Fat Accumulation and Obesity-related Cardiovascular Risk Factors in Middle-aged Japanese Men and Women

ORIGINAL ARTICLE Fat Accumulation and Obesity-related Cardiovascular Risk Factors in Middle-aged Japanese Men and Women Miwa Ryo 1, Tohru Funahashi 1, Tadashi Nakamura 1, Shinji Kihara 1, Kazuaki Kotani 2, Katsuto Tokunaga 3, Yuji Matsuzawa 4 and Iichiro Shimomura 1 Abstract Objective A cluster of multiple risk factors has been noted to constitute the background of cardiovascular disease. The purpose of this study was to evaluate the relationship between the visceral fat area (VFA) or subcutaneous fat area (SFA) and a cluster of obesity-related cardiovascular risk factors, including hyperglycemia, dyslipidemia and elevated blood pressure, in middle-aged Japanese men and women. Methods A total of 571 subjects (m=434; f=137; age: 53±9 years) who underwent health examinations with evaluations of body fat distribution using computed tomography scans and assessments of 75-g oral glucose tolerance tests were enrolled in this study. Results The VFA and SFA were linearly correlated with the number of risk factors in both men and women. The area under the receiver-operating characteristic curve of VFA (m=.741, f=.763) was significantly higher than that of SFA (m=.636, f=.689) with respect to the clustering of risk factors (one or more). The men exhibited larger VFA values and smaller SFA values than the women in similar body mass index (BMI) categories. Men with a VFA of 1 cm 2 irrespective of BMI and women with a VFA of 1 cm 2 and a BMI of 25 kg/m 2 demonstrated a high prevalence of diabetes mellitus and impaired glucose tolerance. Men and women with a VFA of 1 cm 2 irrespective of BMI demonstrated a high prevalence of type IIb dyslipidemia. Conclusion These results suggest that the absolute value of VFA rather than SFA is more closely associated with a cluster of risk factors irrespective of sex and is a good marker for selecting subjects to whom weight reduction should be recommended in order to prevent cardiovascular disease in the general population. Key words: visceral fat, metabolic syndrome, glucose tolerance, dyslipidemia (Intern Med 53: 299-35, 214) (DOI: 1.2169/internalmedicine.53.9476) Introduction Preventing cardiovascular disease (CVD) is an important health issue in industrial countries. We introduced the computed tomography (CT) scan method for precisely evaluating body fat in obese subjects (1), which enabled clinicians to evaluate the amount of intra-abdominal visceral fat for the first time, and found that the accumulation of visceral fat rather than the total mass of body fat is more closely associated with the development of obesity-related disorders, including glucose intolerance, hypertriglyceridemia (2), elevated blood pressure (3), cardiac dysfunction (4) and coronary artery disease (5). Abdominal obesity [an increased waist to hip ratio: (W/H)] has been proposed to be a high risk factor of obesity associated with the development of CVD frequently accompanying cardiometabolic risk factors in Western countries (6-8). In general, Japanese individuals, especially women, have a smaller hip circumference than other ethnic populations worldwide. Therefore, the W/H has not been adopted as a marker of high-risk obesity in Japanese (9). We propose that the visceral fat area (VFA) to subcutaneous fat area (SFA) ratio (V/S) is a better marker in obese Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Japan, Kenkou Club, Sekiyama Clinic, Japan, Itami City Hospital, Japan and Sumitomo Hospital, Japan Received for publication December 6, 212; Accepted for publication August 27, 213 Correspondence to Dr. Miwa Ryo, ryomw@gaia.eonet.ne.jp 299

