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It is generally thought that typical atherosclerotic lesions do not develop in the rodent. The Goto-Kakizaki (GK) rat is a nonobese strain in which a spontaneous type of non-insulin-dependent diabetes mellitus develops without apparent macroangiopathy. In our previous study, making ventromedial hypothalamic (VMH) lesions in GK rats induced hyperphagia and a further deterioration in glucose metabolism. In the current study, male GK rats in which VMH lesions were made were examined for vascular changes, with special reference to atherosclerotic lesions. Marked hyperglycemia in GK rats with VMH lesions (hereafter referred to as VMH lesion rats) was revealed over an observation period (plasma glucose levels 16 weeks after the operation: VMH lesion GK rats, 19.3 +/- 2.0 mmol/L, vs sham-operated GK rats, 10.1 +/- 1.3 mmol/L; p < 0.0001). Light microscopic observation of the descending aorta in VMH lesion GK rats 16 weeks after the surgery revealed that the intimal thickening and the number of infiltrating cells into the intima were significantly increased as compared with sham-operated GK rats (17531 +/- 3747 microm2 vs 3072 +/- 1192 microm2, p < 0.0001; 15.6 +/- 3.1 per one transverse section vs 6.8 +/- 2.5 per one transverse section, p < 0.0005). Electron microscopic observations demonstrated an increased number of microvilli and lysosomes in endothelial cells, infiltration of macrophages and lymphocytes into the intima, and migration of medial smooth muscle cells into the intima that are considered to be early events in atherosclerosis. These morphologic changes could be induced by a deterioration in glucose metabolism. This rat may thus be useful for studying the process of the initiation of atherosclerosis in diabetes mellitus.

Objective: We have reported that ventromedial hypothalamic (VMH) lesions induced marked hyperglycemia and a distinct reduction in pancreatic insulin content during short-term observation in male Goto-Kakizaki (GK) rats, an animal model for non-insulin-dependent diabetes mellitus (NIDDM) (Metabolism 43: 32-37, 1994). We investigated the long-term effect of VMH lesions on glucose metabolism, pancreatic insulin content, abdominal fat distribution and vascular complications in male GK rats., Design: Metabolic and histological examinations in male GK rats during 16 weeks after making VMH lesions were compared to those in sham operated GK or Wistar rats., Subjects: Eleven 9-week-old male GK rats and 4 male Wistar rats. VMH-lesions were made in 6 GK rats and sham operation were performed on 5 GK rats and 4 Wistar rats as controls., Measurements: Food intake, body weight, and plasma glucose, insulin and lipid levels at 2 weeks interval after operation. Urinary protein and albumin levels at 15 weeks after operation. Measurement of pancreatic insulin content, mesenteric fat and abdominal subcutaneous fat weights, and histological examinations of kidney and aorta were performed after 16 weeks., Results: Although food intake increased in VMH-lesioned GK (GK-VMH) rats compared with that in sham-operated GK (GK-sham) rats, the body weight of GK-VMH rats was significantly less than that of GK-sham rats. Plasma glucose was markedly elevated in GK-VMH rats from 2 through 16 weeks after operation, while it was only mildly increased in GK-sham rats. Plasma insulin levels were higher in GK-VMH rats one week after operation and thereafter tended to be lower compared to those in GK-sham rats. Plasma triglyceride levels were significantly increased in GK-VMH rats. The insulin content of pancreas at 16 weeks after operation was markedly decreased in GK-VMH rats. VMH lesions caused a significant 1.2-fold increase in mesenteric fat weight and a 1.3-fold higher ratio of mesenteric fat weight to subcutaneous fat weight in GK rats compared with sham-operated rats at 16 weeks after operation. The urinary excretions of protein and albumin in GK-VMH rats were greater than those in GK-sham rats. Histological examinations of the kidneys in GK-VMH rats revealed that the glomerular basement membranes were thicker than those of GK-sham rats. The descending aorta in GK-VMH rats also showed morphologic changes in the intima characteristic of an early stage of atherosclerosis., Conclusion: Male GK-VMH rats may be a useful animal model for non-obese NIDDM with visceral fat accumulation, which develops typical diabetic complications, including both microangiopathy and macroangiopathy.

