Obesity: Yamashita S

Sugimoto T, Yamashita S, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University. · Nippon Rinsho. · Pubmed #10638197 No free full text.

Abstract: Microsomal triglyceride transfer protein (MTP) plays a central role on secretion of lipoprotein from the liver and the intestine. MTP catalyzes the transfer of triglyceride, cholesteryl ester and phosphatidylcholine between membranes and lipoproteins. In human, defect of MTP activity, result from mutations encoding the MTP large subunit, is the primary cause of abetalipoproteinemia. To investigate the association between hyperlipidemia with obese and MTP, We used Otsuka Long-Evans Tokushima Fatty rat, an animal model of obesity with visceral fat accumulation, hyperlipidemia. In animals, very-low density lipoprotein-triglyceride levels were elevated compared with the control rats. Hepatic mRNA levels of acyl-coenzyme A synthetase, and MTP were also elevated. These results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation may be involved in the pathogenesis of hyperlipidemia in obese animal models.

Nakamura T, Funahashi T, Yamashita S, Nishida M, Nishida Y, Takahashi M, Hotta K, Kuriyama H, Kihara S, Ohuchi N, Nishimura T, Kishino BI, Ishikawa K, Kawamoto T, Tokunaga K, Nakagawa C, Mineo I, Watanabe F, Tarui S, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine Osaka University, 2-2 Yamadaoka, Suita, 565-0871 Osaka, Japan. · Diabetes Res Clin Pract. · Pubmed #11689273 No free full text.

Abstract: BACKGROUND: It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS: Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS: After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. Conclusion: These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Shimano H, Arai H, Harada-Shiba M, Ueshima H, Ohta T, Yamashita S, Gotoda T, Kiyohara Y, Hayashi T, Kobayashi J, Shimamoto K, Bujo H, Ishibashi S, Shirai K, Oikawa S, Saito Y, Yamada N. · The Research Committee for Primary Hyperlipidemia, Research on Measures for Intractable Diseases by the Ministry for Health, Labor, and Welfare in Japan. · J Atheroscler Thromb. · Pubmed #18603817 links to  free full text

Abstract: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases, proposing management for LDL cholesterol as the primary target, have successfully contributed to the prevention of cardiovascular events; however, recently, the impact of hypertriglyceridemia as an additional cardiovascular risk has become understood, especially in light of the rise in obesity, metabolic syndrome, and diabetes in the Japanese population. Rather than waiting to obtain conclusive domestic data confirming that hypertriglyceridemia is a cardiovascular risk factor and that its management is efficacious, we propose guidelines for hypertriglyceridemia using non-HDL cholesterol as a second target.

Chan DC, Watts GF, Ng TW, Uchida Y, Sakai N, Yamashita S, Barrett PH. · School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213, Perth, WA 6847, Australia. · Clin Biochem. · Pubmed #15992790 No free full text.

Abstract: OBJECTIVE: We examined the association of plasma apolipoprotein (apoB) B-48, remnant-like particle (RLP)-cholesterol and non-HDL cholesterol concentrations with apoB-100 kinetics in overweight-obese men. METHODS AND RESULTS: Very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) apoB-100 kinetics were measured in 53 men (BMI 33 +/- 4 kg/m(2)) using stable isotopes and multicompartmental modeling to estimate production rate (PR) and fractional catabolic rate (FCR). Fasting apoB-48 and RLP-cholesterol concentrations were measured using immunoassays. In univariate regression, apoB-48 and RLP-cholesterol were inversely associated with VLDL-apoB-100 FCR and IDL-apoB-100 FCR (P < 0.01 for all), but not with VLDL-, IDL- and LDL-apoB-100 PRs. Plasma non-HDL-cholesterol concentration was significantly and positively associated with the secretion rate of VLDL-apoB-100 (P < 0.05), and inversely correlated with the FCR of LDL-apoB-100 (P < 0.01). CONCLUSIONS: Our findings suggest that in overweight-obese men plasma concentrations of apoB-48, RLP-cholesterol and non-HDL-cholesterol are partly dependent on catabolism of apoB-100 containing lipoproteins.