Intern Med 53: 299-35, 214 DOI: 1.2169/internalmedicine.53.9476 Japanese subjects. Visceral fat comprises metabolically active adipose tissue. It is located in the mesentery and omentum, provides fatty acids and glycerol to the liver via the portal vein and secretes adipocytokines and other vasoactive substances that can influence the risk of developing metabolic syndrome. Excess visceral fat accumulation results in adipocyte dysfunction, i.e., the overproduction of plasminogen activator inhibitor type 1 and tumor necrosis factoralpha, and the underproduction of defensive adipocytokines, such as adiponectin (1-12). We previously demonstrated that the amount of visceral fat is rapidly reduced with weight reduction (13) and that improvements in elevated blood pressure and hypertriglyceridemia are closely associated with the reduction of visceral fat (14). We also previously reported that a decrease in visceral fat achieved within one year is correlated with a decrease in the number of metabolic risk factors (raised blood pressure, dyslipidemia and glucose intolerance) (15, 16) and an increase in the serum level of adiponectin (17). These lines of evidence suggest that reducing the amount of visceral fat is beneficial for improving obesity-related disorders, possibly preventing CVD. This concept has also been adapted to mildly obese or nonobese overweight subjects with the clustering of risk factors known as metabolic syndrome (MetS). In the current study, we investigated the relationship between the VFA or SFA and a cluster of obesity-related risk factors and analyzed glucose tolerance and phenotypes of dyslipidemia in middle-aged Japanese subjects recruited from the general population. Participants Materials and Methods The study group comprised 571 Japanese subjects [434 men (53±9 years), 137 women (54±8 years)] who underwent medical health checkups at institutions that participated in the Japanese Visceral Fat Syndrome (J-VFS) Study Committee of the Ministry of Health and Welfare of Japan. Informed consent was obtained from all subjects following the approval of the ethics committee of Osaka University. Each subject underwent both an oral glucose tolerance test (OGTT) and an evaluation of body fat distribution using a CT scan. The medical health checkup program known as Ningen (Human)-Dock aims to promote public health through the early detection of disease and risk factors. Among the study population, 36 (6.3%), 24 (4.2%) and 17 (3.%) subjects were under treatment for hypertension, dyslipidemia and diabetes mellitus (DM), respectively. Diabetic subjects treated with insulin were not included in this study. All subjects were not clinically normal; however, most were representative of the general or health conscious Japanese population. Anthropometry and laboratory measurements Anthropometric measurements were obtained in the standing position. The body mass index (BMI) was calculated as the weight divided by the square of the height in meters. Waist circumference (WC) was measured at the umbilical level in the late exhalation phase while standing, as previously reported (1). Blood pressure was measured in the sitting position. The CT scans were performed in the routine supine position. The VFA and SFA were measured on CT cross-sectional scans obtained at the umbilical level in the supine position (18) using a commercial software program based on the Japanese guidelines of obesity treatment (Japan Society for the Study of Obesity, in Japanese). Laboratory measurements Blood was withdrawn after an overnight fast. The plasma glucose and insulin concentrations at, 3, 6 and 12 minutes following the ingestion of 75 g of glucose were determined according to the glucose oxidase method and doubleantibody radioimmunoassay, respectively. The sums of the glucose and insulin concentrations measured during the OGTT were calculated as Σ plasma glucose and Σ plasma insulin, respectively. Glucose tolerance was assessed according to the Japanese Diabetes Association criteria for 75 g- OGTT. Therefore, subjects with a fasting plasma glucose level of 126 mg/dl and/or plasma glucose level at two hours