Katsuto Tokunaga

Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity.

The casual relationship between intraabdominal visceral fat accumulation and metabolic disorders was analyzed in 46 obese subjects (15 males, 31 females) having 34.1 +/- 5.5 of body mass index (BMI). The distribution of fat was determined by our CT scanning technique (Int J Obesity 7:437, 1983). The total cross-cut area, subcutaneous fat area, and intra-abdominal fat area was measured at the umbilical level. The fasting plasma glucose level, area under the plasma glucose concentration curve after oral glucose loading (plasma glucose area), fasting serum triglyceride level, and serum total cholesterol level were all significantly higher or otherwise greater in the group with intraabdominal visceral fat to subcutaneous fat ratio (V/S ratio) of not less than 0.4 than in the group with a lower V/S ratio, when either all or sex-matched obese subjects were examined, though BMI or the duration of obesity was not different between the two groups. The V/S ratio was significantly correlated with the level of plasma glucose area (r = 0.45, P less than .001) under the curve of 75 g oral glucose tolerance test and also with the serum triglyceride (r = 0.65, P less than .001) and total cholesterol levels (r = 0.61, P less than .001). These relationships were also observed when examined in each sex separately and found to be significant after adjustment for BMI and age by multiple regression analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.

The presence of obesity increases the risk of thrombotic vascular diseases. The role of fat accumulation and its effect on plasminogen activator inhibitor–1 (PAI–1) levels was investigated in humans and animals. Plasma PAI–1 levels were closely correlated with visceral fat area but not with subcutaneous fat area in human subjects. PAI–1 mRNA was detected in both types of fat tissue in obese rats but increased only in visceral fat during the development of obesity. These data suggest that an enhanced expression of the PAI–1 gene in visceral fat may increase plasma levels and may have a role in the development of vascular disease in visceral obesity.

Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men

Associations between intra-abdominal visceral fat accumulations and coronary risk factors were studied in a sample of 29 non-obese men aged 57 +/- 10 years with coronary artery disease (CAD). Their body mass indexes (BMI) were 23.8 +/- 1.5 (range 18.7-26.3). The visceral fat area (VFA) and the subcutaneous fat area (SFA) were measured at the level of the umbilicus by computed tomography. In patients with CAD, the average VFA was significantly increased compared with that in 54 control subjects without CAD, matched for sex, age, and BMI (117.2 +/- 53.1 vs. 93.8 +/- 38.6 cm2, P < 0.05). However, their average SFA was not statistically different (111.2 +/- 33.3 vs. 106.3 +/- 35.7 cm2, N.S.). Eleven CAD patients (38%) and nine control subjects (17%) had greater than 2 S.D. higher than the mean VFA obtained from 22 healthy subjects extracted from the control subjects. Accordingly, the proportion of the subjects with high VFA was significantly higher in the CAD group. This group also had significantly higher levels of plasma glucose and insulin areas than controls determined by oral glucose tolerance tests. This may be due to insulin resistance. The proportion of the subjects with multiple risk factors including hyperlipidemia, hyperglycemia, and hypertension was significantly higher in the CAD patients with high VFA compared with the control subjects with normal VFA (CAD with high VFA 82% and control with normal VFA 33%). These findings suggest that visceral fat accumulations may play an important role in the occurrence of CAD regardless of obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

Close correlation of intra-abdominal fat accumulation to hypertension in obese women.

The relation between intra-abdominal visceral fat accumulation and blood pressure was investigated in 67 obese women (mean body mass index, 33.6 +/- 3.1; average age, 50 +/- 11 years). As an index of intra-abdominal fat accumulation, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area was determined using a computed tomographic section at the level of the umbilicus. When the obese subjects were divided into a hypertensive group and a normotensive group, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area in the hypertensive group was significantly higher (0.53 +/- 0.33 versus 0.29 +/- 0.12, p less than 0.01). Significant correlations between the ratio of intra-abdominal visceral fat area to subcutaneous fat area and systolic blood pressure (r = 0.62, p less than 0.001) and diastolic blood pressure (r = 0.53, p less than 0.001) also were found. However, no significant difference existed in either the body mass index or the waist-to-hip circumference ratio between the hypertensive and normotensive groups. Plasma renin activity, aldosterone, epinephrine, and norepinephrine levels were not significantly different between the two groups. Moreover, the correlation between the ratio of the intra-abdominal visceral fat area to subcutaneous fat area ratio and blood pressure was found independent of age and body mass index by multiple regression analyses. We conclude that intra-abdominal fat accumulation itself may play an important role in the pathogenesis of hypertension in obesity.

