Obesity: Tanaka M

Tanaka M, Gong J, Zhang J, Yamada Y, Borgeld HJ, Yagi K. · Department of Gene Therapy, Gifu International Institute of Biotechnology, Yagi Memorial Park, Gifu, 505-0116, Mitake, Japan. · Mech Ageing Dev. · Pubmed #10996007 No free full text.

Abstract: Mitochondria are not only the major site of ATP production in cells but also an important source of reactive oxygen species (ROS) under certain pathological conditions. Because mitochondrial DNA (mtDNA) in the mitochondrial matrix is exposed to ROS that leak from the respiratory chain, this extranuclear genome is prone to mutations. Therefore, the mitochondrial genome is a rich source of single nucleotide polymorphisms (SNPs) and the functional significance of SNPs in the mitochondrial genome is comparable to that of SNPs in the entire nuclear genome. To demonstrate the contribution of mitochondrial SNPs to the susceptibility to adult-onset diseases, we analyzed the mtDNA from Japanese centenarians and identified a longevity-associated mitochondrial genotype, Mt5178A. Because this genotype was demonstrated to suppress the occurrence of mtDNA mutations in the oocytes, it also would seem to decelerate the accumulation of mtDNA mutations in the somatic cells with increasing age. This genotype is likely to confer resistance to adult-onset diseases by suppressing obesity and atherosclerosis.

Inukai K, Watanabe M, Nakashima Y, Sawa T, Takata N, Tanaka M, Kashiwabara H, Yokota K, Suzuki M, Kurihara S, Awata T, Katayama S. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Saitama Medical School, 38 Morohongo, Iruma-gun, Saitama-ken 350-0495, Japan. · Diabetes Res Clin Pract. · Pubmed #15936468 No free full text.

Abstract: We investigated the efficacy of glimepiride, a third-generation sulfonylurea (SU), in Japanese type 2 diabetic patients in whom glycemic control had been inadequate with a conventional SU, gliclazide or glibenclamide. A total of 172 Japanese type 2 diabetic patients (HbA1C > or = 7.0%), maintained on a conventional SU, were randomly assigned to the 3rd SU group (SU treatments switched to glimepiride) or the 2nd SU group (treatments not changed). The conventional SU was switched to the indicated doses of glimepiride (gliclazide 40 mg = glimepiride 1 mg, glibenclamide 2.5 mg = glimepiride 2 mg). After 6 months, glycemic control (HbA1C and fasting plasma glucose) had not changed significantly in either the 2nd or the 3rd SU group. The homeostasis assessment model of insulin resistance (HOMA-IR) in the 3rd SU group was decreased by more than 10% (p = 0.015), whereas no change was observed in the 2nd SU group. The triglyceride level was decreased by approximately 10% in the 3rd SU group, not a significant change (p = 0.080). Patients who had been treated with only SU, or treated with SU for a short time (less than 5 years), and who were also obese (BMI > or = 25) or had a high HOMA-IR (HOMA-IR > or = 3), showed significantly reduced insulin resistance. According to logistic regression analysis, high BMI ( > or = 25) was the only variable predicting that glimepiride would more effectively improve HbA1C than conventional SU treatment. In conclusion, switching conventional SUs to glimepiride reduced insulin resistance without improving glycemic control. A notable finding of this study is that glimepiride was more beneficial in obese than in non-obese Japanese type 2 diabetic patients.

Tanaka M, Yamada S, Iwasaki Y, Sugishita T, Yonemoto S, Tsukamoto T, Fukui S, Takasu K, Muso E. · Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan. · Nephron Clin Pract. · Pubmed #19390205 No free full text.

Abstract: BACKGROUND: The pathological role of obesity in the progression of glomerular lesions has rarely been studied in primary glomerular diseases. The purpose of this study is to investigate the influence of non-diabetic obesity on clinicopathological findings in IgA nephropathy. METHODS: 74 patients with biopsy-proven IgA nephropathy were retrospectively divided into two groups according to the criteria for obesity in Japan: non-obese group (group N: n = 50) with BMI <25 kg/m(2), and obese group (group O: n = 24) with BMI > or =25 kg/m(2). Clinical and pathological data at the time of renal biopsy were analyzed. Moreover, the outcome of proteinuria in patients treated with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARB) was evaluated in different groups after a 1-year follow-up. RESULTS: Urinary protein excretion was significantly greater in the obese group compared to normal-weight patients (p < 0.05). There was no significant difference in the prevalence of hypertension and hyperlipidemia. By light microscopy, the obese group showed significantly larger glomerular size (p < 0.0001). On the other hand, the severity of mesangial matrix expansion and crescent formation revealed no difference between the two groups. By electron microscopy, glomerular basement membrane (GBM) thickness was significantly increased in obese patients (p < 0.001). Among 61 patients who were followed up for 1 year in our institute, 15 patients were treated with ACE-I or ARB without steroids. ACE-I or ARB treatment without steroids tended to reduce proteinuria in the obese patients, but this change did not achieve statistical significance. CONCLUSIONS: In IgA nephropathy, obesity induces not only glomerular enlargement but also ultrastructural modification of GBM, which would contribute to increase proteinuria.

