of obesity-related cardiovascular diseases

and disorders[33].

The appropriate approach to reduce the obesity-related health risk

is to reduce body weight. The intentionality of weight loss is now

considered as an essential element in the understanding of the

relationship between weight change and morbidity or mortality[34,35].

In this study, weight loss program is focused on reducing energy

from fat by lowering fat absorption.

- 10 -

2.3. Obesity Related Cardiovascular Risk Factors

2.3.1. Anthropometric Indices

Abdominal adiposity has been shown to be a strong predictor of

cardiovascular events, independently of other cardiovascular risk

factors, whereas the degree of overall obesity has not always been

found to be an independent determinant[36]. Of the ways to measure

total body fat and its distribution, anthropometric measurements still

play an important role in clinical practice. Body mass index is often

used to reflect total body fat amount, while waist circumference(WC),

waist-to-hip ratio(WHR) or waist-to-height ratio is used as a surrogate

of body fat centralization[37]. The World Health Organization has

agreed on an international standard for identifying overweight and

obesity in adult populations using the BMI. An individual with a BMI

of greater 30kg/㎡ is four times more likely to suffer from

cardiovascular disease than an individual with a BMI of 25kg/㎡ or

less[38]. It may be best to define optimal weight for avoidance of

cardiovascular disease as that weight that optimizes the cardiovascular

risk profile. By this criterion, a healthy body weight would correspond

to a BMI of 22.6kg/㎡ in men and 21.1kg/㎡ in women[39]. Increased

weight in the periphery, that is, at sites other than the abdomen may

be relatively free of associated medical risk. Enlargement of peripheral

muscle mass is generally benign and increased peripheral adipose

mass, specially in the lower extremities, may even be associated with

a health benefit[40,41]. However, increased risk of cardiovascular

disease has been found in individuals presenting with distribution of

excess fat in the abdominal region, and at present there is no

- 11 -

standard measure of abdominal obesity that is widely accepted. WHR

has been considered as the traditional anthropometric technique for

assessing central adiposity. But WHR might have more error than WC

for measuring waist circumstance only, and hip circumstance reflecting

some extent individual difference in pelvic structure[42]. The majority

of current studies agree that WC is probably a better indicator of

abdominal fatness and cardiovascular disease than either BMI or WHR

because it reflects both total body fat and fat distribution[37,43].

WHR values of 0.94 for men and 0.88 for women have been found to

correspond to a critical accumulation of visceral adipose tissue. WCs

of 94cm or greater in men and 80cm or greater in women have been

reported to be indicative of the need for weight and to identify those

at risk for cardiovascular disease. But no single cut-off point of WC is

optimal for all ages and for different cardiovascular risk factors[44,45].

2.3.2. Hypertension

One of the most profound effect of obesity on cardiovascular

health and disease is hypertension. Hypertension accelerates

atherogenesis and promotes premature coronary artery disease (CAD).

Elevated blood pressure is often associated with hyperlipidemia,

hyperglycaemia, hyperuricaemia, excess weight, elevated fibrinogen,

and cardiac abnormalities, which enhance the impact of hypertension

on the target organ[16]. An association has been described between

obesity, arterial hypertension, insulin resistance and dyslipidemia,

which comprises core feature of the metabolic syndrome or syndrome

- 12 -

X. The precise mechanisms linking obesity and insulin resistance to

development of hypertension are incompletely defined[47].

The total blood volume in obesity is increased on proportion to

body weight. This increase in blood volume contributes to an increase

in the left ventricular preload and an increase in resting cardiac

output. The increased demand for cardiac output is achieved by an

increase in stroke volume while the heart rate remains comparatively

unchanged[6]. Left ventricular mass increase directly in proportion to

BMI or the degree of overweight[16]. It is well documented that

blood pressure increases with weight gain and decreases with weight

loss. For example, an average of 8.8kg reduction in weight resulted

in a 26mmHg and 20mmHg reduction in systolic and diastolic blood

pressure and weight gain of 10kg overweight increase 5mmHg and

3mmHg in systolic and diastolic blood pressure, respectively[48]. In

the UKPDS, a 15% increased risk for cardiovascular disease was

reported for an elevation in systolic blood pressure of 10mmHg,

which was similar to that report in the general population[49]. At

population level, greater cardiovascular benefit might be obtained by

reducing the mean population blood pressure even by as little as

2-3mmHg[50].

Hypertension is a more frequent cause of stroke on woman (59%

vs 39% in men)[29]. A study reported that morbidity of hypertension

(>140/90mmHg) is 2.6 with 25kg/㎡ of BMI in both sex, and 1.7

with over 0.9 of WHR in men and over 0.8 of WHR in women[51].

- 13 -

2.3.3. Lipid Profile

Lipid profile of women is different to that in men and it changes

with age and hormonal status[52]. Visceral and gynoid fat distribution

are remarkably different in influencing lipoprotein metabolism and

consecutive cardiovascular risk. The difference between patients with

gynoid and visceral fat accumulation might be found in the

postprandial state. Visceral adipose tissue is, in addition to the

intestine (after meal), the source of FFA in the fasting state. The

visceral fat depot is drained directly by the portal vein, resulting in

an increased FFA flux to the liver and consequent overproduction of

LDL. Deep abdominal (or visceral) fat is more metabolically active

than other adipose tissue[26]. Therefore, visceral adiposity may serve

as the specific correlate to metabolic complications, such as

hypertension, dyslipidemia and impairments in glucose tolerance[12].

Hypercholesterolemia is a major risk factor in the development of

coronary heart disease and in the progression of atherosclerosis. Total

cholesterol and HDL cholesterole are significant predictors of

cardiovascular disease in women. In the Framingham Study, women

with cholesterol levels greater than 265mg/dl had a relative risk of

developing new cardiovascular disease that was two to three times

higher than that of women with cholesterol levels less than 205mg/dl.

LDL cholesterol levels are lower in pre-menopausal women than in

men, rising to higher levels than in men after the menopause.

Triglyceride levels and lipoprotein(a) also rise after menopause;

HDL cholesterol levels fall. The evidence about studies on cholesterol

and heart relationship is less strong for women and the absolute risk

for a given cholesterol level is considerably lower. Compared with

- 14 -

LDL cholesterol, HDL cholesterol is a strong (negative) predictor of

coronary heart disease in women[50,53]. In the Framingham and Lipid

Research Clinics Studies, a 10mg/dl change in HDL levels in women

was associated with a 45 to 50% risk difference in cardiovascular

disease. Furthermore, in the Donolo-Tel Aviv Study, total cholesterol

levels did not predict cardiovascular disease in women with high

levels of HDL. That is, women with elevated total cholesterol levels

and high HDL concentrations were not at increase risk of coronary

disease[19]. Fasting hypertriglyceridemia was a strong predictor of

CHD independent of other risk factors, including HDL[54]. On the

basis of data from a total of 46,413 men and 10,864 women, elevated

TG was associated with 30% increase in cardiovascular risk in men

and a 75% increase in cardiovascular risk in women[55].

2.3.4. Endothelial Dysfunction

Plasma free fatty acid levels are elevated in most obese subjects

and the elevated blood levels of FFAs play a key role in the

development of insulin resistance in obesity. Increased availability of

FFAs decreased carbohydrate oxidation because increased availability

of FFAs in blood produces an increase in intramuscular of acetyl-CoA

and citrate content; acetyl-CoA inhibits pyruvate dehydrogenase

allosterically, and this in turn reduces glucose oxidation; citrate

inhibits phosphofructokinase 1 and thus glycolysis itself, eventually

resulting in the impairment of glucose uptake[56,57]. FFAs would

impair insulin sensitivity in skeletal muscle and, together with

glycerol, accelerate gluconeogenesis, thereby inducing insulin resistance

- 15 -

at the site(s) of endogenous glucose production. To overcome the

ubiquitous insulin resistance and preserve glucose homeostasis, the β

-cell would secrete more insulin, thereby causing a state of adaptive

hyperinsulinism[59].

When investigating the significance in skeletal muscle blood flow

in glucose homeostasis, Baron's group first demonstrated that insulin

induced an increase in leg blood flow. Further, this effect was shown

to be blunted in insulin-resistant states.[60,61] The mechanisms

through which insulin impairs endothelial function are not clear. But

in most insulin-resistant states such as obesity, fasting

hyperinsulinemia has impaired endothelial function in healthy

individuals. Modest hyperinsulinemia in insulin-resistant patients after

an overnight fast can cause severe endothelial dysfunction in large

conduit arteries[47].

Markers of inflammation are important predictors of the risk of

cardiovascular events. RP, a sensitive marker of inflammation that has

previously been associated with cardiovascular disease, was

independently related to insulin sensitivity[62]. The risks of vascular

disease associated with CRP were greater for women than for

men[63]. CRP is produced early by the liver during the inflammation

process[64]. Chronic subclinical inflammation emerged as part of

insulin resistance syndrome(IRS). Festa et al showed various

components of IRS were correlated to inflammatory markers and that

an increasing number of components of IRS paralleled increasing

levels of CRP. Previously, in various populations, CRP levels were

associated with BMI, WC, triglyceride level, HDL cholesterol level,

total cholesterol level, and blood pressure[65]. CRP is a potent

predictor of risk regardless of the LDL cholesterol level[66].

