Jong Chul Won

α-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase

Objective—Lipid accumulation in vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis in obese subjects. We showed previously that α-lipoic acid (ALA) activates AMP-activated protein kinase (AMPK) and reduces lipid accumulation in skeletal muscle of obese rats. Here, we investigated whether ALA improves endothelial dysfunction in obese rats by activating AMPK in endothelial cells. Methods and Results—Endothelium-dependent vascular relaxation was impaired, and the number of apoptotic endothelial cells was higher in the aorta of obese rats compared with control rats. In addition, triglyceride and lipid peroxide levels were higher, and NO synthesis was lower. Administration of ALA improved all of these abnormalities. AMPK activity was lower in aortic endothelium of obese rats, and ALA normalized it. Incubation of human aortic endothelial cells with ALA activated AMPK and protected cells from linoleic acid–induced apoptosis. Dominant-negative AMPK inhibited the antiapoptotic effects of ALA. Conclusions—Reduced AMPK activation may play an important role in the genesis of endothelial dysfunction in obese rats. ALA improves vascular dysfunction by normalizing lipid metabolism and activating AMPK in endothelial cells.

Central Administration of an Endoplasmic Reticulum Stress Inducer Inhibits the Anorexigenic Effects of Leptin and Insulin

Leptin and insulin are important anorexigenic hormones acting on the hypothalamus. However, most obese humans and animals have reduced hypothalamic responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has been shown to cause insulin resistance in the livers of obese animals. In the present study, we investigated a role of ER stress in the development of central leptin and insulin resistance. Intracerebroventricular (ICV) administration of the ER stress inducer thapsigargin (TG) increased food intake and body weight. Furthermore, ICV or intra‐hypothalamic administration of TG inhibited the anorexigenic and weight‐reducing effects of leptin and insulin. ICV administration of TG by itself activated signal‐transduction‐activated‐transcript‐3 (STAT3) and Akt in the hypothalamus, but prevented a further activation of hypothalamic STAT3 and Akt by leptin and insulin. We also found that the expression of the ER stress markers such as phosphorylation of the inositol‐requiring kinase‐1 (IRE1), spliced form of X‐box‐binding protein‐1 (XBP‐1s), glucose‐regulated/binding immunoglobulin protein‐78, and C/EBP homology protein (CHOP) increased in the hypothalami of diet‐induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 4‐phenyl butylic acid significantly improved central leptin resistance in DIO mice. These findings suggest that increased hypothalamic ER stress in obese animals may induce central leptin and insulin resistance.

Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α Overexpression Prevents Endothelial Apoptosis by Increasing ATP/ADP Translocase Activity

Objective—Fatty acids increase reactive oxygen species generation and cell apoptosis in endothelial cells. The peroxisome proliferator-activated receptor-&ggr; coactivator 1-&agr; (PGC-1&agr;) is a transcriptional coactivator that increases mitochondrial biogenesis and fatty acid oxidation in various cells. This study was undertaken to investigate the possible preventive effect of PGC-1&agr; on endothelial apoptosis and its molecular mechanism. Methods and Results—Treatment with linoleic acid in cultured human aortic endothelial cells increased reactive oxygen species generation and cell apoptosis. These effects appeared to be mediated by increases in cytosolic fat metabolites, ie, fatty acyl CoA, diacylglycerol, and ceramide, and consequent decreases in ATP/ADP translocase activity of adenine nucleotide translocator. Adenoviral overexpression of PGC-1&agr; prevented linoleic acid-induced increases in reactive oxygen species generation and cell apoptosis in human aortic endothelial cells by increasing fatty acid oxidation, decreasing diacylglycerol and ceramide, and increasing ATP/ADP translocase activity. In isolated aorta, PGC-1&agr; overexpression prevented linoleic acid-induced decrease in endothelium-dependent vasorelaxation, and this effect was abolished by adenine nucleotide translocator1 shRNA. Conclusions—PGC-1&agr; regulates reactive oxygen species generation and apoptosis in endothelial cells by increasing fatty acid oxidation and enhancing ATP/ADP translocase activity. Measures to increase PGC-1&agr; expression or ATP/ADP translocase activity in vascular cells may aid in the prevention or treatment of atherosclerosis.