Based on the analysis of fat distribution by computed tomography (CT) scans, the classification scheme for obesity should include visceral fat obesity in which fat accumulation is predominant in the intra-abdominal cavity. Obese subjects with visceral fat accumulation more frequently demonstrate impairment of glucose and lipid metabolism than those with subcutaneous fat accumulation. We have shown that visceral fat obesity is present in almost 90% of obese patients with ischemic heart disease. Even in non-obese subjects, visceral fat accumulation is correlated with glucose intolerance, hyperlipidemia and hypertension. Forty percent of non-obese subjects with coronary artery disease (CAD) had increased visceral fat. In non-obese subjects, visceral fat area assessed by abdominal CT at the level of the umbilicus correlates with metabolic risk factors, whereas in obese subjects the visceral fat area to subcutaneous fat area ratio provides a more significant correlation. From clinical and basic investigations, aging, sex hormones, excess intake of sucrose and lack of physical exercise have been suggested to be determinants for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) has been shown to have high activities of both lipogenesis and lipolysis, its accumulation can induce high levels of free fatty acids, a product of lipolysis, in portal circulation which go into the liver. Excess free fatty acids may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. Thus we propose a disease entity, visceral fat syndrome, which may increase susceptibility to atherosclerosis due to multiple risk factors induced by visceral fat accumulation.

Based on the analysis of fat distribution by CT scanning, we have proposed a classification of obesity: visceral fat obesity, in which fat accumulation is predominant in the intra-abdominal cavity. This type of obesity is more frequently accompanied by disorders of glucose and lipid metabolism, and also with hypertension, than subcutaneous fat obesity. We also showed that almost 90% of obese patients with ischemic heart disease have visceral fat accumulation. From clinical and basic experiments, aging, imbalance of sex hormone, overintake of sucrose and lack of physical exercise have been suggested to be major factors for visceral fat accumulation. Since intra-abdominal fat (mesenteric and omentum fat) have been show to have high activities of both lipogenesis and lipolysis, its accumulation induces a high content of free fatty acids, a product of lipolysis, in portal circulation which goes into the liver directly. Excess free fatty acid may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis.

It is well known that obesity is frequently associated with low levels of serum high-density lipoprotein (HDL) cholesterol. However, the mechanism for this reduction has not been fully clarified. Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins and plays an important role in regulating the concentration and composition of HDL. To elucidate the mechanism for the reduction of serum HDL cholesterol in obesity, we analyzed serum lipoproteins, CETP, and postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities in 30 obese subjects (17 women and 13 men, age 44 +/- 14 years, mean +/- SD). We also investigated the relationship between these variables, total adiposity, and indices of body fat distribution. The average body mass index of the obese subjects was 33.1 +/- 4.8 kg/m2 (range, 26.4 to 43.8 kg/m2). The obese subjects showed significantly lower serum HDL cholesterol levels than control subjects (1.04 +/- 0.28 versus 1.50 +/- 0.34 mmol/L, P < .01). In the obese subjects, both activities and protein mass of CETP and postheparin HTGL activities were significantly increased, whereas postheparin LPL activities were significantly decreased. CETP activities, independent of postheparin HTGL and LPL activities, were correlated negatively with HDL cholesterol (r = -.39, P < .05) and the cholesteryl ester to triglyceride ratio of HDL2 and HDL3 (r = -.36, P < .05; r = -.46, P < .05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

We performed a cross-sectional study using whole-body computerized tomographic (CT) scans in order to clarify age-related changes in whole-body fat distribution in both genders. The subjects were 66 men and 96 women, whose body mass index (BMI) was over 25 kg/m2. CT scans were performed at seven levels (head, fore-arms, upper arms, chest, abdomen, thighs and calves), and the fat volumes of the segments were calculated from the cross-sectional areas of the fat tissues. After calibrating to the total fat volumes, the relationship between age and the relative segmental fat volumes was analysed. In both genders, the relative intra-abdominal visceral fat volume increased and that of the legs decreased with age. The relative abdominal subcutaneous fat volume decreased with age only in male subjects. The increase in the relative visceral fat volume with age was about 2.6 times larger in males than in pre-menopausal females, while post-menopausal females showed the same increase as male subjects. These data suggest that there is a definite gender difference in the age-related changes in whole-body fat distribution, especially in the abdominal fat tissues. In addition, the accumulation of visceral fat is markedly accelerated by menopause in women.