Koga R, Tanaka M, Tsuda H, Imai K, Abe S, Masuda T, Iwamoto M, Nakazono E, Kamohara T, Sakata T. · Graduate School of Health and Nutrition Sciences, Health Promotion Center, Nakamura Gakuen University, Fukuoka, Japan. · Am J Med Sci. · Pubmed #19092316 No free full text.

Abstract: BACKGROUND: Visceral adiposity is an essential component of metabolic syndrome. Reduction of excessive visceral fat prevents metabolic syndrome and improves atherosclerotic diseases. This study aimed to identify dietary patterns and physical exercise during the training-education period that predict visceral adiposity regain during the follow-up period. METHODS: One hundred one moderately obese Japanese women, 23 to 67 years of age, participated in 0- to 4-month training-education and 12-month follow-up periods. Dietary patterns of food groups during training-education were analyzed by principal components analysis, and 3 major dietary patterns were derived. The change in visceral fat over the follow-up, adjusted for 4-month visceral fat area (VFA) and 4- to 16-month body mass index change, was analyzed using stepwise multiple linear regression. RESULTS: VFA and body weight decreased during training-education (P<0.001) and were maintained during follow-up. One major dietary pattern (of 3) (P=0.030) and standard deviations of daily exercise duration (P=0.012) during training-education predicted VFA regain during follow-up. This regain correlated negatively with combinations of bread, milk and dairy products, fruits, seeds and nuts, and mushrooms, but positively with combinations of rice, pickles, miso, alcohol, and meat. The large standard deviation of daily exercise duration during training-education showed greater VFA regain during follow-up than did the smaller standard deviation (P=0.023), but body mass index did not show a similar trend. CONCLUSION: Our results revealed that daily exercise fluctuations and dietary patterns were useful predictors of visceral fat regain.

Ma G, Zhao X, Ueno M, Tanaka M, Machida Y, Aikawa H, Usuda K, Sagawa M, Ueda Y, Sakuma T. · Thoracic Surgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan. · Tohoku J Exp Med. · Pubmed #18987456 links to  free full text

Abstract: Diabetic patients have a decreased incidence of acute respiratory distress syndrome, but the mechanism responsible for the decreased incidence is uncertain. Reabsorption of alveolar edema fluid (alveolar fluid clearance) has been considered to play an important role in resolution of acute respiratory distress syndrome. However, little is known regarding alveolar fluid clearance in diabetes mellitus. Since the obese Zucker rat has been used as an experimental model for diabetes mellitus, we determined if alveolar fluid clearance increased in the obese Zucker rat. First, we compared alveolar fluid clearance in obese Zucker rats with that in lean Zucker rats and Sprague-Dawley (SD) rats. Then, we determined the role of sodium channel, Na,K-ATPase, and beta(2)-adrenoceptor, which drives alveolar fluid clearance, in obese Zucker rats. Alveolar fluid clearance was estimated by the progressive increase in alveolar albumin concentrations in the isolated lungs. We found that basal alveolar fluid clearance in obese Zucker rats was two-fold greater than that in lean Zucker rats and SD rats. The mRNA expression of alpha(1)-, beta(1)-Na, K-ATPase and beta(2)-adrenoceptor, but not mRNA expression of sodium channel, increased in obese Zucker rats. A selective beta(2)-agrenergic antagonist, but not a Na, K-ATPase inhibitor, specifically inhibited the increase in alveolar fluid clearance in obese Zucker rats. These results indicate that overexpression of beta(2)-adrenoceptor primarily increases basal alveolar fluid clearance in the obese Zucker rat. We speculate that the stimulation of alveolar fluid clearance ameliorates acute respiratory distress syndrome in patients with diabetes mellitus.

Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, Kobayashi Y, Nitta N, Yasuda K, Hirata Y, Kuziel WA, Takeya M, Kanegasaki S, Kamei Y, Ogawa Y. · Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8510, Japan. · J Biol Chem. · Pubmed #18977759 No free full text.