- 16 -

Concerning the relationship between CRP concentration and BMI

level, the third National Health and Nutrition Examination Survey

found that the prevalence of elevated CRP levels (CRP concentration

≥0.22mg/dl) is higher both in overweight (BMI 25-29.9kg/㎡) and

obese (BMI ≥30kg/㎡) patients than in normal weight (BMI <25kg/

㎡) subjects[67].

In particular, the visceral to subcutaneous adipose tissue are ratio,

which is closely related with metabolic and cardiovascular disorders,

was the stronger predictor of the degree of the endothelial

damage[94,95]. It was observed that the presence of a close association

between a marker of endothelial function, body fat distribution

measured by computerized tomograph(CT) and a marker of insulin

sensitivity[69].

Measurement of markers of inflammation such as hs-CRP can

significantly improve models for the prediction of cardiovascular risk

may lead to better clinical identification of patients who might benefit

from primary prevention and for whom the cost-to-benefit ratio for

long-term use of statins would be improved[66].

- 17 -

2.4. Obesity Related Protein

In vertebrates, a complex physiological system has evolved to

regulate fuel stores and energy balance at an optimum level. Leptin

(from the Greek leptos, meaning thin) is a protein hormone with

important effects in regulating body weight, metabolism and

reproductive function[70]. Leptin, the product of the obesity gene, is

one of the main regulations of adipogenesis affecting food intake and

thermogenesis. Leptin is produced only in adipose tissue[71]. Leptin

might be an afferent signal in a negative-feedback loop regulating the

size of adipose tissue mass. Leptin concentration are sensed by groups

of neurons in the hypothalamus[72,73]. Circulating concentrations

correlate with fat mass both in normal weight and obese subjects, and

decline with weight loss[74]. Leptin concentrations declined

proportionally with decreasing body fat in persons who still were

overweight[75]. Administration of leptin by injection or, with greater

potency, as a constant subcutaneous infusion results in a

dose-dependent decrease in body weight at incremental increase of

plasma leptin levels within the physiological range. Leptin treatment

blunts the changes in circulating thyroid hormone and corticosterone

levels that are normally associated with food deprivation[72,76]. Leptin

levels predict neither size of visceral fat nor insulin sensitivity. In

other words, visceral fat and body fat distribution are probably

determined via different mechanisms that do not involve the leptin

pathways[77].

- 18 -

2.5. Menopause-related Change

Older age is associated with increased fat deposition around the

trunk and abdomen and the further redistribution of fat from

subcutaneous abdominal to visceral depot[78].

In comparison with the pre-menopausal women, the post

menopausal women had worsen cardiovascular disease risk factor,

which were mediated by the independent effect of age, menopause

and especially central fat distribution[79]. Greater tendency for central

fat deposition after the menopause may be particularly relevant to the

higher incidence of CHD in post-menopausal women, since, although

central obesity has been shown to be a strong risk factor for both

men and women, studies in women generally produce values for

relative risk that are higher than those found in men. When compared

with pre-menopausal women, elevated blood pressure, increased

glucose intolerance and dyslipidemia are not uncommon in

postmenopausal women. A study showed a greater increase in fat

mass and the waist-hip ratio and a greater loss of fat-free mass in

middle-aged women who became postmenopausal compared to women

who remained pre-menopausal during a by follow-up[80]. The

metabolic phenotype of post-menopausal women, which includes an

increased tendency for body fat deposition in the abdominal region,

suggests that insulin resistance may underlie the characteristic features

of post-menopausal dyslipidemia. In post-menopausal women,

heightened circulating insulin levels associated with greater fat

accumulation have adequately compensated for the apparent loss of

insulin sensitivity with respect to glucose metabolism[81].

- 19 -

Menopause-related changes in body composition may be partially

explained by changes in bone mineral density. The rapid loss of bone

mineral density during the early-postmenopausal period may have

reduced the density of fat-free mass and caused percentage body fat

to be overestimated in those women who became post-menopausal[82].

Interpretation of greater intra-abdominal fat is that the menopause

transition is associated with a preferential storage of fat in the

intra-abdominal compartment. Changes at the cellular level, such as

increased lipoprotein lipase activity or decreased lipolysis, that result

from estrogen deficiency and increased androgenicity induced by the

menopause transition, may explain the redistribution of fat to the

intra-abdominal depot[69]. Loss of ovarian function and endogenous

estrogen secretion, with consequent adverse effects HDL levels,

increased small dense LDL level and a decline in endothelial function,

are likely aetiological factors[81].

- 20 -

2.6. Food Intake Reducing Substances

2.6.1. Hydroxy Citric Acid (HCA)

HCA is an ingredient extracted from the rind of the fruit Garcinia

Cambogia, a native species from India, and is promoted as a weight

loss agent[83]. In vitro and in vivo, HCA in animals not only

inhibited the actions of citrate cleavage enzyme and suppressed de

novo fatty acid synthesis, but also increased rates of hepatic glycogen

synthesis, suppressed food intake, and decrease body weight gain[84].

Limitation results in increased hepatic glycogen synthesis, which might

result in reduction of energy intake[85].

The fact that the main energy intake reduction took place between

meals might indicate that HCA works by increasing fat oxidation

(inhibiting malonyl-CoA synthesis, thus stimulating carnitine palmitoyl

transferase activity) since fat is oxidized after protein and

carbohydrate, thus later during the intermeal interval. During this

interval satiety might be sustained by increased fat oxidation and

ketone body formation[86].

Results on the effects on HCA on appetite and body weight

regulation in humans showed positive and negative outcomes[87,88].

2.6.2. Chitosan

Chitosan is the deacetylated form of chitin found in the shells of

invertebrates such as shrimp and crabs[46]. Chitosan is similar to

dietary fiber in being a polysaccharide that is indigestible by

mammalian digestive enzymes. Chitosan decrease fat digestibility.

Chitosan is polymers containing more than 5000 acetylglucosamine

- 21 -

and glucosamine units. The polymer has also been investigated as a

potential adjuvant for swellable controlled drug delivery systems.

Chitosan exhibits myriad biological actions, namely

hypocholesterolemic, antimicrobial and wound healing properties[90].

Inclusion of chitin-chitosan in the diet, reduced total plasma

cholesterol and inhibited the absorption of cholesterol and

triacylglycerol from lymph in animal model[91] and human[92].

Fecal fat excretion was greater with chitosan feeding. The greater

fecal fat excretion with chitosan feeding is of particular interest in

light of studies in humans showing that chitosan hypocaloric diets[42].

It would appear that a higher dietary concentration of chitosan is

required to decrease fat digestibility than to achieve cholesterol

lowering[80].

- 22 -

3. SUBJECTS and METHODS

3.1. Subjects

Seventy one overweight middle-aged women with over 110% of

ideal body weight were included in this study. All women were

healthy volunteers. We excluded those with heart disease

hypertension, hyperlipidemia or diabetes mellitus by the self-report of

doctor's diagnosis. These disease conditions and treatment might affect

the weight and cardiovascular disease risk factor changes during the

follow up. All subjects were divided into 2 groups with case(n=34)

and control(n=37). Their mean age of case group was

53.0±1.53yrs(29-64yrs) with 27.5±0.48kg/㎡(22.0-33.9kg/㎡) of BMI and

control group was 52.30±1.49yrs(33-66yrs) with 27.1±0.46kg/㎡

(23.0-33.0kg/㎡) of BMI. Table 1 shows the clinical characteristics of

study subjects in each group.

We supplied substance in the form of tablets(450mg/capsule). All

Table 1. Clinical characteristics of subjects: Control and Case

Mean±S.E.

¹range

Control (n=37) Case(n=34)

Age(yrs) 52.3 ± 1.49 (33-66)₁ 53.0 ± 1.53 (29-64)

Height(cm) 156 ± 0.74 (147-165) 158 ± 0.89 (142-170)

Weight(kg) 66.9 ± 1.21 (53.5-85.1) 68.5 ± 1.44 (53.5-85.1)

BMI(kg/㎡) 27.1 ± 0.46 (23.0-33.0) 27.5 ± 0.48 (22.0-33.9)

Body fat (%) 36.9 ± 0.69 (25.4-45.6) 38.6 ± 1.01 (25.4-50.7)

Lean body mass(kg) 41.6 ± 0.62 (33.4-49.1) 42.0 ± 0.73 (31.2-49.1)

- 23 -

Table 2. Supplement facts in 450mg of a capsule

participants took 2 tablets 3 times a day before every meal for 8

weeks. Table 2 shows the ingredients and their amounts of the

tablet supplied to the case group subjects. The tablets for the placebo

group contained 100% of dextrin. Subjects consumed a self-selected

diet comprising commercially available food products in a free-living

environment. None of the women were involved in an exercise

program before entering this study. Subjects did not take any

medications known to affect plasma lipid levels. None had a family

history of diabetes milletus and cardiovascular disease. At the time of

subjects enrollment, the baseline cardiovascular risk factors were

reported in all study participants include age, smoking status (past,

current or never), height, weight, history of hypertension and diabetes,

menopausal state and alcohol intake. All methods and procedures

were approved by the Institutional Review Board for Clinical Research

of the Yonsei University(Severance Hospital). All subjects provided

written informed consent to participate in the study, which was

approved by the institutional committee of ethical practice of our

institution.