following the ingestion of a 75-g glucose load (2-hour plasma glucose) of 2 mg/dl were classified as having DM, and subjects with a fasting plasma glucose level of 11-126 mg/dl and/or a 2-hour plasma glucose level of 14-2 mg/dl were classified as having impaired glucose tolerance (IGT). Furthermore, subjects with a fasting plasma glucose level of <11 mg/dl and a 2-hour plasma glucose level of <14 mg/dl were classified as having normal glucose tolerance. Insulin resistance was estimated according to the homeostasis model assessment of insulin resistance (HOMA-IR), defined as: fasting plasma glucose (mg/dl) fasting plasma insulin (μu/l)/45. The serum total cholesterol and triglyceride concentrations were determined using enzymatic methods. The level of high-density lipoprotein (HDL) cholesterol was also measured using an enzymatic method following heparin and calcium precipitation. The phenotypes of dyslipidemia were defined as follows: type IIa, serum total cholesterol 22 mg/dl and triglyceride <15 mg/dl; type IIb, serum total cholesterol 22 mg/dl and triglyceride 15 mg/dl; type IV, serum total cholesterol <22 mg/dl and triglyceride 15 mg/dl. Assessment of risk factors We defined MetS according to the guidelines for the diagnosis of MetS in Japan (19), including abdominal obesity (a WC greater than or equal to 85 cm in men and greater than or equal to 9 cm in women) in addition to the presence of at least two of the following abnormalities: 1) hypertriglyc- 3

Intern Med 53: 299-35, 214 DOI: 1.2169/internalmedicine.53.9476 Table 1. Clinical Characteristics of the Study Subjects men (n=434) women (n=137) Age, years 53.±8.9 54.1±8.2 BMI, kg/m 2 23.5±2.8 22.7±3. WC, cm 85.1±7.4 78.2±9.2 VFA, cm 2 13.1±52.8 64.3±37.3 SFA, cm 2 112.9±5.2 159.4±72. Obesity (BMI 25kg/m 2 ),% 27.7 18.2 Visceral fat accumulation (VFA 1cm 2 ), % 47.7 16.1 Dyslipidemia, % (under treatment, %) 41.2 (3.9) 15.3 (5.1) Total cholesterol, mg/dl 198.1±31.6 26.8±32. Triglyceride, mg/dl 136.6±91.5 93.±46.1 HDL cholesterol, mg/dl 51.5±14.6 66.9±17.1 Hypertension, % (under treatment, %) 33.9 (6.5) 28.5 (5.8) Systolic blood pressure, mm Hg 122.8±16.9 116.8±2.4 Diastolic blood pressure, mm Hg 72.9±12. 68.4±14. Hyperglycemia, % (under treatment, %) 16.4 (3.5) 8. (1.5) Fasting plasma glucose, mg/dl 99.±19.9 94.9±22.3 Fasting plasma insulin, L 5.9±3.8 5.7±3.6 HOMA-IR 1.5±1.3 1.4±1. Metabolic syndrome, % 17.7 3.7 BMI: body mass index, WC: waist circumference, VFA: visceral fat area, SFA: subcutaneous fat area, HDL: high-density lipoprotein, HOMA-IR: homeostasis model assessment of insulin resistance, Continuous variables, results are presented as mean±sd or percent. p<.5, p<.1, p<.1, p<.1 by Mann-Whitney -test or chi-square test (compared with women) eridemia (a serum triglyceride level of at least 15 mg/dl) and/or low HDL cholesterolemia (a serum HDL cholesterol level of less than 4 mg/dl), 2) hypertension (a systolic blood pressure of at least 13 mmhg and/or diastolic blood pressure of at least 85 mmhg) and 3) high fasting glucose (a serum glucose level of at least 11 mg/dl). Subjects who received specific treatment(s) for each of the metabolic risk factors were considered to be positive for that factor. Statistical analysis Comparisons of variables and incidences between men and women were made using the Mann-Whitney U-test or chi-square test. Pearson s correlation coefficient was used to examine the association between the VFA or SFA and clinical parameters of metabolic syndrome. Comparisons of the mean number of risk factors and VFA or SFA and the mean values of VFA or SFA and BMI were made using the Kruskal-Wallis test for trends. The Mann-Whitney test was used to compare the mean number of risk factors between men and women in each category of VFA or SFA. The ability of the VFA and SFA to detect the clustering of risk factors (one or more) was examined using receiver-operating characteristic (ROC) curve