Okazaki M, Usui S, Ishigami M, Sakai N, Nakamura T, Matsuzawa Y, Yamashita S. · Laboratory of Chemistry, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, 2-8-30, Kohnodai, Ichikawa-shi, Chiba 272-0827, Japan. · Arterioscler Thromb Vasc Biol. · Pubmed #15637308 links to  free full text

Abstract: OBJECTIVE: The contribution of visceral fat accumulation to the development of coronary heart disease was previously reported, but the relation between visceral fat accumulation and serum lipoprotein subclasses was unknown. METHODS AND RESULTS: We examined the relation of lipoprotein subclasses with visceral fat accumulation in 62 male subjects (aged 22 to 67 years) with visceral fat syndrome or obesity. Cholesterol levels in very low-density, low-density, and high-density lipoprotein subclasses (VLDL, LDL, and HDL) were determined by computer-assisted high-performance liquid chromatography. Subcutaneous fat area and visceral fat area were measured by computed tomographic scanning. There was no significant correlation between the subcutaneous fat area and the cholesterol levels in all lipoprotein subclasses. In contrast, the visceral fat area was correlated positively (P<0.002) with VLDL and LDL subclasses, except for large LDL, but negatively (P<0.001) with those in large and medium HDL subclasses. The observed positive correlations of small and very small LDL subclasses remained significant (P<0.005) after adjustment for serum cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol, respectively, but a significant negative correlation (P<0.005) of large LDL was obtained after adjustment for LDL cholesterol. CONCLUSIONS: These findings indicate that this simple high-performance liquid chromatography method may be applied for easy detection and evaluation of abnormal distribution of lipoprotein subclasses.

Matsumoto S, Kishida K, Shimomura I, Maeda N, Nagaretani H, Matsuda M, Nishizawa H, Kihara S, Funahashi T, Matsuzawa Y, Yamada A, Yamashita S, Tamura S, Kawata S. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. · Biochem Biophys Res Commun. · Pubmed #11922634 No free full text.

Abstract: The mechanism by which the obese subjects are more associated with vascular disease remains unclear. We reported that the adipose tissues produce and secrete many bioactive molecules, conceptualized as adipocytokines. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), produced locally by vascular macrophages and smooth muscle cells, has been suggested to induce the migration and proliferation of vascular smooth muscle cells. The current study reveals that (1) HB-EGF mRNA is abundantly expressed in human adipose tissue, (2) HB-EGF mRNA increases in the fat tissues of obese mice, (3) plasma HB-EGF levels increase in parallel with fat accumulation in human, and (4) the subjects with coronary artery disease have higher plasma HB-EGF levels, associated with fat accumulation. These results suggest that increased plasma HB-EGF derived from the accumulated fat contributes to the higher incidence of vascular disease in obesity, proposing HB-EGF as an adipocytokine directly linking adipovascular axis.

Takahashi M, Nagaretani H, Funahashi T, Nishizawa H, Maeda N, Kishida K, Kuriyama H, Shimomura I, Maeda K, Hotta K, Ouchi N, Kihara S, Nakamura T, Yamashita S, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. · Obes Res. · Pubmed #11445660 No free full text.

Abstract: OBJECTIVE: Adipocytes secrete various cytokines and matrix proteins. Several of them precipitate in obesity-associated diseases, including atherosclerosis. In the current study, we have examined the expression of secreted protein, acidic and rich in cysteine (SPARC) in adipose tissue and its significance in obesity and coronary artery disease (CAD). RESEARCH METHODS AND PROCEDURES: The SPARC mRNA expressions both in vivo and in vitro were detected by Northern blot analysis. Plasma SPARC concentrations were measured by enzyme immunosorbent assay. First, we investigated the plasma SPARC levels of 88 unrelated adult Japanese subjects (62 men and 26 women; average age: [+/- SD] 50 +/- 12 years; body mass index [BMI]: 16 to 46 kg/m(2)). Additionally 31 subjects with CAD diagnosed by coronary angiography (20 men and 11 women) were also investigated. RESULTS: Human adipose tissues expressed abundant SPARC mRNA. SPARC expression in adipose tissues was upregulated in obese db/db mice. Markedly enhanced expression of SPARC mRNA was observed in 3T3-L1 fibroblasts during adipocyte differentiation. Consistent with these results, plasma SPARC levels proved a positive correlation with BMI in humans (r = 0.27; p < 0.01). Interestingly, plasma SPARC concentrations were significantly elevated in age- and BMI-matched subjects with CAD (p < 0.05). DISCUSSION: SPARC was expressed in adipose tissues and its expression was enhanced in obese mice. In human, plasma SPARC levels were elevated in obesity and CAD patients. This elevated SPARC may be involved in the progression of CAD.