Abstract: The MCP-1 (monocyte chemoattractant protein-1)/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue. Here we investigated the role of CCR2 in the recruitment of bone marrow-derived macrophages into obese adipose tissue in vitro and in vivo. Using the TAXIScan device, which can measure quantitatively the directionality and velocity of cell migration at time lapse intervals in vitro, we demonstrated that bone marrow cells (BMCs) from wild type mice migrate directly toward MCP-1 or culture medium conditioned by adipose tissue explants of genetically obese ob/ob mice, which are efficiently suppressed by pharmacological blockade of CCR2 signaling. The number of F4/80-positive macrophages was reduced in the adipose tissue from high fat diet-fed obese KKAy or ob/ob mice treated with a CCR2 antagonist propagermanium relative to vehicle-treated groups. We also found that the number of macrophages is reduced in the adipose tissue from ob/ob mice reconstituted with CCR2(-/-) BMCs (ob/ob + CCR2(-/-) BMCs) relative to those with CCR2+/+ BMCs (ob/ob + CCR2+/+ BMCs). Expression of mRNAs for CD11c and TLR4 (Toll-like receptor 4) markers of proinflammatory M1 macrophages was also decreased in the adipose tissue from ob/ob + CCR2(-/-) BMCs relative to ob/ob + CCR2+/+ BMCs, whereas mannose receptor and CD163, markers of anti-inflammatory M2 macrophages, were unchanged. This study provides in vivo and in vitro evidence that CCR2 in bone marrow cells plays an important role in the recruitment of macrophages into obese adipose tissue.

Ichihara S, Yamada Y, Kato K, Hibino T, Yokoi K, Matsuo H, Kojima T, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Yasunaga A, Park H, Tanaka M, Nozawa Y. · Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie 514-8507, Japan. · Genomics. · Pubmed #18442890 No free full text.

Abstract: The aim of the present study was to identify gene polymorphisms that confer susceptibility to obesity. A total of 5448 unrelated Japanese individuals from two independent populations were examined: subject panel A comprised 4252 individuals who visited participating hospitals; subject panel B comprised 1196 community-dwelling elderly individuals. The genotypes for 95 polymorphisms of 67 candidate genes were determined. The chi(2) test revealed that six polymorphisms were related (p<0.05) to the prevalence of obesity in subject panel A; after application of Bonferroni's correction, however, only the 2677G --> A/T polymorphism (rs2032582) of the ATP-binding cassette, subfamily B, member 1 gene (ABCB1) was significantly associated (p=0.0003) with obesity. Subsequent multivariable logistic regression analysis also revealed that the 2677G --> A/T polymorphism of ABCB1 was significantly associated with obesity. For validation of this association, the 2677G --> A/T polymorphism of ABCB1 was examined in subject panel B and again found to be significantly associated with obesity. Body mass index was significantly (p=0.01) greater for individuals with the variant T allele of this polymorphism than for those with the GG genotype in the combined subject panels A and B. Our results suggest that the ABCB1 genotype may prove informative for assessment of genetic risk for obesity in Japanese individuals.

Itoh M, Suganami T, Satoh N, Tanimoto-Koyama K, Yuan X, Tanaka M, Kawano H, Yano T, Aoe S, Takeya M, Shimatsu A, Kuzuya H, Kamei Y, Ogawa Y. · Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. · Arterioscler Thromb Vasc Biol. · Pubmed #17569885 links to  free full text

Abstract: OBJECTIVES: Fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) or n-3 PUFAs have been shown to reduce the incidence of coronary heart disease. Here we investigated the effect of highly purified eicosapentaenoic acid (EPA) on production of adiponectin, the only established antiatherogenic and antiinflammatory adipocytokine, in rodent models of obesity and human obese subjects. METHODS AND RESULTS: We demonstrated that EPA increases adiponectin secretion in genetically obese ob/ob mice and high-fat diet-induced obese mice. In the in vitro coculture of adipocytes and macrophages, EPA reversed the coculture-induced decrease in adiponectin secretion at least in part through downregulation of tumor necrosis factor-alpha in macrophages. We also showed significant increase in plasma adiponectin concentrations in human obese subjects after a 3-month treatment with EPA (1.8 g daily). Multivariate regression analysis revealed that EPA treatment is the only independent determinant of plasma adiponectin concentrations. CONCLUSION: This study demonstrates that EPA increases adiponectin secretion in rodent models of obesity and human obese subjects, possibly through the improvement of the inflammatory changes in obese adipose tissue. Because EPA has reduced the risk of major coronary events in a large-scale, prospective, randomized clinical trial, this study provides important insight into its therapeutic implication in obesity-related metabolic sequelae.

Tanaka M, Tsujii T, Komiya T, Iwasaki Y, Sugishita T, Yonemoto S, Tsukamoto T, Fukui S, Takasu A, Muso E. · Department of Nephrology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan. · Contrib Nephrol. · Pubmed #17495442 No free full text.