The effects of ventromedial hypothalamic (VMH) lesions were examined in male and female non-obese non-insulin-dependent diabetic (Goto-Kakizaki [GK]) rats with respect to glucose metabolism and pancreatic insulin content. VMH lesions produced hyperphagia and hyperinsulinemia in both male and female GK rats. In male rats, plasma glucose levels of VMH-lesioned GK rats (22.7 +/- 3.1 mmol/L) were significantly greater than the levels of sham-operated GK rats (10.6 +/- 1.0 mmol/L, P < .001) at 7 weeks after the operation, although there were no differences in these levels between VMH-lesioned and sham-operated groups in Wistar rats. Plasma insulin levels in male VMH-lesioned GK rats tended to be lower at 7 weeks than at 1 week. VMH lesions caused a significant decrease in the pancreatic insulin content of male GK rats (12.0 +/- 2.3 nmol/L/g pancreas) compared with male sham-operated rats (15.8 +/- 1.4 nmol/L/g pancreas, P < .05) 9 weeks postoperatively. In contrast to the results in male rats, female GK rats showed no differences in plasma glucose levels between VMH-lesioned and sham-operated groups at 7 weeks. Female VMH-lesioned GK rats also showed no difference in plasma insulin levels between 1 week and 7 weeks. The pancreatic insulin level of female VMH-lesioned GK rats was unchanged from that of female sham-operated GK rats. The insulin content was significantly greater in the VMH-lesioned Wistar group than in the sham-operated Wistar group, regardless of sex.(ABSTRACT TRUNCATED AT 250 WORDS)

To clarify the role of acyl-CoA synthetase in development of obesity, the mRNA levels and activities were studied in Zucker fatty rats (fa/fa). In Zucker fatty rats compared with their lean littermates, marked enhancement of ACS were observed in adipose tissues. Obese/lean rats ratio of ACS activity and mRNA in abdominal subcutaneous fat (3.3- and 3.9-fold, respectively) were greater than in mesenteric fat (2.0- and 2.2-fold). The enhancement of ACS activity and mRNA in the liver of fatty rats (1.2- and 1.8-fold) were less than those in the adipose tissues. There were no enhancement of ACS activities and mRNA levels in heart tissue of the obese rats. LPL mRNA levels were also enhanced in adipose tissue of fatty rats and obese/lean ratio of LPL mRNA was also higher in abdominal subcutaneous fat than mesenteric fat (6.2- vs 3.1-fold). The larger obese/lean rats ratio of LPL and ACS parameters in abdominal subcutaneous fat than mesenteric fat may be related to the observation that the increase of subcutaneous fat weight was larger than that of mesenteric fat weight in fatty rats (21.1- vs 4.9-fold). Integrated enhancement of LPL and ACS gene expression in adipose tissue may play an important role in the development of obesity.

