No abstract

Atherosclerosis is caused by many factors, one of which is oxidative stress. We recently demonstrated that systemic oxidative stress increased secretory sphingomyelinase (sSMase) activity and generated ceramides in the plasma of diabetic rats. In addition, we also showed that the total ceramide level in human plasma correlated with the level of oxidized low-density lipoprotein. To investigate the relationship between ceramide species and atherogenesis during aging, we compared age-related changes in ceramide metabolism in apolipoprotein E knock out mice (apoE −/− ) and wild type mice (WT). Although the total plasma ceramide level was higher in apoE −/− than that in WT at all ages, it decreased with increasing age. sSMase activity increased at 65 weeks (w) of age in both strains of mice. When apoE −/− developed atherosclerosis at 15 w of age, C18:0, C22:0, and C24:0 ceramide levels in the apoE −/− aorta significantly increased. Furthermore, at 65 w of age C16:0 and C24:1 ceramide levels were significantly higher than those in WT. These results suggested that elevation in levels of specific ceramide species due to sSMase activity contributed to atherogenesis during aging.

Peroxisomal proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. The aim of this study was to investigate the effects of a maternal high-fat (HF) diet on serum lipid concentration and PPAR gene expression in liver and adipose tissue in the early life of the rat offspring. Female Sprague-Dawley rats were fed either an HF or control (CON) diet 6 weeks before mating and throughout gestation and lactation. Blood and tissue samplings of male offspring were carried out at birth or weaning. Birth weights were similar and serum triglyceride (TG) and nonesterified fatty acid (NEFA) levels showed no significant difference between HF and CON newborns, despite greatly increased hepatic PPARα mRNA expression in the HF newborns (p<0.05). Both HF newborns and weanlings revealed significantly decreased hepatic PPARγ expression compared with controls (p<0.0001). Hepatic PPARα expression in the HF weanlings was reduced markedly compared with CON weanlings (p<0.0001) and showed a negative correlation with serum TG levels (r=-0.743, p<0.05). However, epididymal expression of PPARγ in the HF weanlings was upregulated significantly compared with controls (p<0.05) and demonstrated a positive correlation with epididymal fat mass (r=0.733, p<0.05). These were accompanied by obesity as well as a rise in serum TG by 79% (p<0.05) and NEFA concentration by 36% (p<0.05) in these HF weanlings. Our findings suggest that maternal HF diet leads to alterations in PPAR gene expression in the weanling offspring, which is associated with the disturbed lipid homeostasis.

Glucocorticoid (GC) excess promotes adipose tissue accumulation, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in the local amplification of GC. Therefore, in this study, we investigated the effects of carbenoxolone (CBX), an 11β-HSD1 inhibitor, on morphological changes in visceral fat, and the expression of genes involved in adipogenesis and lipid metabolism in high-fat (HF) diet-fed mice. Mice were fed a HF diet from 5 weeks of age. At 10 weeks of age, the mice received an intraperitoneal injection of CBX or vehicle every day for 2 weeks. CBX decreased body weight and visceral fat mass, and improved insulin sensitivity in HF-fed mice. This was accompanied by reduced adipocyte size and a decrease in large-sized adipocytes in visceral fat. The expression of adipogenesis (PPARγ and C/EBPα), glucose transport (GLUT4) and lipid metabolism (LPL, ATGL, and HSL)-related genes were suppressed in CBX mice. CBX treatment induced beneficial morphological changes in visceral fat and decreased the expression of adipogenesis, glucose transport and lipid metabolism-related genes. These findings reveal a potential mechanism underling the effects of CBX on reduced fat accumulation and improved insulin sensitivity.

Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes and improves hyperglycemia and insulin resistance in obese (ob) diabetic ob/ob mice. We investigated the effects of nobiletin on lipid metabolism and accumulation of body fat in rats. The control group was fed a 20% high-fat diet and 1% cholesterol, and the nobiletin group was fed same diet supplemented with 0.1% (w/w) nobiletin. The rats were fed for 4 weeks. Weights of epididymal, perirenal, total white adipose tissues (WAT: mesenteric, perirenal, and epididymal), and the subcutaneous WAT in the nobiletin group were significantly lower than those in the control group. This decrease was brought about by nobiletin without affecting triglyceride (TG) levels in the liver and skeletal muscle. Plasma TG levels tended to be decreased by nobiletin. The size and diameter of WAT adipocytes in the nobiletin group were significantly lower than those in the control group. This decrease may be partly due to lower lipoprotein lipase (a major determinant for the development of obesity) levels in WAT of the nobiletin group than that of the control group. Plasma levels of high density lipoprotein cholesterol and apolipoprotein A-I increased significantly with administration of nobiletin. These results suggested a beneficial effect of nobiletin on lipid metabolism. However, no significant differences were observed between the nobiletin and the control groups in proteins such as ATP-binding cassette transporter A1, and sterol regulatory element-binding protein-1 in the liver, PPARγ and tumor necrosis factor-α (TNF-α) in WAT, and adiponectin and TNF-α in plasma.