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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.

Obesity is frequently accompanied by metabolic and cardiovascular complications. The accumulation of intra-abdominal visceral fat has been shown to be more closely related to various complications of obesity than that of subcutaneous fat. To elucidate the metabolic characteristics of visceral fat during fat accumulation, we examined the changes of acyl-CoA synthetase (ACS) mRNA abundance and its activity, glucose transporter (GLUT)-4, lipoprotein lipase (LPL), and very-low-density lipoprotein (VLDL) receptor mRNA abundances in mesenteric and subcutaneous fat in early stages of ventromedial hypothalamus (VMH)-lesioned rats. ACS activity increased 4.9-fold in the mesenteric fat on the 1st day, remaining unchanged in the subcutaneous fat. ACS, GLUT-4, and LPL mRNA levels were all increased in both fat tissues of VMH rats. The relative increase of mRNAs in VMH day 1 was greater in the mesenteric fat, suggesting that mesenteric fat shows rapid response during fat accumulation. VLDL receptor mRNA levels showed no significant change in either fat tissue. We conclude that ACS, GLUT-4, and LPL may contribute to fat accumulation at the gene expression level from a very early stage during the development of obesity.

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 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.