Ingredients Amount(%)

Chitosan 30%

Hydroxycitric acid 32%

L-carnitine 15%

vitamin E 5%

SiO2 3%

Cellulose 15%

- 24 -

3.2. Materials and Methods

For laboratory assay, all measurement were done in a single batch

at the end of the study.

3.2.1 Anthropometric Measurements and Fat Distribution

Assessment

During the 8 weeks, the weight, arm muscle circumference, waist

and hip circumferences, fat %, lean body mass, BMI, blood pressure,

and abdominal adipose tissue area of each subject were measured

twice(0 and 8weeks).

In the morning fasting state, body weight, fat %, learn body mass

and BMI were directly measured with body fat analyzer

TBF-105(Tanita Co, Japan). Waist and hip circumference were

measured to the nearest ㎜ with a non-elastic tape measure. The waist

circumference at the level midway between the lateral lower rip

margin and the superior anterior iliac crest and hip circumference at

the maximum extension of the buttocks were measured. The WHR

was defined as the ratio of waist circumference divided by hip

circumference. Arm muscle circumference was measured with tape

and triceps skinfold thickness was also measured with

Skyndex(Caldwell & Justiss Co.) at the midpoint of upper arm.

Systolic and diastolic blood pressure were measured after 10-min rest

by using a automatic sphygmomanometer.

Visceral and abdominal subcutaneous fat were measured by the

CT with a High Speed Advantage 9800 CT scanner(General Electric

Co, USA). Cross sectional images were made of the abdomen at the

- 25 -

L1 and L4 vertebrae, thigh (midway between, patella and pubis), and

calf (at the most protruding area). Participants were scanned in a

supine position. The parameters for total abdominal fat density at the

L1 and L4 vertebrae were selected between -150 and -50 Hounsfield

units. Total abdominal fat area was divided into visceral and

subcutaneous fat area, then each area was calculated. Parameters for

the muscle areas of the thigh and the calf were selected as between

the range of -49 and +100HU and for fat areas between -150 and -50

HU.

3.2.2. Diet and Physical Activity Assay

For the diet assay, the subject reported all the foods and beverage

intake 24 hours before at the first visit(0 week) and were instructed to

report the consumed foods and their amount for 3 days (2 weekdays

and 1 weekend) every 2 weeks throught the intervention. Measuring

instruments were used to measure the amount of the foods and the

beverage for the quantity assay. For the physical activity assay, each

subjects also reported their activitied and behaviors with expending

time during the 3 days. Total food energy was analyzed with N3

program (N-squared Computing, First Data bank Division, USA). Total

energy expenditure was estimated with their physical activity and

behavior.

3.2.3. Metabolic Studies

On the days of study (0 and 8 weeks), venous blood was

sampled in EDTA-treated tubes and plain tubes from each subject

after a 12h overnight fasting. The tubes were immediately covered

- 26 -

with aluminum foil and placed on ice in the dark until they arrived

at the laboratory room (within 1-3 hrs) and stored at -70℃ until the

analysis. The serum concentration of the total cholesterol, triglyceride,

HDL, glucose, insulin and FFA, and the plasma concentration of CRP,

TAS and leptin levels were measured.

3.2.3.1. Glucose Tolerance Test

The 75g oral glucose tolerance test(OGTT) was performed after a

12-hour overnight fast to the all subjects. Blood samples were

subsequently collected at 0, 30, 60, 90, and 120 minutes after loading

to determine the serum levels and the response areas of glucose,

insulin and FFA. Glucose and FFA levels were measured by a glucose

oxidase method using a multiparametric analyzer (Hitachi 7600-100,

Tokyo, Japan). Insulin level was assayed by antibody

radioimmunoassay of Dainbot(Tokyo, Japan). Each response area of

glucose and insulin was determined by calculating the area under the

each response curve.

Insulin resistance and sensitivity were calculated with formula

described by Matthews using the homeostasis model assessment of

insulin resistance (HOMAIR ; (fasting glucose(mmol/L) × fasting

insulin(μU/ml)/22.5) and insulin secretion sensitivity (HOMAβcell function

; 20 × fasting insulin(μU/ml)/{(fasting glucose(mmol/L)―3.5)}),

mathematical estimate of insulin sensitivity based on fast glucose and

insulin concentration[92].

3.2.3.2. Serum Lipid Profiles and Leptin

Blood levels of total cholesterol, triglyceride and HDL-cholesterol

were assayed enzymatically using a multiparametric analyzer (Hitachi

- 27 -

7600-100, Tokyo, Japan). LDL-cholesterol was estimated using the

Friedewald formula; total cholesterol ― HDL ― Triglyceride/5.

Leptin was measured by immunoradiometric assays using

human leptin RIA kit.

3.2.3.3. Plasma C-reactive Protein

Plasma CRP levels were measured using a commercially available

high-sensitivity kit, CRP-Latex(II)×2 supplied by Seiken Laboratories

Ltd(Tokyo, Japan) that allowed detection of CRP levels as low as

0.01mg/dl and as high as 32mg/dl. The assay principle is that latex

microparticles coated with monoclonal antibodies against CRP reacts

with the CRP in the added samples for immunoagglutination

reactions[93].

The measurements of these immunoagglutination reactions were

performed on Express Plus autoanalyzer (Chiron Diagnostics Co., MA,

USA) using reaction buffer. The absorbance change was calculated at

572nm for 3 minutes. Because the absorbance change is proportional

to the CRP concentrations in samples, CRP values of samples were

automatically calculated from calibration curve prepared with the 5

points RP(II) H standard (Seiken Laboratories Ltd. Tokyo, Japan)

consisted of 5 different concentrations (0.5, 2, 4, 16, 32mg/dl) of CRP.

The normal references value was less than 0.3mg/dl.

3.2.3.4. Plasma Total Antioxidant Status

Plasma total antioxidant status(TAS) was measured

spectrophotometrically with the use of a commercial kit, Randox total

- 28 -

antioxidant status kit supplied by Randox Laboratories Ltd (Antrim,

United Kingdom) on Auto Chemistry Analyzer Express Plus (Chiron

Diagnostics Co., MA, USA). The assay principle is that a peroxidase

(such as metmyoglobin) reacts with H2O2 to form the radical species

ferrylmyoglobin. Achromogen ABTSR

(2,2'-Azino-di-[3-ethylbenzthiazoline-sulphonate]) is incubated with the

ferrylmyoglobin to produce the relatively long-lived radical cation

species, ABTSR+. This has a relatively stable blue-green color, which is

measured at 600nm. Antioxidants in the added samples cause

suppression of this color production to a degree that is proportional

to their concentration[94]. The system was standardized with the use

of Trolox (6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carbosylic acid), a

(+)-α-tocopherol analog with enhanced water solubility. The unit of

activity is the concentration (mM) of Trolox having the equivalent

antioxidant capacity to a 10mM solution of the substance under

investigation. The results were expressed as the Trolox equivalent

antioxidant capacity[95].

TAS thus characterizes the capacity of a plasma sample to

neutralize lipid peroxidation, which means, that a low level reflects

decreased antioxidant capacity, due to exhaustion by accelerated in

vivo lipid peroxidation[94]. The average values of the two

measurements were used. The normal reference value was 1.30∼

1.77mmol/L

3.2.4 Statistical Analysis

The main goal of statistical analysis was to compare the

differences in the responses of anthropometric and metabolic

parameters with the weight reduction. Statistical analysis was

- 29 -

performed with Win SPSS ver 11.0 (Statistical Package for the Social

Science, SPSS Ins., Chicago, IL, USA). Values are expressed as

mean±S.E. In order to describe our study subject, paired t-test was

used to compare and find the correlation between the data at the

baseline and end point values. To examine the associations between

the weight loss variables and changes in each cardiovascular disease

risk factor, Pearson's correlation coefficients are calculated to use to

evaluated the correlation of the variables. A P value of <0.05 was

considered statistically significant.

- 30 -

4. RESULTS

4.1. Total Calorie Intake and Energy Expenditure

Interventions to induce negative energy balance may focus on energy

intake(diet) or energy expenditure(exercise) or a combination of these elements.

Nutrition should be a primary consideration in approaches to dealing with

obesity.

Total dietary energy intake and total energy expenditure were

estimated by the reports of all the participants. Nutrient intakes were similar

between the control and the case group in the beginning(the data is not

shown). Despite their free will for choosing food, the consumed foods amounts

and their energy were significantly different between the control and the case

group over an 8 week period (p<0.001). Their physical activity was little

changed throughout the program. A few women had increased in physical

activity to encourage weight loss. But the values were too small to influence

the whole group. Table 3 shows the significant decrease during the study in

total calorie intake in case group(p<0.001) and the insignificant difference in

total energy expenditure of all the subjects before and after 8 week study

4.2. Clinical Characteristics of Subjects

In this study, seventy one healthy middle aged overweight women

were attended. They were divided into two group having similar average

weight and BMI to attain the high reliability in comparing the several

measurements. Their smoking and alcohol intakes were little.

Thirty four women were studied in case group, and thirty seven

- 31 -

Table 3. Total calorie intake and total energy expenditure in each group before

and after study

Mean±S.E.