Visceral fat obesity (VFO) with predominant intra-abdominal fat accumulation has been shown to be more often associated with metabolic disorders than subcutaneous fat obesity (SFO). In the present study, changes in fat distribution and their effects on metabolic complications were investigated in forty premenopausal female obese patients in whom substantial weight reduction was obtained by means of a low calorie diet. Analysis of fat distribution by CT scanning demonstrated that visceral fat decreased to a greater extent than abdominal subcutaneous fat, which was particularly evident in VFO patients. On the other hand, change of fat distribution was small in SFO patients. That is, visceral to subcutaneous abdominal fat ratio (V/S ratio) decreased from 0.62 +/- 0.36 to 0.46 +/- 0.33 in VFO, whereas from 0.23 +/- 0.07 to 0.20 +/- 0.09 in SFO after weight reduction. Although obese patients, especially those with VFO, were frequently associated with glucose intolerance and hyperlipidemia, marked diminution was observed in the elevated levels of plasma glucose area on 75g OGTT, serum total cholesterol and triglyceride after weight reduction. By the examination of interrelationship between the changes in body weight, BMI, total and regional fat volume and changes in glucose and lipid metabolism, we found that the decrease in the V/S ratio and visceral fat volume were more strongly correlated with the improvement in plasma glucose and lipid metabolism compared to the decrease in body weight, BMI, total fat volume and abdominal subcutaneous fat volume. Furthermore, partial correlation analyses demonstrated that the metabolic improvements were associated with changes in visceral abdominal fat after control for changes in total adipose tissue volume.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously reported that metabolic abnormalities in obese subjects are closely related to intraabdominal fat accumulation. In order to clarify the causal relationship between high sucrose intake and intraabdominal visceral fat accumulation, the effects of a high sucrose diet on mesenteric fat weight, fasting plasma glucose (FPG) and triglyceride (TG) levels were investigated in bilateral ventromedial hypothalamic-lesioned obese rats (VMH) and control rats (control). The mesenteric fat weight (g)/abdominal subcutaneous fat weight (g) (M/S ratio), a parameter of visceral fat accumulation, was significantly higher in a high sucrose diet fed group (HSD group) (VMH 1.94 +/- 0.71, control 1.63 +/- 0.28) than in a lab chow fed group (LC group) (VMH 1.30 +/- 0.31, control 1.27 +/- 0.33) (P less than 0.01). In addition, the fat cell volume of mesenteric fat deposits was significantly greater in the HSD group (VMH 1.17 +/- 0.26 nl, control 0.24 +/- 0.10 nl) than in the LC group (VMH 0.74 +/- 0.27 nl, control 0.14 +/- 0.07 nl) (P less than 0.001), although the fat cell number did not differ among any experimental rat groups. FPG and TG levels were higher in the HSD group than in the LC group in VMH-lesioned rats, and a significant correlation was observed between mesenteric fat volume and FPG levels (VMH r = 0.58, P less than 0.05; control r = 0.50, P less than 0.05) as well as between mesenteric fat volume and TG levels (VMH r = 0.49, P less than 0.05; control r = 0.56, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The ideal body weight (kg) of each individual can be calculated by the following formula: ideal body mass index x the height (m)2, since body mass index is expressed by the body weight in kilogram divided by the height squared in meters. We investigated an ideal body mass index with respect to morbidity in 4565 Japanese men and women aged 30-59 years. Ten medical problems served as indices of morbidity: lung disease, heart disease, upper gastrointestinal disease, hypertension, renal disease, liver disease, hyperlipidemia, hyperuricemia, diabetes mellitus and anemia. The value of body mass index associated with the lowest morbidity was 22.2 kg/m2 in men and 21.9 kg/m2 in women, according to the quadratic regression curves relating body mass index to morbidity. From these findings, we propose that the ideal body weight is 22 x height (m)2. Our recommendations apply to the age group studied, namely 30-59 years.

The relationship between blood pressure and anthropometric or metabolic factors was studied in 324 obese children aged 9.5 +/- 1.8 years (mean +/- standard deviation). Obese children had a significantly higher blood pressure than non-obese children (systolic blood pressure: 121 +/- 14 mmHg in obese children vs 112 +/- 11 mmHg in non-obese children, P less than 0.001; diastolic blood pressure: 72 +/- 9 mmHg in obese children vs 66 +/- 7 mmHg in non-obese children, P less than 0.001). When the obese children were divided into hypertensive and normotensive groups, there was a significant difference in fasting serum insulin levels between the two groups (19.3 +/- 9.3 microU/ml in the hypertensive group vs 13.0 +/- 6.1 microU/ml in the normotensive group), and a close correlation between fasting serum insulin levels and systolic blood pressure was demonstrated (r = 0.63, P less than 0.001). However, there was no significant correlation between blood pressure and the degree of obesity itself or the waist-to-hip ratio in the obese children. There was no significant correlation between blood pressure and fasting plasma glucose, serum total cholesterol, or triglycerides levels in the obese children. Moreover, the correlation between fasting insulin levels and blood pressure was shown to be independent of the degree of obesity or waist-to-hip ratio and age by multiple regression analysis. These results indicate that hyperinsulinemia itself may play an important role in the pathogenesis of hypertension in obese children.

