Molecular mechanism of vascular disease in metabolic syndrome X

Abstract

Syndrome X is a clinical syndrome in which multiple risks are clustered in an individual and is a common basis of vascular disease in the industrial countries. However, the molecular basis of syndrome X has not been elucidated. We have analyzed body fat distribution using CT scanning and have shown that accumulated intra-abdominal visceral fat is frequently accompanied by multiple risks and vascular diseases. Thus, ‘‘visceral obesity’’ is a clinical entity compatible with syndrome X. Our studies demonstrated that the V/S ratio (visceral fat area, V/subcutaneous fat area, S) significantly correlated with the glucose area after oral glucose tolerance test (OGTT) and the plasma triglyceride or cholesterol level in obese subjects. Visceral fat accumulation is associated with not only quantitative change in serum lipid and lipoprotein but also qualitative changes in lipoproteins such as the appearance of small, dense LDL particles, which may be related to the high triglyceride–low HDL dyslipidemic state found in visceral fat obesity. Many people believe that insulin resistance or the hyperinsulinemic state that is often found in visceral fat obesity plays a key role in the development of metabolic disorders. Previous reports have shown that hyperinsulinemia, although not so predominant in Japanese subjects, is present in visceral type obesity. Studies using the glucose clamp technique by Kissebah et al. and our steady-state plasma glucose method clearly demonstrated that patients with visceral fat obesity have greater insulin resistance than those with subcutaneous fat obesity. Visceral fat accumulation has been shown to have causative effects in circulatory disorders in addition to metabolic disorders. We demonstrated a close correlation between the V/S ratio and the diastolic dimension index or stroke index in obese subjects that reflected the presence of a hypervolemic state in visceral fat obesity. There was a close correlation between systolic blood pressure and V/S ratio in premenopausal female subjects. As stated above, visceral fat obesity is characterized by high-risk obesity with multiple complications including insulin resistance, disorders of glucose and lipid metabolism, hypertension, and cardiac enlargement. We also demonstrated that the accumulation of visceral fat was related to the development of both metabolic disorders and circulatory disorders even in normal-weight subjects. Thus, a disease entity, ‘‘visceral fat syndrome,’’ can be proposed as a state that is accompanied frequently by glucose intolerance, hyperlipidemia, and hypertension irrespective of absolute body weight. Furthermore, several studies have shown that visceral adiposity determined by CT scanning is related to coronary artery disease (CAD). For example, according to our study on the fat distribution of 38 male patients with CAD, 9 cases were classified as obese with a BMI greater than 26.5 and 29 cases as non-obese. Eight of those nine obese subjects had extremely high V/S ratios compared with those of obese subjects without CAD. Among the non-obese subjects, the mean visceral fat area (VFA) in the patients with CAD was significantly larger than that of non-CAD controls. Thirtyeight percent of non-obese CAD subjects had VFAs greater than the mean ± 2 S.D. of the values obtained in non-CAD controls. The patients with high VFAs showed significantly higher levels of plasma glucose and insulin area after glucose ingestion than those with low VFAs, suggesting the presence of insulin resistance (Matsuzawa, 1997). The incidence of multiple risk factors including hyperlipidemia, hyperglycemia, and hypertension was higher in patients with high VFAs. These results together with previous reports indicate that visceral fat syndrome is a syndrome predisposing to susceptibility to atherosclerosis in which visceral fat accumulation often accompanies insulin resistance, glucose intolerance, hyperlipidemia, and hypertension, and the clustering of these risk factors may result in the occurrence of atherosclerosis. To clarify the molecular mechanism of the disorders in visceral fat syndrome, we analyzed the expressed genes in adipose tissue by large scale random sequencing. Unexpectedly, adipocytes, especially visceral adipocytes expressed a variety of the genes for secretory proteins including various bioactive substances and we designated