***p<0.001 compared with initial value in each group

1total calorie intake

2total energy expenditure

women were studied in control group. Table 4 shows their clinical

characteristics in anthropometric levels and blood pressure at 0 and 8 week. In

the beginning, both group were similar in average age, height, weight, BMI

and body fat %. In the control group and the case group, they were

52.3±1.49yrs and 53.0±1.53yrs, 156.81±0.74cm and 157.9±0.89cm, and 66.8±1.21kg

and 68.5±1.44kg, respectively. Their BMI and body fat % were 27.1±0.46 vs

27.5±0.48 and 36.8±0.69% vs 38.6±1.01% in the control group vs case group.

They were all overweight or obese with the definition of BMI in the

Asia-Pacific Guide. The control group participants had average 41.6±0.62kg of

lean body mass(LBM), 91.1±1.24cm of waist circumference and 0.91±0.01 of

waist-to-hip ratio. The case group participants had average 42.0±0.73kg of lean

body mass, 93.2±1.79cm of waist circumference and 0.91±0.01 of waist-to-hip

ratio. They were all central obesity women having ≥80cm of waist

circumference which was defined central obesity as recently proposed by

the International Association for the Study of Obesity[96]. Systolic and diastolic

blood pressures of the control group vs the case group were 124.3±2.89㎜Hg

Control(n=37) Case(n=34)

0 week 8 week 0 week 8 week

TCI¹ 2243±30 2220±31 2242±28 2194±30***

TEE² 2089±28 2107±25 2115±29 2116±30

- 32 -

Table 4. Clinical characteristics in each group before and after study

Mean±S.E.

*p<0.05,

**p<0.01,


1systolic blood pressure

2diastolic blood pressure

and 79.0±1.94㎜Hg vs 130.8±2.83㎜Hg and 80.1±1.87㎜Hg. Their blood pressure

were belong to normal range by the definition of hypertension which is

systolic blood pressure(SBP) ≥160㎜Hg and/or diastolic blood pressure(DBP) ≥

95㎜Hg as definite hypertension and SBP ranging from 140 to 159㎜Hg, or

DBP ranging from 90 to 94㎜Hg as borderline hypertension.

After 8 weeks, average weight, BMI, waist circumference, and hip

circumference of the case group was significantly decreased (p<0.001). Body fat

% was also significantly decreased in 8 weeks (p<0.01). Insignificant changes



Age(yrs) 52.3±1.49 53.0±1.53

Height(cm) 156.8±0.74 157.9±0.89

Weight(Kg) 66.8±1.21 66.7±1.23 68.5±1.44 66.6±1.41***

BMI(kg/㎡) 27.1±0.46 27.1±0.47 27.5±0.48 26.7±0.46***

Body fat % 36.8±0.69 36.4±0.69 38.6±1.01 36.7±0.97**

LMB(kg) 41.6±0.62 41.8±0.54 42.0±0.73 42.1±0.72

Waist(cm) 91.1±1.24 90.3±1.09 93.2±1.79 89.8±1.64***

Hip(cm) 100.5±0.92 99.7±0.88 102.2±1.03 100.1±0.97***

WHR 0.91±0.01 0.91±0.01 0.91±0.01 0.89±0.01

SBP(㎜Hg) 124.3±2.89 121.6±2.78 130.8±2.83 130.6±2.93

DBP(㎜Hg) 79.0±1.95 76.4±1.86 80.1±1.87 80.1±1.99

- 33 -

were occurred in lean body mass or waist-to-hip ratio. The blood pressure was

also insignificantly changed.

4.3. Serum Lipid Profiles of Subjects

Table 5 shows serum lipid profiles of study subjects before and after

the 8 week program. Subjects without one or more of the following results are

considered as dislipidemic: plasma total cholesterol 130-200㎎/㎗, triglycerides

≤250㎎/㎗, LDL 55-155㎎/㎗, and HDL 35-80㎎/㎗. Most variables of the

subjects were in the normal ranges. Total cholesterol values were slightly

higher than the defined normal range but were regarded as normal.

Triglyceride levels of the case group women were significantly decreased by

the weight loss program(p<0.05). After 8 weeks, total cholesterol, HDL and

LDL values were not significantly changed.

Table 5. Serum lipid profiles in each group before and after study

Mean±S.E.

*p<0.05 compared with the initial value in each group

1Atherogenic index=(Total cholesterol-HDL cholesterol)/HDL cholesterol

2HDL/Total cholesterol ratio



Total cholesterol(㎎/㎗) 208±6.29 210±6.75 203±5.75 203±6.54

Triglyceride(㎎/㎗) 138±8.91 144±12.9 158±10.5 144±11.5*

HDL cholesterol(㎎/㎗) 47.9±1.68 47.5±1.62 44.9±1.95 46.2±1.77

LDL cholesterol(㎎/㎗) 133±5.52 133±5.48 126±5.17 128±5.63

Atherogenic index1 3.48±0.17 3.55±0.17 3.73±0.23 3.57±0.23

H/TC ratio2

0.24±0.10 0.23±0.01 0.23±0.01 0.23±0.01

- 34 -

4.4. Serum Glucose, Insulin, and Free Fatty Acid

Concentrations of Subjects

The fasting serum concentrations of glucose, insulin and free fatty acid

of the subjects are presented in Table 6. All the mean values of fasting glucose

were in the normal range(70∼110㎎/㎗). In the oral glucose tolerance test, the

level of serum glucose after 2 hours loading of 75g of glucose powder were in

the range of normal(≤140㎎/㎗)(the data were not shown). The mean fasting

glucose concentration was significantly decreased after 8 weeks in the case

group subjects(p<0.05). There were insignificant differences over the 8 week

period in the insulin levels and free fatty acid levels in both group. The

changes in insulin resistance and insulin secretion sensitivity were not

significant during the 8 weeks program.

Table 6. Concentrations of Serum glucose, insulin and free fatty acid in each

group during the oral glucose tolerance test before and after study

Mean±S.E.


1{fasting insulin(μU/㎖)×fasting glucose(m㏖/L)}/22.5

2{20×fasting insulin(μU/㎖)}/{(fasting glucose(m㏖/L)-3.5}



Fasting level

Glucose(㎎/㎗) 89.7±3.47 87.2±3.07 93.6±5.69 88.3±5.19*

Insulin(μU/ml) 11.5±0.96 11.3±0.85 12.1±0.82 12.1±1.03

Free fatty acid(μU/ml) 715±66.5 720±59.7 699±62.08 616±58.4

Response area(×hr)

Glucose area 301±15.7 295±14.3 301±19.6 291±18.8

Insulin area 105±10.3 101±11.7 116±13.4 113±13.9

Free fatty acid area 793±78.3 767±59.8 881±76.6 762±56.3

HOMAIR1

2.53±0.22 2.45±0.21 2.94±0.34 2.71±0.28

HOMAβ cell function2 214±24.9 323±77.8 132±47.2 242±50.8

- 35 -

4.5. Fat and Muscle Area at Different Levels of the Body

of Subjects

Computerized tomography scanning was provided to quantify the

central obesity. Table 7 presents the fat and the muscle areas at L1 and L4

levels of the body, and the fat and the muscle amounts at mid-thigh and at

calf in both groups.

At L1 level, the total fat amounts were decreased insignificantly, and

Table 7. Fat and muscle area at different levels of the body in each group

before and after study

Mean±S.E.

§p<0.1,

*p<0.05,

**p<0.01,


Control Case


1st lumber(L1) vertebra

Total fat(㎠) 277±11.1 276±10.3 291±11.1 285±11.8

Visceral fat(㎠) 112±5.61 111±5.40 121±4.73 120±5.68

Subcutaneous fat(㎠) 165±6.73 165±6.85 171±8,14 165±8.27*

V/S fat ratio 0.67±0.03 0.68±0.03 0.74±0.03 0.76±0.04

4th lumber(L4) vertebra

Total fat(㎠) 317±10.0 325±10.3 334±12.47 319±12.7***

Visceral fat(㎠) 102±5.55 102±5.11 112±5.30 102±5.83**

Subcutaneous fat(㎠) 215±7.36 222±7.60 222±9.93 217±10.2

V/S fat ratio 0.49±0.31 0.47±0.02 0.53±0.03 0.49±0.03§

Calf

Fat(㎠) 25.9±0.84 26.1±0.97 27.4±1.29 26.4±1.32**

Muscle(㎠) 60.3±1.40 61.6±1.59 64.2±1.85 63.8±1.94

Mid thigh

Fat(㎠) 80.5±2.79 82.1±2.78 79.4±3.32 80.1±3.32

Muscle(㎠) 105.1±2.42 103±2.25 104±2.43 102±2.00

- 36 -

0

20

40

60

80

100

120

140

160

180

V F SF V F SF

0 week 8 week

control case

L1 vertebra

**

Fat (cm2)

0

50

100

150

200

250

VF SF VF SF

0 week 8 week

control case

L4 vertebra

***

Fat (cm2)

Fig. 2 Comparison of visceral fat and subcutaneous fat area at L1 and L4

levels in each group before and after study

- 37 -

visceral fat amounts were also decreased insignificantly in both groups.