analyses. Comparisons of the mean values of VFA and SFA between men and women in each category of BMI were made using the Mann-Whitney test. Scheffé s post hoc test was used to compare the prevalence of IGT, DM, type IIa dyslipidemia, type IIb dyslipidemia and type IV dyslipidemia with or without visceral fat accumulation (VFA 1 cm 2 ) or obesity (BMI 25 kg/m 2 ). All statistical analyses were performed using the StatView- J5. (SAS Inc.) software program. Results Clinical characteristics of the study participants The descriptive characteristics of the study participants are shown in Table 1. The BMI, WC and VFA values were higher and the SFA values were lower in men than in women. Visceral fat accumulation (VFA 1 cm 2 ) was identified in 47.7% of the men and 16.1% of the women. The systolic and diastolic blood pressures were higher in men than in women. The serum triglyceride levels were higher and the serum total cholesterol and HDL cholesterol levels were lower in the men than in the women. A total of 17.7% of the men and 3.7% of the women were diagnosed with MetS. Relationships between the VFA or SFA and each risk factor As shown in Table 2, simple regression analyses revealed that the systolic and diastolic blood pressure, levels of serum total cholesterol, triglycerides and fasting plasma insulin, Σ plasma glucose, Σ plasma insulin and HOMA-IR were positively and the HDL cholesterol level was negatively correlated with the VFA and SFA in men. The fasting plasma glucose level was positively correlated with the VFA but not SFA in men. In women, the systolic and diastolic blood pressure, levels of triglycerides and fasting plasma insulin, Σ plasma glucose and HOMA-IR were positively and the HDL cholesterol level was negatively correlated with the VFA and SFA. The total cholesterol and fasting plasma glucose levels and Σ plasma glucose were positively correlated with the VFA but not SFA in women. 31

Intern Med 53: 299-35, 214 DOI: 1.2169/internalmedicine.53.9476 Table 2. Correlation Coefficients of the Relationships between Visceral Fat Area, Subcutaneous Fat Area, and Various Parameters of the Metabolic Syndrome men (n=434) women (n=137) VFA SFA VFA SFA Systolic blood pressure.291.158.335.193 Diastolic blood pressure.39.145.285.252 Total cholesterol.165.17.21.132 Triglyceride.316.223.387.211 HDL cholesterol -.335 -.21 -.349 -.274 Fasting plasma glucose.285.67.35.116 Fasting plasma insulin.237.385.334.349 HOMA-IR.237.322.364.348 plasma glucose.352.128.283.78 plasma insulin.156.29.452.313 VFA: visceral fat area, SFA: subcutaneous fat area, HDL: high-density lipoprotein, HOMA-IR: homeostasis model assessment of insulin resistance, plasma glucose: sum of the glucose concentrations during the oral glucose tolerance test, plasma insulin: sum of the insulin concentrations during the oral glucose tolerance test p<.5, p<.1, p<.1, p<.1 by Pearson s correlation coefficients. A B mean number of risk factors 2. 1.5 1..5 men p<.1 women p<.1 mean number of risk factors 2. 1.5 1..5 men p<.1 women ns VFA (cm 2 ) M n 49 46 53 79 55 51 11 F n 4 26 3 19 13 9 SFA (cm 2 ) M n 25 24 58 68 95 54 11 F n 3 4 8 13 18 1 81 Figure 1. Relationships between the (A) VFA or (B) SFA and the mean number of risk factors; men (n=434), women (n=137). Risk factors: hyperglycemia, hypertriglyceridemia/low high-density lipoprotein-cholesterolemia and elevated blood pressure. The error bars represent 95% confidence intervals. Kruskal-Wallis test for trend. p<.5, p<.1, p<.1 according to the Mann-Whitney test. VFA: visceral fat area, SFA: subcutaneous fat area, M: men, F: women Relationships between the VFA or SFA and the cluster of risk factors The proportions of subjects with zero, one, two or more risk factors of hyperglycemia, hypertriglyceridemia/low HDL cholesterolemia and elevated blood pressure were 37.1%, 39.2% and 23.7% in men and 59.1%, 3.7% and 1.2% in women, respectively. The frequency