Variations in the FTO gene are associated with severe obesity in the Japanese

AbstractVariations in the fat-mass and obesity-associated gene (FTO) are associated with the obesity phenotype in many Caucasian populations. This association with the obesity phenotype is not clear in the Japanese. To investigate the relationship between the FTO gene and obesity in the Japanese, we genotyped single nucleotide polymorphisms (SNPs) in the FTO genes from severely obese subjects [n = 927, body mass index (BMI) ≥ 30 kg/m2] and normal-weight control subjects (n = 1,527, BMI < 25 kg/m2). A case-control association analysis revealed that 15 SNPs, including rs9939609 and rs1121980, in a linkage disequilibrium (LD) block of approximately 50 kb demonstrated significant associations with obesity; rs1558902 was most significantly associated with obesity. P value in additive mode was 0.0000041, and odds ratio (OR) adjusted for age and gender was 1.41 [95% confidential interval (CI) = 1.22–1.62]. Obesity-associated phenotypes, which include the level of plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure were not associated with the rs1558902 genotype. Thus, the SNPs in the FTO gene were found to be associated with obesity, i.e., severe obesity, in the Japanese.

Two decades of annual medical examinations in Japanese obese children : do obese children grow into obese adults?

OBJECTIVE: To investigate trends in frequency of obese children in Japan over two decades, the frequency of obese children who grow into obese adults and predictive factors for adult obesity. DESIGN: Annual cross-sectional studies for 22 y (1974–1995) with a follow-up study. SUBJECTS: Cross-sectional: Cumulatively 13 186 obese (% of standard body weight (SBW): ≥120%) schoolchildren including 3158 extremely obese (≥140% of SBW) children out of 203 088 schoolchildren (age: 6–14 y) in Izumiohtsu City, Osaka, Japan. Follow-up: 151 initially obese children (initial age: 6–14 y and age at follow-up: 20–35 y) who lived in Izumiohtsu City. Control: 3552 Japanese men and 4631 Japanese women (age: 20–35 y). MEASUREMENTS: Cross-sectional: height, weight, trunk circumference, skin-fold thickness, blood pressure and blood biochemicals. Follow-up: height, weight, trunk circumference, skin-fold thickness during childhood, and body height and weight at follow-up. Adulthood obesity: ≥120% of the average body mass indices (BMI) of the controls. RESULTS: Frequency of obese children increased from 5% to more than 10%, and that of extremely obese children increased from 1% to more than 2% during these 22 y. These increases were most prominent in the schoolboys aged 9–11 y. Prevalence of hyperglycemia and hyperlipidemia in the extremely obese children did not change, and that of hypertension and abnormal liver function gradually decreased during these two decades. After coming of age, 32.2% of the initially obese boys (relative risk: 5.3) and 41.0% of the initially obese girls (relative risk: 6.7) remained obese. BMI, percentage of the SBW and skin-fold thickness at the biceps during childhood were significantly larger in currently-obese girls. Positive correlations were demonstrated between these variables and percentage SBW at follow-up. CONCLUSIONS: Childhood obesity is increasing in Japan, especially in boys aged 9–11 y. Approximately 32% of the obese boys and 41% of the obese girls grow into obese adults, and the degree of obesity is a predictive factor for adult obesity.

Correlation of intraabdominal fat accumulation and left ventricular performance in obesity.