Subcutaneous fat amounts of L1 level were significantly decreased in the case

group(p<0.05). At L4 level, total fat amounts were significantly

decreased(p<0.001) and especially visceral fat amounts were significantly

decreased in the case group(p<0.01). Subcutaneous fat amounts of L4 level

were not significantly changed in both group. The comparison of the visceral

and the subcutaneous fat area between at L1 and L4 vertebrae are shown in

Fig.2. Abdominal fat reduction of the case group was shown in subcutaneous

fat at L1 level and in visceral fat at L4 level. The ratios of visceral fat to

subcutaneous fat of L4 level in the case group were decreased

significantly(p<0.1) The ratios of visceral fat-to-thigh muscle and visceral

fat-to-thigh fat in the case group were decreased significantly(p<0.01, the data

are not shown). There were significant decreasing in calf fat amounts(p<0.01),

not in calf muscle amounts in the case group. Thigh fat and muscle amounts

were not significantly decreased in both group.

- 38 -

4.6. Leptin, TAS and CRP Values of Subjects

Table 8 presents leptin, TAS and CRP values of the subjects during

the 8 weeks study.

As the high leptin value was expected in the obesity, the levels of

leptin were significantly decreased with the weight reduction in the case

group(p<0.01). All the participants had the normal range of TAS and CRP

values(TAS ; 1.30~1.77mmol/L, CRP ;≤0.3mg/dl). The TAS levels of the case

group were increased insignificantly and the CRP levels were increased

significantly during the 8 week study(p<0.05).

Table 8. Leptin, TAS, and CRP values in each group before and after the

study

Mean±S.E.

§p<0.1,

*p<0.05,

**p<0.01,




Leptin(ng/ml) 13.3±0.80 11.9±0.75 14.3±1.35 10.8±0.83**

TAS(mmol/L) 1.39±0.01 1.34±0.02 1.29±0.05 1.35±0.01

CRP(mg/dl) 0.21±0.05 0.18±0.02 0.20±0.08 0.14±0.03*

- 39 -

4.7. Correlations between Body Compositions, and

between body Compositions & Metabolic Profiles

During the study, the weights were significantly decreased in the case

group. With the weight loss, body composition values and metabolic profiles

were significantly changed.

Some relations were found between the decreased weight and

anthropometric parameters in case group. The interrelations among the

anthropometric variables in the beginning are shown in Table 9. Many of the

anthropometric variables were highly correlated(p<0.01), which led that BMI,

body fat %, waist circumference, hip circumferences, abdominal fat, thigh fat

and calf fat measure were distinct aspect of body fat distribution or body

composition. In this study, waist-to-hip ratio was not interrelated with weight.

Table 10 shows the correlations between the anthropometric variables and

metabolic profiles including cardiovascular disease risk factors. The weight was

significantly related with the leptin & the fasting insulin level, insulin

resistance, insulin sensitivity and systolic blood pressure(p<0.01). Significant

correlation with some cardiovascular disease risk factors were found in WHR.

The WHR ratio was significantly correlated with the concentrations of total

cholesterol, LDL cholesterol and triglyceride(p<0.01). Fat amounts of L1 and L4

levels were highly correlated with the level of total cholesterol, leptin, fasting

glucose, fasting insulin, insulin resistance, insulin sensitivity, free fatty acid, and

systolic blood pressure.

Table 11 and Table 12 show the interrelations among changes of the

body compositions and the relations between the changes of anthropometric

variables and the changes of metabolic profiles, respectively. Weight reduction

was strongly associated with the reduction of BMI and hip circumference.

Abdominal visceral fat reduction was also significantly related with weight

- 44 -

reduction in table 11. Table 12 presents that the changes of body composition

were not significantly related with the changes of the most metabolic profiles.

Only the changes of leptin amounts were significantly related with the

reduction of the total fat and the visceral fat at L4 level.

Most subjects were still overweight after the weight reduction.

Interrelations among the anthropometric variables after the study were shown

in Table 13. The relations were similar to those of Table 8. Table 14 shows

that the concentrations of total cholesterol, triglyceride, HDL and LDL were

insignificantly related with the adiposity measurements after the weight

reduction. Abdominal fat was significantly correlated with the levels of liptin,

FFA, insulin, glucose & CRP, insulin restance, and systolic and diastolic blood

pressure.

- 47 -

4.8. Comparison of Parameters of Subjects in Menopausal

Status

All the subjects were divided by menopausal status to compare the

anthropometric variables and the metabolic profiles between pre- and

post-menopausal women and to assess the influence of menopausal status on

the weight reduction. Among the participants, pre-menopausal women were

30 and postmenopausal women were 41. In the case group, 10 were

pre-menopausal and 24 were postmenopausal.

4.8.1. Comparison of Anthropometric and Metabolic Parameters between Pre-

and Post-menopausal Subjects before the Study

Table 15 and Table 16 presents the differences in anthropometric and

metabolic variables of all the participants with menopausal status respectively.

Post-menopausal women were significantly older than the pre-menopausal

women(p<0.001). In this study, the differences of anthropometric variables were

not significant between the different menopausal status. Among the metabolic

values, systolic & diastolic blood pressure, total cholesterol & LDL cholesterol

level and HDL-to-total cholesterol ratio had significant differences with

menopausal status. The post-menopausal women had significantly higher

systolic blood pressure and total cholesterol & LDL cholesterol level than the

pre-menopausal women(p<0.01). Response area of the glucose and the free fatty

acid in the glucose tolerance test and atherogenic index were significantly

bigger in the post-menopausal women than in the post-menopausal

women(p<0.05).

- 48 -

Table 15. Differences in clinical characteristics between pre- and

post-menopausal participants before study

Mean±S.E.

***p<0.001 compared with the pre-menopausal participants

Table 17 shows the differences in fat and muscle area at L1 and L4

vertebrae, and thigh & calf level between pre- andpost-menopausal subjects.

Distribution of adiposity was significantly different in visceral fat at L1 and L4

vertebrae with menopause transition(p<0.01). Total fat amounts of L1 and L4

vertebrae in the post-menopausal women were significantly bigger than the

pre-menopausal women(p<0.1). The post-menopausal women had significantly

more visceral fat than the pre-menopausal women. The ratios of visceral to

subcutaneous fat were significantly higher at L4 vertebra(p<0.01) and at L1

vertebra(p<0.05) in post-menopausal women than in the pre-menopausal

women. The differences in the calf fat and muscle amounts between different

menopausal status were not significant. But there were significant differences

between the pre- and the post-menopausal subjects in mid thigh muscle

Pre-menopausal(n=30) Post-menopausal(n=41)

Age(yrs) 44.4 ± 1.49 57.0 ± 0.79***

Height(cm) 157.4 ± 0.96 157.1 ± 0.58

Weight(kg) 67.7 ± 1.55 67.1 ± 1.00

BMI(kg/㎡) 27.3 ± 0.48 27.2 ± 0.38

Body fat (%) 36.1 ± 1.06 37.5 ± 0.68

LBM(kg) 43.0 ± 1.14 43.4 ± 1.09

Waist(cm) 91.9 ± 1.83 92.3 ± 1.13

Hip(cm) 101.2 ± 0.95 100.7 ± 0.82

WHR 0.91 ± 0.01 0.92 ± 0.00

SBP(㎜Hg) 118 ± 2.91 128 ± 2.16**

DBP(㎜Hg) 76 ± 2.03 79 ± 1.45

- 49 -

Table 16. Differences in the concentrations of serum lipid profiles, glucose,

insulin, and free fatty acid between pre- and post-menopausal

participants before study

Mean±S.E.

*p<0.05, **p<0.01, ***p<0.001 compared with the pre-menopausal participants

amounts (p<0.01). Post-menopausal women had significantly less mid thigh

muscle amounts than pre-menopausal women(p<0.01). Table 18 shows the

values of leptin, TAS and CRP in the pre- and the post-menopausal women.

The differences in the values of leptin and TAS between the different

menopausal status were insignificant. The post-menopausal women had

significant higher values than pre-menopausal women(p<0.01).


Total cholesterol 192 ± 5.26 214 ± 5.00**

Triglyceride 144 ± 13.5 152 ± 6.60

HDL cholesterol 47.0 ± 1.70 46.0 ± 1.54

LDL cholesterol 116 ± 4.25 138 ± 4.34**

Atherogenic index 3.23 ± 0.17 3.87 ± 0.17*

Fasting level

Glucose(㎎/㎗) 88.7 ± 4.57 95.1 ± 4.07

Insulin(μU/ml) 11.2 ± 0.92 12.0 ± 0.77

Free fatty acid(μU/ml) 615 ± 63.0 779 ± 49.1

Response area(×hr)

Glucose area 269 ± 14.9 330 ± 15.4*

Insulin area 107 ± 11.8 108 ± 9.04

Free fatty acid area 693 ± 68.9 920 ± 63.9*

HOMAIR1

2.56 ± 0.33 2.86 ± 0.23

HOMAβ cell function2

191 ± 46.1 174 ± 27.0

- 50 -

Table 17. Differences in fat and muscle area at different levels of a body

between pre- and post-menopausal participants before study

Mean±S.E.

§p<0.1, *p<0.05, **p<0.01, ***p<0.001 compared with the pre-menopausal participants

Table 18. Differences in Leptin, TAS, and CRP values between pre- and

post-menopausal participants before study

Mean±S.E.