1,5-Anhydroglucitol reflects postprandial hyperglycemia and a decreased insulinogenic index, even in subjects with prediabetes and well-controlled type 2 diabetes

To examine the serum 1,5-anhydroglucitol (AG) levels as a surrogate measure of postprandial hyperglycemia (PPH) and insulin secretion in a wide range of hyperglycemia, we compared the relationship between the glycemic index during a 75g oral glucose tolerance test (OGTT) and the insulinogenic index and 1,5-AG according the overall glycemic state. Fasting serum 1,5-AG levels were lower in the type 2 diabetic group (18.0+/-7.0microg/mL) than in the normal glucose tolerance (NGT, 25.4+/-4.0microg/mL), impaired fasting glucose (IFG, 24.6+/-6.2microg/mL), and impaired glucose tolerance (IGT, 22.1+/-6.2microg/mL) groups and were clearly correlated with glycemic values from the OGTT. 120-min post-challenge plasma glucose (PPG(120)) emerged as an independent predictor for 1,5-AG levels after multiple linear regression analysis (beta=-0.554, P<0.001). Additionally, 1,5-AG levels were significantly correlated with PPG(120) in each quartile of A1C, and the coefficients increased with higher A1C quartiles. Subjects with low 1,5-AG levels had both increased insulin resistance and decreased insulin secretion. Decreased 1,5-AG levels are closely correlated with PPH and decreased insulin secretion capacity across a wide range of glycemia, even in relatively well-controlled diabetes.

Plasma Clusterin (ApoJ) Levels Are Associated with Adiposity and Systemic Inflammation

Obesity and insulin resistance are hallmarks of the metabolic syndrome, which is associated with low-grade chronic inflammation. Clusterin/apolipoprotein J is an abundant plasma chaperone protein that has recently been suggested as a potential biomarker that reflects the inflammatory process in Alzheimers disease. In the present study, we investigated anthropometric and clinical factors affecting the plasma levels of clusterin in healthy Korean subjects. We measured fasting plasma clusterin levels in healthy Korean adults (111 men and 93 women) using ELISA kit. We analyzed the relationship between plasma clusterin concentrations and anthropometric and clinical parameters. Fasting plasma clusterin concentrations were higher in overweight and obese subjects than in lean subjects. Correlation analysis revealed that the plasma clusterin levels were positively associated with indices of obesity such as body mass index (BMI), waist circumference and waist-hip ratio and markers of systemic inflammation such as high sensitivity C-reactive protein (hsCRP), uric acid, ferritin and retinol binding protein-4. Multiple linear regression analysis showed that sex, BMI and hsCRP were independent determinants of plasma clusterin levels. Furthermore, plasma clusterin levels showed an upward trend with increasing numbers of metabolic syndrome components. These findings suggest that fasting plasma clusterin levels correlate with the parameters of adiposity and systemic inflammation in healthy adults. Therefore, the circulating clusterin level may be a surrogate marker for obesity-associated systemic inflammation.

Mechanisms of adipose tissue redistribution with rosiglitazone treatment in various adipose depots.

Treatment with thiazolidinediones (TZDs) improves glucose homeostasis by increasing insulin sensitivity, but it also leads to weight gain. Our hypothesis was that, in individual adipose depots, there is depot specificity for lipid storage and energy expenditure genes after TZD treatment. After 5 weeks of rosiglitazone treatment on Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus with obesity, and Long-Evans Tokushima Otsuka rats as controls, we measured changes in lipid storage and energy expenditure gene expression in various adipose depots, such as mesenteric and nonmesenteric adipose tissues (subcutaneous, epididymal, and retroperitoneal). Mesenteric fat masses did not change after TZD treatment in OLETF rats, but nonmesenteric fat masses increased. Messenger RNA expression of lipid storage genes increased in nonmesenteric fat, but energy expenditure gene expression increased in mesenteric fat after rosiglitazone treatment. In conclusion, our findings suggest that TZD treatment may be associated with the depot-specific effects of lipid storage and energy expenditure genes on fat redistribution in individual adipose tissues in OLETF rats.

Association of Low Muscle Mass and Combined Low Muscle Mass and Visceral Obesity with Low Cardiorespiratory Fitness

Objective Previous studies have shown that low cardiorespiratory fitness (CRF), visceral obesity and low muscle mass may share pathophysiological mechanisms, such as insulin resistance and chronic inflammation. In this study, we investigated whether low CRF is associated with low muscle mass, visceral obesity, and visceral obesity combined with low muscle mass. Research Design and Methods The associations between CRF and low muscle mass and combined low muscle mass and visceral obesity were examined in 298 apparently healthy adults aged 20–70 years. Low muscle mass was defined using a skeletal muscle mass index (SMI) that was calculated using dual energy X-ray absorptiometry. Visceral obesity was defined as a visceral fat area (VFA) exceeding 100 cm2 in women and 130 cm2 in men. We classified the participants into 4 low muscle mass/visceral obesity groups according to SMI and VFA. CRF was measured using a cycle ergometer test. Results CRF level correlated positively with SMI and negatively with VFA. Individuals with low muscle mass had lower CRF values than those without low muscle mass. After adjustment for age, sex, lifestyle factors, and markers for insulin resistance and inflammation, participants in the lowest quartile of CRF had an odds ratio (OR) for low muscle mass of 4.98 compared with those in the highest quartile (95% confidence interval (CI) = 1.19–12.99; P for trend = 0.001) and an OR for combined low muscle mass and visceral obesity of 31.46 (95% CI = 4.31–229.68; P for trend = 0.001). Conclusions Individuals with lower CRF exhibited increased risk of low muscle mass and combined low muscle mass and visceral obesity. These results suggest that low CRF may be a potential indicator for low muscle mass and combined low muscle mass and visceral obesity in Korean adults.