Body mass index (BMI) is expressed by the body weight (kg) divided by height (m) squared. Therefore, if we know ideal BMI, ideal body weight (kg) of each individual can be calculated by a formula: Ideal BMI x height (m)2. In order to estimate ideal BMI, we investigated average BMI with the lowest morbidity using 4565 Japanese men and women aged 30 to 59 years. Their BMI distributed widely with the highest frequency at 23 in men and 21 in women. The morbidity was evaluated by the number of medical problems that the subjects with each BMI have. The BMI associated with the lowest morbidity was calculated to be 22.2 kg/m2 in men and 21.9 kg/m2 in women according to the quadratic regression curves derived from the relation between BMI and morbidity. From these data, we propose that an ideal body weight in Japanese is 22 x height (m)2.

The livers of Zucker fatty (fa/fa) and lean (Fa/-) rats treated with standard rat chow diet containing 0, 10 or 50 ppm alpha-glucosidase inhibitor (AO-128) for 10 weeks were studied morphologically and biochemically. Light microscopic examination of livers from untreated Zucker fatty rats showed severe steatosis. The triglyceride content in the livers from Zucker fatty rats was significantly higher than that from lean rats (73 +/- 9 micrograms/mg protein for Zucker fatty rats vs. 30 +/- 10 for lean rats, p less than 0.01). Administration of the inhibitor caused a marked decrease in the number and size of lipid droplets in the hepatocytes from Zucker fatty rats and a decrease in the triglyceride content in the liver (73 +/- 9 micrograms/mg protein for untreated, 54 +/- 16 for 10-ppm-treated and 48 +/- 23 for 50-ppm-treated rats, p less than 0.05). This is the first report showing an inhibitory effect of an alpha-glucosidase inhibitor on steatosis in Zucker fatty rats.

The mRNA level of apolipoprotein B (apoB), which is a principal protein component of nascent very low density lipoprotein (VLDL), was determined in parallel with the measurement of acetyl-coenzyme A (Ac-CoA) carboxylase activity in the liver of ventromedial hypothalamus (VMH) lesioned obese rats. Eight weeks after the electrolysis of the bilateral VMH, the level of apoB mRNA in the VMH-lesioned rats was about 1.5-fold higher than that in the sham-operated rats, indicating increased apoB synthesis in the liver of the VMH-lesioned obese rats. The activity of Ac-CoA carboxylase, which is a rate-limiting enzyme for the fatty acid biosynthesis, was about 1.8-fold higher in the VMH-lesioned rats. These observations indicated that VLDL synthesis is increased in the liver of VMH-lesioned obese rats.

The relationship between mesenteric fat accumulation and metabolic disorder was studied in genetically obese Zucker fatty rats. These animals had high levels of plasma glucose, triglyceride and total cholesterol as well as increased liver triglyceride in comparison with lean rats. In addition, portal free fatty acid (FFA) levels were also higher in fatty rats than in lean rats. Direct measurement of fat weight revealed a substantial increase of mesenteric as well as subcutaneous fat. The volume of mesenteric fat cells was greater than that of subcutaneous fat cells in Zucker fatty rats (1.67 +/- 0.49 nl versus 1.00 +/- 0.31 nl), although the mesenteric fat cell volume was less than half of the subcutaneous fat cell volume (0.05 +/- 0.02 nl versus 0.14 +/- 0.07 nl) in lean rats. An increase in mesenteric fat cell volume was thus more predominant than that of subcutaneous fat cells in the fatty rats. Administration of AO-128 (50 p.p.m./day), a new alpha-glucosidase inhibitor, caused a substantial reduction of mesenteric fat weight accompanied by a marked decrease in fat cell volume in Zucker fatty rats. The drug also caused a significant reduction of FFA levels in the portal vein in parallel with a marked reduction of triglyceride content in the liver. These observations indicate that the fat accumulation in the markedly enlarged mesenteric fat cells is related to the elevated levels of FFA in the portal vein, which in turn may cause metabolic disorders in the liver. A new alpha-glucosidase inhibitor improves these disorders, at least in part, by preventing an enlargement of mesenteric fat cells.