**p<0.01 compared with the pre-menopausal participants



Total fat(㎠) 268 ± 14.3 293 ± 7.77§

Visceral fat(㎠) 105 ± 7.21 123 ± 3.22**

Subcutaneous fat(㎠) 163 ± 8.80 170 ± 5.43

V/S ratio 0.65 ± 0.04 0.74 ± 0.02*


Total fat(㎠) 305 ± 13.2 334 ± 8.34§

Visceral fat(㎠) 90.3 ± 5.79 113 ± 3.81**

Subcutaneous fat(㎠) 214 ± 9.66 220 ± 6.61

V/S ratio 0.43 ± 0.03 0.54 ± 0.02**

Calf

Fat(㎠) 26.8 ± 1.22 26.0 ± 0.90

Muscle(㎠) 63.0 ± 2.11 61.1 ± 1.20

Mid thigh

Fat(㎠) 80.6 ± 3.61 78.1 ± 2.62

Muscle(㎠) 110 ± 2.66 100 ± 1.70**


Leptin(ng/ml) 13.3±1.07 14.2±1.06

TAS(mmol/L) 1.35±0.01 1.33±0.03

CRP(mg/dl) 0.12±0.02 0.23±0.06**

- 51 -

4.8.2 Comparison of Clinical Characteristics, TCI, and TEE in Different

Menopause Status of Case Group

Table 19 presents the clinical characteristics, total calorie intake(TCI)

and total energy expenditure(TEE) of the case group subjects with menopausal

status. Weight, BMI, body fat %, waist circumference and hip circumference

were significantly reduced in both group. Total calorie intake amounts were

significantly reduced in both status(p<0.01). Total energy expenditure was

slightly increased in the pre-menopausal women and slightly decreased in the

post-menopausal women. Insignificant differences were found in total energy

expenditure in both status.

Weight reduction of the pre-menopausal(p<0.01) women and the

post-menopausal(p<0.001) women was significant. Average weight loss of the

pre-menopausal women and the post-menopausal women were 1.8kg and 1.9kg,

respectively. These weight reductions were similar with the average of the

whole group weight reduction. BMI levels of the two groups were significantly

decreased(p<0.001). Body fat % values were also significantly decreased in both

group. Waist circumferences were reduced in both status. The pre-menopausal

women showed insignificant reduction and the post-menopausal women

showed significant reduction(p<0.01) in the waist circumference. The hip

circumferences were reduced significantly in pre-(p<0.01) and post-menopausal

status(p<0.001). The waist-to-hip ratios were insignificantly reduced in both

group. In blood pressure, both group showed insignificant change in systolic

and diastolic blood pressure.

- 52 -

Table 19. Clinical characteristics, total calorie intake and total energy

expenditure of the case group subjects in different menopausal

status

Mean±S.E.

§p<0.1, *p<0.05, **p<0.01, ***p<0.001 compared with initial value in each group

1Total calorie intake

2Total energy expenditure

pre-menopausal(n=10) post-menopausal(n=14)


Age(yrs) 44.3±3.21 56.6±1.08

Height(cm) 156.9±2.48 158.4±0.75

Weight(Kg) 66.8±2.70 65.0±2.57**

69.2±1.71 67.2±1.69***

BMI(Kg/㎡) 27.1±0.57 26.3±0.56***

27.6±0.64 26.8±0.62***

Body fat % 39.6±1.56 35.8±1.01* 38.2±1.29 37.1±1.28*

LMB(Kg) 40.9±1.29 41.4±1.43 42.5±0.89 42.4±0.82

Waist(cm) 89.6±3.32 85.2±2.40 94.7±2.10 91.5±1.98**

Hip(cm) 99.6±1.26 96.9±1.16**

103±1.31 101±1.17***

WHR 0.90±0.03 0.88±0.02 0.91±0.01 0.90±0.01

SBP(㎜Hg) 121±3.01 125±4.82 134±3.49 132±3.60

DBP(㎜Hg) 77.3±2.40 76.2±2.88 81.1±2.41 81.8±2.51

TCI1

2276±53 2240±48**

2227±33 2175±37**

TEE2 2118±47 2124±46 2115±39 2111±37

- 53 -

4.8.3. Comparison of Serum Lipid Profile in Different Menopausal Status of

Case Group

Table 20 shows the serum lipid profiles of pre-menopausal and

pro-menopausal subjects in the case group over the 8 week study program.

Triglyceride levels were significantly decreased in the post-menopausal

subjects(p<0.1). After the 8 week study, the total cholesterol levels were less

than initial levels in both status with not significant differences. HDL

cholesterol levels were increased insignificantly in both status. The changes of

LDL cholesterol values were insignificant in both subjects. Atherogenic indices

were significantly decreased in the pre-menopausal(p<0.1) The Post-menopausal

women showed insignificant decrease of atherogenic index. HDL-to-total

cholesterol ratio was significantly increased in the pre-menopausal women.

Table 20. Serum lipid profiles of the case group subjects in different

menopausal status

Mean±S.E.

§p<0.1 compared with initial value in each group

1Atherogenic index=(Total cholesterol-HDL cholesterol)/HDL cholesterol

2HDL/Total cholesterol ratio



Total cholesterol(㎎/㎗) 187±5.95 180±10.1 212±7.54 210±5.25

Triglyceride(㎎/㎗) 156±10.65 154±13.0 158±10.62 148±8.23§

HDL cholesterol(㎎/㎗) 42.1±1.89 43.3±1.66 46.2±2.62 47.5±2.39

LDL cholesterol(㎎/㎗) 114±5.23 105±9.24 131±6.79 137±6.15

Atherogenic index1 3.56±0.30 3.22±0.32§ 3.80±0.31 3.75±0.21

H/TC ratio2

0.23±0.01 0.25±0.02§

0.23±0.01 0.23±0.01

- 54 -

4.8.4. Comparison of Serum Glucose, Insulin, and Free Fatty Acid in

Different Menopausal Status of Case Group

Table 21 presents the serum glucose, insulin and free fatty acid

concentrations of the case group subjects during the oral glucose tolerance test

in different menopausal status.

The post-menopausal women had significant reduction in fasting

glucose levels and glucose area(p<0.1). The pre-menopausal women showed

insignificant decrease in the fasting glucose levels and glucose response area.

Fasting free fatty acid levels and their area were insignificantly decreased in

both groups. Changes of the fasting insulin levels and their response area were

insignificant in both status. Insulin resistance and sensitivity were not

significantly improved in both status.

Table 21. Concentrations of serum the glucose, insulin and free fatty acid

during the oral glucose tolerance test in different menopausal status

of the case group

Mean±S.E.


1{fasting insulin(μU/㎖)×fasting glucose(m㏖/L)}/22.5

2{20×fasting insulin(μU/㎖)}/{(fasting glucose(m㏖/L)-3.5}



Fasting level

Glucose(㎎/㎗) 92.4±12.3 89.2±14.1 94.2±6.42 87.9±4.75*

Insulin(μU/ml) 12.6±1.65 11.4±2.12 11.9±0.96 12.5±1.19

Free fatty acid(μU/ml) 613±136 484±128 735±67.8 672±61.7

Response area(×hr)

Glucose area 276±40.3 285±45.1 312±22.3 294±19.6*

Insulin area 129±31.2 119±32.9 111±14.2 111±14.6

Free fatty acid area 957±156 787±119 849±88.3 753±64.0

HOMAIR1 3.15±0.84 2.51±0.56 2.85±0.34 2.85±0.34

HOMAβ cell function2

115±111 317±51.5 140±49.9 211±68.4

- 55 -

4.8.5. Comparison Of Fat and Muscle Area at Different Levels of Body in

Different Menopausal Status of the Case Group

Table 22 shows that both abdominal subcutaneous and intra-abdominal

fat were greater in the post-menopausal women compared with the

pre-menopausal women. The reduction of abdominal fat in different

menopausal status were different with weight reduction.

At L1 level, total fat, visceral fat, subcutaneous fat, visceral to

subcutaneous fat ratio were insignificantly decreased in the pre-menopausal

Table 22. Fat and muscle area at different levels of the body in different

menopausal status of the case group

Mean±S.E.

§p<0.1,

*p<0.05,

**p<0.01,





Total fat(㎠) 267±16.7 257±17.7 300±13.7 295±14.4

Visceral fat(㎠) 110±10.9 102±9.28 124±4.95 127±6.56

Subcutaneous fat(㎠) 158±12.1 155±12.6 175±10.2 168±10.4*

V/S ratio 0.72±0.09 0.68±0.07 0.74±0.03 0.79±0.04§


Total fat(㎠) 303±19.8 300±19.5 345±15.0 325±15.8***

Visceral fat(㎠) 97.6±9.28 93.7±9.78 117±6.17 105±7.15**

Subcutaneous fat(㎠) 206±16.5 206±16.4 223±6.61 220±12.7§

V/S ratio 0.49±0.05 0.47±0.06 0.55±0.04 0.50±0.04§

Calf

Fat(㎠) 27.3±2.16 26.4±2.29 27.4±1.60 26.4±1.32**

Muscle(㎠) 67.4±3.51 67.1±3.84 63.0±2.17 62.7±2.24

Mid thigh

Fat(㎠) 75.1±5.49 76.7±6.35§

81.0±4.09 80.2±3.98

Muscle(㎠) 112±5.56 105±4.26* 100±2.40 100±2.23

- 56 -

group. Post-menopausal group showed significant decrease of subcutaneous

fat(p<0.05) and visceral to subcutaneous fat ratio(p<0.1) at L1 level.