Nakamura T, Tsubono Y, Kameda-Takemura K, Funahashi T, Yamashita S, Hisamichi S, Kita T, Yamamura T, Matsuzawa Y, Anonymous00022. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Japan. · Jpn Circ J. · Pubmed #11153815 links to  free full text

Abstract: A case-control study was performed to clarify the cause of ischemic heart disease (IHD), such as acute myocardial infarction and angina pectoris, in Japanese employees. Among 122,051 workers from 31 industries, 94 cases of IHD were the subjects of the study, and a total of 191 age-matched subjects from the same department, but who did not develop IHD, served as the controls. Compared with the control group, body mass index, blood pressure, fasting plasma glucose, serum total cholesterol and serum triglyceride were significantly higher, and cigarette consumption and serum uric acid also tended to be higher, in the patient group from at least 10 years prior to onset. The frequency of moderate-drinkers tended to be lower in the case group. Electrocardiograms showed that, compared with the control group, the frequency of myocardial ischemia was higher in the case group from 9 years prior to onset and further rapidly increased from 3 years prior. The frequency of subjects with arrhythmia was the same as the control group until 3 years before onset and increased rapidly from 2 years prior. The frequency of subjects with multiple risk factors, particularly obesity, hypertension, hyperlipidemia and hyperglycemia, was consistently higher in the case group compared with the control group from 10 years prior to onset. Conditional logistic regression analysis demonstrated that having more than one risk factor greatly increased the risk; in particular, the combination of 3 or more factors increased the relative risk to 10.56 (95% confidence interval: 3.30-33.78). These findings suggest that a long duration of multiple risks is involved in the onset of IHD in Japanese employees, and that annual ECG monitoring as part of the medical examination was important in the prognosis.

Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. · Circulation. · Pubmed #10982546 links to  free full text

Abstract: BACKGROUND: Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CIRCULATION: 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. METHODS AND RESULTS: The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 microg/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced IkappaB-alpha phosphorylation and subsequent NF-kappaB activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. CONCLUSIONS: These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappaB signaling pathways.

Takahashi M, Arita Y, Yamagata K, Matsukawa Y, Okutomi K, Horie M, Shimomura I, Hotta K, Kuriyama H, Kihara S, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. · Int J Obes Relat Metab Disord. · Pubmed #10918532 No free full text.

Abstract: BACKGROUND: Adiponectin is a collagen-like plasma protein specifically synthesized in adipose tissue. Plasma adiponectin concentrations are decreased in obesity whereas it is adipose-specific. OBJECTIVE: To clarify the significance of the genetic variations in adiponectin gene on its plasma concentrations and obesity. SUBJECTS: Two hundred and nineteen unrelated adult Japanese subjects (123 men and 96 women, age: 20-83 y, BMI: 16-43 kg/m2) including 77 obese subjects (BMI>26.4 kg/m2). MEASUREMENT: Human adiponectin gene was isolated from PAC DNA pools. Mutations in the adiponectin gene were screened by direct sequencing or restriction-fragment polymorphism. The levels of plasma adiponectin were determined by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin gene spanned 17 kb on chromosome 3q27, consisting of three exons and two introns. Within 2.1 kb of the 5'-flanking region, there were two octamer elements present in the promoter of adipsin. Two nucleotide changes were identified. One was a polymorphism (G/T) occurring in exon 2, and the other was a missense mutation (R112C) in exon 3. The mean plasma adiponectin levels of the subjects carrying G allele were low (G/G: 4.5 microg/ml; G/T: 5.9 microg/ml; and T/T: 6.3 microg/ml), but were not statistically significant. The allelic frequency between the obese and the non-obese showed no significant difference. The subject carrying R112C mutation showed markedly low concentration of plasma adiponectin. CONCLUSION: Two nucleotide changes have been identified in the adiponectin gene. G/T polymorphism in exon 2 was associated with neither plasma adiponectin concentrations nor the presence of obesity. A subject carrying missense mutation (R112C) showed markedly low plasma adiponectin concentration.

Hotta K, Matsukawa Y, Nishida M, Kotani K, Takahashi M, Kuriyama H, Nakamura T, Wada K, Yamashita S, Funahashi T, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Japan. · Horm Metab Res. · Pubmed #10727011 No free full text.