Association of Plasma Levels of Resistin with Subcutaneous Fat Mass and Markers of Inflammation but not with Metabolic Determinants or Insulin Resistance

The aim of the present study was to investigate the relationship of plasma resistin levels with determinants of the metabolic syndrome (MetS) and anthropometric parameters in healthy Korean subjects. Plasma resistin levels were determined in 276 subjects. In subjects with MetS, the plasma resistin levels were not significantly increased compared to those without MetS (8.3±4.3 ng/mL vs. 8.5±3.6 ng/mL, respectively, P=0.84). In addition, the plasma resistin levels were not correlated with the body mass index, the waist circumference, homeostasis model assessment-insulin resistance (HOMA-IR), fasting plasma glucose or insulin levels. However, the plasma resistin levels were positively correlated with the abdominal subcutaneous fat (r=0.18, P<0.01) in all subjects and correlated with TNF α(r=-0.16, P<0.05) and hsCRP (r=0.15, P<0.05) in subjects without MetS but not with MetS. With multiple linear regression analysis, these linear associations remained to be significant. The results of this study show that plasma resistin levels in humans were not associated with markers of insulin resistance, obesity or other determinants of the MetS.

α-Lipoic acid activates dimethylarginine dimethylaminohydrolase in cultured endothelial cells

Asymmetric dimethylarginine (ADMA) is a risk factor of cardiovascular diseases. alpha-Lipoic acid (ALA) was shown to improve vascular dysfunction, and to decrease plasma ADMA level. In this study, we investigated whether ALA activates dimethylarginine dimethylaminohydrolase (DDAH), the metabolizing enzyme of ADMA, in cultured endothelial cells. ALA significantly decreased ADMA level in culture media of endothelial cells. ALA increased the gene expression and activity of DDAH, and signal transducer and activator of transcription (STAT)3 phosphorylation. Transfection of STAT3 increased DDAH II promoter activity, and ALA amplified it. ALA-induced increase in DDAH II promoter activity was attenuated in the promoter that had mutation in putative STAT3-binding site. These results suggest that ALA reduces ADMA level by enhancing DDAH activity and DDAH II gene expression, thus providing a novel mechanism by which ALA regulates endothelial function.

Relationship Between Sarcopenia and Albuminuria: The 2011 Korea National Health and Nutrition Examination Survey

Abstract Studies have shown that albuminuria, obesity, and sarcopenia may share pathophysiological processes related to cardiovascular disease risk. Their direct relationships, however, have not been examined. This study investigated the association between albuminuria and sarcopenia in a representative fraction of the Korean population. Of the 10,589 people who participated in the 2011 Korea National Health and Nutrition Examination Survey, 2158 participants aged over 19 years had been tested for albumin-to-creatinine ratio and for body composition data using dual-energy x-ray absorptiometry. Albuminuria was defined as an albumin-to-creatinine ratio ≥30 mg/g. Sarcopenia was defined as a skeletal muscle index (SMI) (SMI (%) = total appendicular skeletal muscle mass [kg]/weight [kg] × 100) of less than 1 standard deviation (SD) (grade 1) or 2 SD (grade 2) below the sex-specific mean for a younger reference group. The prevalence of albuminuria was higher in those with grade 2 sarcopenia than in those with a normal SMI or grade 1 sarcopenia (33.3% versus 8.4% and 8.9%; P < 0.001). Conversely, grade 2 sarcopenia was also more prevalent in participants with albuminuria than in those with the upper tertile of normoalbuminuria. In addition, multiple logistic regression analysis showed the odds ratio for albuminuria risk in the grade 2 sarcopenia group was 2.93 (95% confidence interval [CI], 1.46–5.88), compared with normal SMI after adjusting for potential confounding factors, including the presence of obesity, diabetes, and hypertension. Moreover, individuals with albuminuria had an odds ratio of 3.39 (95% [confidence interval], 1.38–8.37) for grade 2 sarcopenia compared with those in the lowest tertile of normoalbuminuria. This is the first study to demonstrate that individuals with sarcopenia exhibited increased risk of albuminuria and vice versa.