The pre-menopausal women had insignificant reduction in total fat,

visceral fat, subcutaneous fat and visceral to subcutaneous fat ratio at L4 level.

The pre-menopausal women had significant reduction in total fat(p<0.001),

visceral fat(p<0.01), subcutaneous fat(p<0.1) and visceral to subcutaneous fat

ratio(p<0.1) ar level 4.

Different patterns were observed in the reduction of thigh and calf

amounts with menopausal status. Calf fat was decreased significantly in the

post-menopausal(p<0.01) and insignificantly in the pre-menopausal women. The

pre-menopausal women had significant reduction in mid thigh muscle(p<0.05).

The post-menopausal women had insignificant reduction in mid thigh fat and

muscle.

- 57 -

4.8.6. Comparison of Leptin, TAS, and CRP Values in Different Menopausal

Status of the Case Group

Table 23 presents the values of leptin, TAS and CRP of the case

group subjects in different menopausal status. Leptin concentration was higher

in the pre-menopausal than in the post-menopausal[97]. Leptin levels were

reduced significantly in the post-menopausal subjects. The concentrations of

TAS were also higher in the pre-menopausal than in post-menopausal and

increased insignificantly in both group. The pre-menopausal group had lower

CRP concentrations compar with the post-menopausal group. The CRP levels

were decreased significantly in post-menopausal subjects(p<0.05).

Table 23. Leptin, TAS and CRP values of the case group subjects in

different menopausal status

Mean±S.E.

§p<0.1, *p<0.05, **p<0.01, ***p<0.001 compared with initial value in each group



Leptin(ng/ml) 14.8±2.45 11.64±1.41 14.1±1.66 10.5±1.03§

TAS(mmol/L) 1.35±0.02 1.37±0.02 1.27±0.07 1.34±0.02

CRP(mg/dl) 0.13±0.03 0.15±0.03 0.23±0.13 0.14±0.04*

- 58 -

4.8.7. Correlation between Menopausal Transition & Body Composition, and

between Menopause Transition & Metabolic Profiles

Table 24 presents the correlation between the anthropometric variables

and the menopause transition, and the correlations between the metabolic

profiles and the menopause transition. The subjects would have significant high

visceral fat at L1 and L4 levels with the menopause transition(p<0.01). In some

studies, the high waist-to-hip ratio in post-menopausal group has been

attributed to wasting of leg muscle and increased visceral fat area with

menopausal. This study also showed larger visceral fat area and smaller leg

muscle amounts in the post-menopausal subjects compare with the

pre-menopausal subjects. The menopausal transition was significantly associated

with increased central adipositiy(p<0.01). Furthermore, the menopause transition

appears to promote the selective accumulation of fat in the intra-abdominal

compartment. In metabolic profiles, total cholesterol was significantly related

with the menopause transition(p<0.01).

Table 25 presents the correlations between the changes of body

composition and menopause transition, and the correlations between the

metabolic profiles and the menopause transition. All the variables were not

significantly related with menopausal transition. This result was not accorded

with the results of the comparison between pre- and post-menopausal women.

- 60 -

5. DISCUSSION

Dietary influences on fatness are complicated, but most experimental

and observational evidence tends to incriminate dietary fat rather than

carbohydrate or protein. This study used chitosan and HCA to decrease the fat

intake and fat absorption during the program. As table 2 shows, total calorie

intake was significantly decreased and the total energy expenditure was not

significantly increased in the case group with supplementation. Those

supplements were acted to decrease the food intake and fat absorption in the

body.

This present study examined the effects of moderate weight loss

induced by diet and supplementation of chitosan and HCA on regional body

composition, and blood levels of lipids, insulin, leptin and c-reactive protein.

Subjects were studied before and after weight loss, which allowed us to assess

the changes in several cardiovascular disease risk factors in response to an 8

week weight loss program. Such an approach provides information on the

short-range benefits of weight loss as it relates to CV risk, which may be

useful in the design/development of long-term therapeutic strategies to combat

obesity and CVD. This study was further investigated the factors that were

likely to be implicated in the menopausal state in physical and metabolic

parameter levels.

As a group, the women in this study demonstrated significant

reductions in CVD risk factors such as total body fat %, BMI, WC, hip

circumference, fat amounts at the L1 and L4 vertebrae, and serum

concentrations of triglyceride, fasting glucose, leptin and CRP with the weight

reduction(1.9kg; about 3% of intial weight). On the other hand, other CV risk

factors including total cholesterol, serum HDL cholesterol, LDL cholesterol,

- 61 -

WHR, fasting insulin levels, and systolic and diastolic blood pressure were not

significantly altered by the weight loss.

Most variables measured in this study were in the normal range

except WC and WHR. Improvement of WC and WHR with the weight

reduction were not enough to be in the healthy criteria. Their cut-off points in

CVD criteria are WC<80cm and WHR<0.88. The WC was decreased

significantly but the WHR was not significantly decreased with significant

reduction of hip circumferences. Pre-menopausal subjects, who had significant

reduction in hip circumference, and post-menopausal subjects, who had

significant reduction in WC and hip circumference, showed insignificant

reduction of WHR.

Recently, WC is found to be a better estimate of abdominal visceral

adipose accumulation than WHR and may be a better predictor of multiple

cardiovascular risk factors than WHR using computed tomographic scanning to

measure adipose tissue[97].

In this study, weight, BMI, WC, body fat % and the abdominal

visceral fat were closely related to the cardiovascular risk factors of middle

aged overweight or obese women. With Table 8, 10 and 12, it was observed

that abdominal fat variables were affected by weight reduction. In the

beginning, the weights of subjects were significantly intercorrelates with other

physical parameters such as BMI, body fat %, WC, hip circumference, and fat

amounts of L1 and L4 vertebrae, thigh and calf(p<0.01). The result of

computerized tomography scanning of L1 and L4 level fat amounts showed the

significant relation with weight, BMI and body fat % at the baseline(p<0.01).

After the study, the weight changes were significantly associated with the

changes of BMI and hip circumference(p<0.01). Visceral fat reduction of L4

vertebra was significantly associated with the weight reduction(p<0.05). The

average weight reduction was not significantly associated with the changes of

- 62 -

the mean WC, and WHR, but significantly related to reductions of BMI and

hip circumferences(p<0.01). In this study, all the participants of the case group

women had relatively more reduction of WC than hip circumferences although

the differences of WHR were insignificant. Both decreased waist and hip

circumferences reflect decreased total body fat %.

The relationships are statistically insignificant between the changes in

CVD associated anthropometric parameters and the changes in total cholesterol

and LDL levels. With Table 11, most metabolic profile changes were not

affected with weight reduction in this study. Only the leptin reduction was

relevant to the abdominal fat reduction. HDL concentration was not only in

the normal range but also not significantly changed with weight reduction.

This was probably because present weight loss was achieved solely by energy

restriction, short term study and small weight loss. The HDL/total cholesterol

ratio was not affected by the changes of weight. In this study, the associations

were not significant between the changes in weight and the changes in the

levels of triglyceride and the fasting glucose. No association was found in the

changes of BMI with the changes of the triglyceride and fasting glucose

concentrations.

Usually, weight change is statistically significantly associated with

systolic and diastolic blood pressure. More than 2kg of weight loss caused

least increasing systolic blood pressure and decreasing diastolic blood pressures

in a 2 years follow-up study[37]. In this study, little changes of systolic and

diastolic blood pressure were found although case group participants had

around 130mmHg of systolic and 80mmHg of diastolic blood pressure.

Moderate weight loss of short-term might be not enough to change the blood

pressure.

The comparison of pre-menopause and post-menopause participants in

the beginning showed some differences. Body fat % and lean body mass were

- 63 -

not significantly different between pre- and post-menopausal women.

Anthropometric variables were similar between different menopause state. The

significant differences were the increased abdominal fat and systolic blood

pressure, the decreased mid-thigh muscle, and metabolic changes with the

menopause transition.

The accumulation of body fat is accelerated during or directly

following the menopause transition[98]. Greater intra-abdominal and abdominal

subcutaneous fat was found in the post-menopausal compared with the

pre-menopausal subjects. Menopause was clearly associated with an increase in

intra-abdominal fat. Age would influence the increase in intra-abdominal fat.

This study did not compare the abdominal fat between pre-menopausal and

post-menopausal women with similar ages. But the results of this study

indicate that the menopause transition is associated with a preferential storage

of fat in the intra-abdominal compartment. Changes at the cellular level, such

as increased lipoprotein lipase activity or decreased lipolysis, that result from

estrogen deficiency and increased androgenicity induced by the menopause

transition, may explain the redistribution of fat to the intra-abdominal

depot[99].

Total cholesterol &, LDL cholesterol and atherogenic index were

significantly higher in the post-menopausal women compare with the

pre-menopausal(p<0.01). Glucose area and free fatty acid area in the glucose

tolerance test response were larger in the post-menopausal compare with the

pre-menopausal(p<0.05). These findings support that the menopause

transition-associated increase in total and visceral adiposity may contribute to

the increase in the levels of the triglyceride, total cholesterol, LDL and CRP

with age. In other words, the post-menopausal women have more CV risk

profiles than the pre-menopausal women.