of obesityrelated risk factors was higher in men than in women. As shown in Fig. 1, each group was divided into 2-cm 2 categories of VFA or SFA. The mean number of risk factors significantly linearly increased with the VFA (p<.1 for trend) and was more than 1. at approximately 1 cm 2 for VFA in both men and women (Fig. 1A). In men, the proportion of subjects within each VFA category was widely distributed, with 48% having a VFA greater than 1 cm 2. In contrast, in women, the distribution of VFA was shifted to smaller values, with the frequency of subjects with a VFA greater than 1 cm 2 being only 16%. The mean number of risk factors also increased with the SFA; however, the slope was more gentle (Fig. 1B). In women, the mean number of risk factors in each SFA category was less than that observed in men. In women, the mean number of risk factors did not reach 1., even in the largest category of SFA. The area under the ROC curve (AUC) for VFA and SFA with respect to detecting the clustering of risk factors (one or more) was.741 (95%CI.697-.782; p<.1) and 32

Intern Med 53: 299-35, 214 DOI: 1.2169/internalmedicine.53.9476.636 (95%CI.589-.681; p<.1), respectively, in men. In women, the AUC for VFA and SFA with respect to detecting the clustering of risk factors (one or more) was.763 (95%CI.683-.832; p<.1) and.689 (95%CI.64-.765; p<.1), respectively. Associations between the VFA or SFA and BMI Each group was divided into 1.5-kg/cm 2 categories of BMI (Fig. 2). The mean values of VFA and SFA significantly increased with BMI in both men and women (p<.1 for trend). The men exhibited larger VFA values and smaller SFA values than the women in each BMI category. Prevalence of MetS As shown in Fig. 3, the prevalence of MetS increased starting in the 4s in men, ranging from 17% to 24% between ages in the 4s and 7s. In contrast, the prevalence of MetSbegantoincreasestartingattheageof5byaless degree in women. VFA (cm 2 ) SFA (cm 2 ) 3 2 1 5 4 3 2 1 men p<.1 women p<.1 men p<.1 women p<.1 BMI M n 7 59 87 98 64 3 16 1 F n 36 29 24 23 11 5 4 5 Prevalence of IGT, DM and dyslipidemia Fig. 4 presents the prevalence of IGT, DM, type IIa dyslipidemia, type IIb dyslipidemia and type IV dyslipidemia with or without visceral fat accumulation (VFA 1 cm 2 )orobesity(bmi 25 kg/m 2 ). The prevalence of IGT prevalence of metabolic syndrome (%) 3 2 1 men women Figure 2. Relationships between the VFA or SFA and BMI; men (n=434), women (n=137). The error bars represent 95% confidence intervals. Kruskal-Wallis test for trend. p<.5, p<.1, p<.1 according to the Mann-Whitney test. VFA: visceral fat area, SFA: subcutaneous fat area, BMI: body mass index, M: men: F: women all -39 4-49 5-59 6-69 7-79 age (y) n M /F 434 / 137 37 / 6 98 / 32 2 / 69 91 / 32 8 / 2 Figure 3. Age-specific prevalence of metabolic syndrome; men (n=434), women (n=137). M: men, F: women prevalence (%) 4 3 2 1 men prevalence (%) 4 3 2 1 women IGT DM IIa IIb IV VFA < 1cm 2 BMI < 25kg/m 2 VFA < 1cm 2 BMI 25kg/m 2 VFA 1cm 2 BMI < 25kg/m 2 VFA 1cm 2 BMI 25kg/m 2 n M 193 /F 11 M 34 /F 14 M 121 /F 11 M 86 /F 11 Figure 4. Prevalence of IGT, DM, type IIa dyslipidemia, type IIb dyslipidemia and type IV dyslipidemia with or without visceral fat accumulation or obesity. Men (n=434), women (n=137). Scheffé post hoc test. p<.5, p<.1, p<.1. IGT: impaired glucose tolerance, DM: diabetes mellitus, IIa: type IIa dyslipidemia, IIb: type IIb dyslipidemia, IV: type IV dyslipidemia, VFA: visceral fat area, BMI: body mass index, M: men, F: women 33