The correlation of intraabdominal visceral fat accumulation and left ventricular performance was investigated in 37 obese patients who had 154 +/- 23% of ideal body weight. The left ventricle was studied noninvasively by means of echocardiography, whereas the distribution of body fat was determined by computed tomography. The end-diastolic left ventricular dimension and stroke volume were greater in obese patients than in non-obese control subjects. Not only the absolute values of these parameters, but also the diastolic left ventricular dimension index (calculated as end-diastolic dimension/cube root of body surface area) and stroke index were greater in obese patients. When the obese patients were divided into 2 groups according to the intraabdominal visceral fat area to subcutaneous fat area ratio (V/S) determined by computed tomography, the diastolic dimension index and the stroke index were significantly greater in visceral-type obesity (V/S greater than or equal to 0.4) than in subcutaneous-type obesity (V/S less than 0.4) (43.2 +/- 2.9 vs 40.3 +/- 3.1 mm/m2/3, p less than 0.01 and 49.3 +/- 6.1 vs 40.3 +/- 5.6 ml/m2, respectively). Multiple regression analysis with independent variables of age, body weight, duration of obesity and V/S ratio showed that diastolic dimension index and stroke index significantly correlated with the V/S ratio. Thus, the alteration of cardiac function in obese patients is attributable not only to excess body weight and duration of obesity but also to intraabdominal fat accumulation.

Decrease in Intra-Abdominal Visceral Fat May Reduce Blood Pressure in Obese Hypertensive Women

We investigated the relationship between changes in blood pressure and fat distribution after a 12-week low-calorie diet in 26 obese hypertensive women whose average age was 50 +/- 13 years, mean body mass index was 33.7 +/- 3.1 kg/m2, and mean blood pressure was 112 +/- 9 mm Hg. As an index of intra-abdominal fat accumulation, we used the ratio of the intra-abdominal visceral fat area to subcutaneous fat area, determined by a computed tomographic section at the level of the umbilicus. Subjects lost a mean of 9.4 +/- 4.1 kg on a 1200-kcal (5040-kJ) diet for 12 weeks. Their mean blood pressure fell from 112 +/- 9 to 101 +/- 12 mm Hg (P < .001). The ratio of the visceral to subcutaneous fat area was significantly reduced after weight reduction from 0.56 +/- 0.33 to 0.45 +/- 0.27 (P < .02). Fasting plasma glucose and plasma glucose area after a 75-g oral glucose tolerance test also were significantly reduced by weight reduction. The change in mean blood pressure after weight reduction was not correlated with the change in body weight or body mass index but was correlated with the reduction in visceral fat area or ratio of visceral fat to subcutaneous fat area. Changes in mean blood pressure also were correlated with changes in fasting plasma glucose levels and the plasma glucose area determined by 75-g oral glucose tolerance test. Results indicate that a decrease in intra-abdominal visceral fat, rather than simply of body weight, may reduce blood pressure in obese hypertensive subjects. The mechanism may involve an improvement in glucose tolerance caused by weight reduction.

Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial

BACKGROUND It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. CONCLUSION These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population

There is evidence that the obesity phenotype in the Caucasian populations is associated with variations in several genes, including neuronal growth regulator 1 (NEGR1), SEC16 homolog B (SCE16B), transmembrane protein 18 (TMEM18), ets variant 5 (ETV5), glucosamine-6-phosphate deaminase 2 (GNPDA2), prolactin (PRL), brain-derived neurotrophic factor (BDNF), mitochondrial carrier homolog 2 (MTCH2), Fas apoptotic inhibitory molecule 2 (FAIM2), SH2B adaptor protein 1 (SH2B1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF), Niemann-Pick disease, type C1 (NPC1), melanocortin 4 receptor (MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15). To investigate the relationship between obesity and these genes in the Japanese population, we genotyped 27 single-nucleotide polymorphisms (SNPs) in 14 genes from obese subjects (n=1129, body mass index (BMI) ⩾30 kg m−2) and normal-weight control subjects (n=1736, BMI <25 kg m−2). The SNP rs10913469 in SEC16B (P=0.000012) and four SNPs (rs2867125, rs6548238, rs4854344 and rs7561317) in the TMEM18 gene (P=0.00015), all of which were in almost absolute linkage disequilibrium, were significantly associated with obesity in the Japanese population. SNPs in GNPDA2, BDNF, FAIM2 and MC4R genes were marginally associated with obesity (P<0.05). Our data suggest that some SNPs identified by genome-wide association studies in the Caucasians also confer susceptibility to obesity in Japanese subjects.