During the weight loss program, pre- and post-menopausal women

- 64 -

had similar weight reduction. Although the weight loss of each group was

similar with the whole group weight loss, the changes in pre-menopausal

women were different with the changes in the post-menopausal women in

some measurements. The post-menopausal group showed significant reduction

of abdominal fat at L1 and L4 vertebrae, but the pre-menopausal group

showed insignificant reduction of abdominal fat at L1 and L4 vertebrae. The

levels of triglyceride, HDL, leptin, fasting glucose & CRP and glucose response

area were significantly changed in the post-menopausal women, but not in the

pre-menopausal participants.

The present study examined the effect of weight reduction on the

anthropometric and metabolic profiles before and after study, and the

relationships between anthropometric measurements and metabolic parameters.

For 8 weeks, decreases in total energy intake caused significant decreases in

body weight, BMI, body fat %, WC, hip circumferences, the levels of

triglyceride, fasting glucose, leptin & CRP, abdominal fat in L1 and L4

vertebrae and calf fat. Differences in the decreases in different parameters

between the pre- and post-menopausal women seem to influence the decreases

in fat distribution and the changes in lipid profiles. Weight reduction was

related significantly with BMI, hip circumferences and visceral fat of L4

vertebra.

There was a report which explained that weight loss induced by diet

alone resulted in less fat loss (69% of total weight loss) compared with weight

loss induced by diet plus endurance and resistance training which resulted in

greater fat loss (97% of total weight loss) in overweight men[100]. Results from

studies using women have shown that combined resistance training and dieting

not only attenuates but also maintains or increase fat-free mass[101,102]

In conclusion, the changes in certain measurements reflected the

independent effects of weight loss. Although all the case group subjects were

- 65 -

remained into the overweight after the 8 week program, 1.9kg of weight loss

affected CV risk factor measurements such as BMI, WC, triglyceride, abdominal

fat and CRP. When analyzed the results In terms of pre- & post-menopausal

women, the effects of weight reduction on CV risk factors were greater with

weight reduction could be due to the short-term duration of the study, the

nature of the weight loss program, insufficient number of subjects or the fact

that baseline values for many subjects were within the normal range for adults.

Longer duration would result in significant improvement in glucose and insulin

concentrations in the present diet program. If endurance and heavy resistance

exercise training were included, greater relative losses in fat and preservation

of lean tissue were expected. Since energy balance was restored at about three

months in most subjects. In the future, gradual loss of weight combining diet

and exercise for about 12 weeks or longer would be better to get more

benefits on the CV risk factors.

- 66 -

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국문요약

체중감소가 심혈관 질환의 위험요소에 미치는 효과

최근 경제성장과 함께 생활이 편리해짐에 따라 신체활동량의 감소와

식생활의 서구화로 비만의 유병률이 증가하고 있으며 그에 따른 고혈압,

이상 지질혈증 환자의 증가와 함께 심혈관 질환이 사망순위 1위를 차지

하고 있다(2000, 보건통계청).

여성에게 있어 체중은 심혈관 질환에 이환되는 잠재적 척도이며 체

중이 증가하면서 혈압상승과 HDL저하 및 LDL과 중성지방의 증가를 가

져와 심혈관 질환의 위험요소를 상승시킨다.

본 연구에서는 71명의 비만도 110%이상의 과다한 체중의 건강한 중

년여성을 대상으로 실험군(34명)과 대조군(37명)으로 나누어 chitosan과

HCA가 주 성분인 제재를 8주간 하루에 3회 2캡슐씩 복용시켜 지방섭취

와 그 흡수를 낮춤으로써 체중 감소를 유도 하 다. 모든 인체 계측과

혈액 검사를 통한 대사측정 그리고 lumber spine의 1번과 4번에 해당하

는 척추의 가운데를 횡단하는 컴퓨터 단층 촬 을 0주와 8주 2회에 걸쳐

실시했으며 그 결과의 비교로서 체중감소와 그에 따르는 변화를 연구하

다. 또한 대상자중 폐경군(41명)이 포함되어있어 비폐경군(30명)과 인

체계측, 혈액검사와 컴퓨터 단층촬 결과를 비교하 으며 실험군에 포

함되어있는 폐경군(14명)과 비폐경군(10명)의 체중감소로 인한 변화를 비

교 분석하 다.

대상자들이 연구원들의 지도에 따라 보고한 식품섭취와 활동량을 분

석하 다. 그 결과 전체 대상자에서 연구 시작과 후의 비교에서 활동량

의 유의적인 변화는 없었으나 실험군에서 식품섭취량의 유의적인 에너지

섭취 감소가 나타났고(p<0.001), 그에 따라 평균 1.9kg의 유의적인 체중

감소를 보 다(p<0.001). 대조군에서는 에너지섭취와 체중의 유의적인 감

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소 현상이 없었다. 실험군에서 체중감소와 더불어 인체계측에 BMI와 허

리둘레, 엉덩이둘레의 유의적인 감소가 나타났고 체지방 감소와 특히 컴

퓨터 단층 촬 의 결과로 L1과 L4 수준에서 피하지방 및 내장지방의 감

소가 유의적으로 나타났다(p<0.001). 혈액분석 결과로는 중성지방과 공복

혈당이 유의적으로 감소하 고(p<0.05) 비만유전 단백질인 leptin(p<0.01)

과 심혈관 질환에 관계하는 염증 민감 지표인 CRP가 유의적으로 감소하

다(p<0.05). 혈압은 유의적인 변화를 보이지 않았다.

체중감소로 인한 상관관계 연구에서는 본 연구의 시작 시 체중을

비롯한 모든 인체계측 값이 서로 유의적인 상관관계를 보 으며(p<0.01)

대사에 관한 측정값은 leptin과 insulin 및 insulin 저항성 그리고 혈압이

체중과 복부지방에 유의적인 상관관계를 보 다(p<0.01). 체중감소와 그

로인한 인체계측의 변화와의 상관관계는 BMI와 엉덩이 둘레, 복부지방

의 감소가 유의적으로 나타났으며(p<0.01) 대사측정값은 leptin의 감소만

이 체중이 감소하면서 나타나는 복부지방 감소와 유의적인 관계를 보

다(p<0.05). 체중감소 후 실험군의 인체계측과 대사측정값과의 상관관계

는 연구 시작 시의 상관관계와 비슷하게 나타났다.

폐경군과 비폐경군의 비교에서는 비폐경군의 연령이 유의적으로 높

았다(p<0.001). 체중과 BMI, 체지방 백분율, 허리둘레 엉덩이 둘레 등의

인체 계측치는 두 군이 비슷하 지만 심장 수축 혈압과 혈액분석의 결과

중 총 콜레스테롤과 LDL 콜레스테롤이 폐경군에서 유의적으로 높았다

(p<0.01). 동맥경화지수와 내당검사로 인한 혈당 및 유리지방산의 반응

면적도 비폐경군에 비하여 폐경군이 유의적으로 높았다(p<0.05). L1과

L4 수준에서 폐경군이 유의적으로 더 많은 지방을 갖고 있음을 보 으

며(p<0.1) CRP도 폐경군에서 유의적으로 높은 값을 보 다(p<0.01). 이

러한 차이를 갖고 있는 두 군에서 체중감소로 인한 변화 결과에서는 에

너지 섭취량을 비롯한 체중, BMI, 체지방 백분율, 엉덩이 둘레가 두 군

에서 유의적인 감소를 보 다(p<0.01). 허리둘레도 두군 모두 감소하 으

나 비폐경군의 감소는 유의적이지 않았고 폐경군의 감소는 유의적이었다

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(p<0.01). 혈액분석 결과는 비폐경군은 동맥경화지수와 HDL/TC가 유의

적으로 감소하 고(p<0.1) 폐경군은 중성지방이 유의적으로 감소하 다.

내당검사의 결과는 폐경군이 공복혈당과 혈당반응면적의 유의적인 감소

를 보 다(P<0.05). 복부지방은 폐경군에서 유의적인 감소를 보 고

(p<0.001) 종아리는 폐경군에서(p<0.01) 대퇴부는 비폐경군에서(p<0.1)

유의적인 감소가 있었다. Leptin(p<0.1)과 CRP(p<0.05)도 폐경군에서 유

의적인 감소를 보 다. 결과적으로 심혈관 질환 위험요소를 더 많이 갖

고 있는 폐경군에서 체중감소로 인한 개선이 더 많이 이루어졌다.

폐경유무가 중년여성에 미치는 향의 연구로 상관관계를 살펴 본

결과에서는 폐경이 복부지방과 총 콜레스테롤 농도와 유의적인 상관관

계를 보 으며(p<0.01) 체중감소로 인한 인체 변화에는 유의적인 상관관

계를 보이지 않았다.

본 연구를 통하여 적은 양의 체중감소 이지만 여러 심혈관 위험요소

의 개선을 볼 수 있었다. 하지만 더 오랜 기간과 운동을 겸한 체중감소

를 시도 한다면 더 많은 위험요소의 유의적인 개선을 기대할 수 있다고

생각되며 폐경군과 비폐경군의 연구에서도 각 군에 비슷한 인원의 더 많

은 대상자가 참여한다면 더 나은 비교 분석의 결과를 얻으리라 보여진

다.

핵심되는 말: 비만/심혈관 질환/체중감소/복부지방/인체계측/심혈관 질환

위험요소/폐경

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