Abstract: Bombesin receptor subtype-3 (BRS-3) is one of the candidate genes of obesity. The mice lacking BRS-3 have been shown to develop mild obesity. These mice also showed hypertension and impaired glucose metabolism, supporting these mice as a good model for human obesity. We screened 104 Japanese obese men (BMI > 26.4, 26.5-44.1) to investigate whether there is any genetic defect in BRS-3 gene. The DNA fragments containing each exon of BRS-3 gene were amplified by polymerase chain reaction (PCR) and were directly sequenced. No mutation, nor polymorphism was found in the coding region of BRS-3, suggesting that mutation of this gene is not a major cause of obesity in humans.

Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. · Circulation. · Pubmed #10604883 links to  free full text

Abstract: BACKGROUND: Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the molecular basis for the link between obesity and vascular disease has not been fully clarified. The present study investigated whether adiponectin could modulate endothelial function and relate to coronary disease. METHODS AND RESULTS: For the in vitro study, human aortic endothelial cells (HAECs) were preincubated for 18 hours with the indicated amount of adiponectin, then exposed to tumor necrosis factor-alpha (TNF-alpha) (10 U/mL) or vehicle for the times indicated. The adhesion of human monocytic cell line THP-1 cells to HAECs was determined by adhesion assay. The surface expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1) was measured by cell ELISA. Physiological concentrations of adiponectin dose-dependently inhibited TNF-alpha-induced THP-1 adhesion and expression of VCAM-1, E-selectin, and ICAM-1 on HAECs. For the in vivo study, the concentrations of adiponectin in human plasma were determined by a sandwich ELISA system that we recently developed. Plasma adiponectin concentrations were significantly lower in patients with coronary artery disease than those in age- and body mass index-adjusted control subjects. CONCLUSIONS: These observations suggest that adiponectin modulates endothelial inflammatory response and that the measurement of plasma adiponectin levels may be helpful in assessment of CAD risk.

Yoshizumi T, Nakamura T, Yamane M, Islam AH, Menju M, Yamasaki K, Arai T, Kotani K, Funahashi T, Yamashita S, Matsuzawa Y. · Division of Radiology, Minoh City Hospital, Osaka, Japan. · Radiology. · Pubmed #10189485 links to  free full text

Abstract: The authors estimated abdominal fat distribution on the basis of measurements at computed tomography (CT). The attenuation range for fat tissue was defined as the interval within the mean plus or minus 2 SDs considered to be individual variation. Fat areas found with this method were closely correlated with those obtained by means of the computed planimetric method or with a fixed attenuation range from -190 to -30 HU as the standard of reference. Although the average CT numbers obtained with different scanners were distributed widely, the calculated fat areas were almost identical. This method might be a practical and standardized method at CT.

Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. · Graduate School of Medicine, Institute for Molecular and Cellular Biology, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. · Biochem Biophys Res Commun. · Pubmed #10092513 No free full text.

Abstract: We isolated the human adipose-specific and most abundant gene transcript, apM1 (Maeda, K., et al., Biochem. Biophys. Res. Commun. 221, 286-289, 1996). The apM1 gene product was a kind of soluble matrix protein, which we named adiponectin. To quantitate the plasma adiponectin concentration, we have produced monoclonal and polyclonal antibodies for human adiponectin and developed an enzyme-linked immunosorbent assay (ELISA) system. Adiponectin was abundantly present in the plasma of healthy volunteers in the range from 1.9 to 17.0 mg/ml. Plasma concentrations of adiponectin in obese subjects were significantly lower than those in non-obese subjects, although adiponectin is secreted only from adipose tissue. The ELISA system developed in this study will be useful for elucidating the physiological and pathophysiological role of adiponectin in humans.

Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. · Department of Medicine and Pathophysiology, Graduate School of Medicine, and Department of Organismal Biosystems, Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. · Science. · Pubmed #15604363 links to  free full text

Abstract: Fat tissue produces a variety of secreted proteins (adipocytokines) with important roles in metabolism. We isolated a newly identified adipocytokine, visfatin, that is highly enriched in the visceral fat of both humans and mice and whose expression level in plasma increases during the development of obesity. Visfatin corresponds to a protein identified previously as pre-B cell colony-enhancing factor (PBEF), a 52-kilodalton cytokine expressed in lymphocytes. Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. Mice heterozygous for a targeted mutation in the visfatin gene had modestly higher levels of plasma glucose relative to wild-type littermates. Surprisingly, visfatin binds to and activates the insulin receptor. Further study of visfatin's physiological role may lead to new insights into glucose homeostasis and/or new therapies for metabolic disorders such as diabetes.