Intern Med 53: 299-35, 214 DOI: 1.2169/internalmedicine.53.9476 and DM was higher in men with a VFA of 1 cm 2 irrespective of BMI and women with a VFA of 1 cm 2 and a BMI of 25 kg/m 2. The prevalence of type IIb dyslipidemia was significantly higher in the men with a VFA of 1 cm 2 irrespective of BMI than in those with a VFA of <1 cm 2 and a BMI of <25 kg/m 2. The men with a VFA of 1 cm 2 and a BMI of 25 kg/m 2 and the women with a VFA of <1 cm 2 and a BMI of 25 kg/m 2 exhibited a significantly higher prevalence of type IV dyslipidemia than those with a VFA of <1 cm 2 and a BMI of <25 kg/m 2. Discussion The accumulation of visceral fat is closely related to the development of obesity-related disorders. We previously demonstrated that significant correlations are observed between the V/S ratio and plasma glucose area after adjusting for oral glucose loading, the serum triglyceride level (2), blood pressure (3) and the cardiac function, independent of BMI (4). These results highlight the importance of accumulated visceral fat in the pathogenesis of obesity-related disorders and suggest a protective role of subcutaneous fat against overnutrition. A survey of 17, Japanese office workers revealed that the odds ratio of the risk of CVD was high among the subjects with multiple risk factors, such as obesity, hyperglycemia, hypertension and dyslipidemia (2). It is known that even mildly obese and overweight Japanese individuals are prone to develop obesity-related disorders. In addition, scientific researchers have found the dysregulated production of adipocytokines due to adipocyte dysfunction to be the molecular basis underlying the development of obesityrelated disorders (22, 22). Recently, the Visceral Fat Accumulation and Coronary Artery Disease Investigation in Japanese (VACATION-J) study revealed that an absolute VFA value of approximately 1 cm 2 is associated with the accumulation of obesity-related cardiovascular risk factors, irrespective of gender, age and BMI (23). Based on this clinical and scientific background, it has become important to effectively select subjects from the general population, including nonobese subjects, for body weight reduction in order to prevent CVD. In the present study, the VFA was linearly correlated with the number of obesity-related cardiovascular risk factors, irrespective of sex, in the general population. A ROC curve analysis revealed that the VFA was a significantly better indicator of the clustering of risk factors than the SFA in both men and women. The men had larger VFA values and smaller SFA values than the women at similar BMI values. In the International Day for the Evaluation of Abdominal Obesity study, a significant increase was observed in both men and women in the frequency of CVD, with a stronger relationship for WC than for BMI, across regions in 63 countries (24). The WC values were larger in women than in men with a similar frequency of CVD. The present study also found that the prevalence of DM diagnosed based on OGTT was high in the subjects with visceral fat accumulation irrespective of BMI. This result emphasizes the importance of evaluating the postprandial glucose and insulin levels in subjects with visceral fat accumulation. Substantial reports have demonstrated IGT determined based on the 2-hour plasma glucose concentration to be a risk factor for the development of CVD (25, 26). The diagnostic criteria for MetS do not include hypercholesterolemia (hyper-low-density lipoprotein (LDL) cholesterolemia) because MetS is considered to be a pathogenetic mechanism of CVD, independent of hyper-ldl cholesterolemia. The present study showed that subjects with visceral fat accumulation frequently have type IIb dyslipidemia as well as type IV dyslipidemia. Type III dyslipidemia resulting from high levels of chylomicrons and intermediatedensity lipoproteins, known as broad beta disease or dysbetalipoproteinemia, was not distinguished from other types of dyslipidemia in this study. It is possible that the combination of MetS with hypercholesterolemia increases the risk of CVD. One limitation of this study is that the enrolled subjects were health conscious enough to undergo both oral glucose challenge tests and evaluations of their body fat distribution using CT scans. 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