Abstract: The pathological role of obesity has rarely been studied in primary glomerular diseases. The purpose of this study is to examine the clinicopathological influence of obesity in IgA nephropathy (IgAN). 74 patients with IgA nephropathy in our institution from October 2000 to January 2004 were retrospectively divided into two groups according to body mass index (BMI): the non-obese group (group N) with BMI < 25 kg/m(2), and the obese group (group O) with BMI > or = 25 kg/m(2). There were 50 patients in group N and 24 patients in group O. Clinical analysis showed no significant difference between these two groups in blood pressure, serum cholesterol, creatinine clearances or grade of hematuria. However, urinary protein excretion and serum creatinine were significantly greater in group O than in group N. Although semiquantitative analysis of light-microscopical findings showed no significant differences in the severity of mesangial proliferation, matrix expansion, glomerulosclerosis or crescent formation, image analysis showed that total glomerular area and tuft area were significantly larger in group O. In addition, ultrastructural study revealed significantly higher glomerular basement membrane thickness in group O. 62 patients (46 patients, group N; 16 patients, group O) were followed in our institution for one year. Urinary protein was significantly decreased only in patients who received steroid in both groups. Although administration of ACE inhibitor or ARB tended to decrease urinary protein in group O, the change was not statistically significant. Our findings indicate that obesity may accelerate the increase of proteinuria in IgAN through ultrastructural modification of the glomerular basement membrane.

Tanaka S, Yoshiyama M, Imanishi Y, Nakahira K, Hanaki T, Naito Y, Imai M, Tanaka M. · Department of Radiology, Wakakusa Daiichi Hospital, and Department of Internal Medicine and Cardiology, Graduate School of Medicine, Osaka City University, Japan. · Magn Reson Med Sci. · Pubmed #17332712 links to  free full text

Abstract: One diagnostic criterion for metabolic syndrome is obesity from the accumulation of visceral fat; others include abdominal circumference and area of visceral fat as measured by computed tomography (CT) at the umbilical level. We evaluated visceral fat using frequency-selective excitation magnetic resonance (MR) imaging SPAIR (spectral attenuation with inversion recovery) water suppression THRIVE (3D T1-high resolution isotropic volume examination). Fifty of 70 slices with 2-mm interval were used to render and measure volume of visceral fat ranging within 10 cm of the umbilicus; the area of visceral fat at the umbilical level was also measured. Imaging was completed using breath hold within 14 s. Image processing was easier than using CT.

Tanaka M, Fuku N, Nishigaki Y, Matsuo H, Segawa T, Watanabe S, Kato K, Yokoi K, Yoko K, Ito M, Nozawa Y, Yamada Y. · Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology-Tokyo, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan. · Diabetes. · Pubmed #17259400 links to  free full text

Abstract: To identify mitochondrial haplogroups that confer resistance against or susceptibility to metabolic syndrome, we performed a large-scale association study on 1,337 unrelated Japanese individuals, including 871 subjects with metabolic syndrome and 466 control subjects. Metabolic syndrome was diagnosed according to modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using the cutoff point for obesity as a BMI of >/=25 kg/m(2) instead of waist circumference. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups, i.e., F, B, A, N9a, M7a, M7b, G1, G2, D5, and D4. Multivariate logistic regression analysis revealed that the haplogroup N9a was significantly associated with resistance against metabolic syndrome in women with an odds ratio (OR) of 0.21 (95% CI 0.07-0.58, P = 0.0042). Women with haplogroups G1 and D5 tended to be resistant against metabolic syndrome with an OR of 0.22 (0.06-0.68, P = 0.0129) for G1 and with an OR of 0.32 (0.10-0.96, P = 0.0469) for D5, respectively. These results indicate that mitochondrial haplogroup N9a may be a protective factor against metabolic syndrome in Japanese women.

Segawa K, Fukuhara A, Hosogai N, Morita K, Okuno Y, Tanaka M, Nakagawa Y, Kihara S, Funahashi T, Komuro R, Matsuda M, Shimomura I. · Department of Medicine and Pathophysiology, Graduate School of Medicine, Osaka University, Osaka, Japan. · Biochem Biophys Res Commun. · Pubmed #16970912 No free full text.

Abstract: Obesity is associated with metabolic disorders, such as insulin resistance. Visfatin is an adipose-derived secretory factor to exert insulin-mimetic effects. Plasma visfatin levels and mRNA levels of visfatin in adipose tissues are increased in obesity. However, the mechanism that mediates induction of visfatin mRNA in adipose tissue of obesity remains unknown. Recent studies have reported that fat tissue is hypoxia in obesity. In this study, we investigated the effects of hypoxia on mRNA expression of visfatin in adipocytes. Hypoxia increased visfatin mRNA expression. Desferoxamine and Cobaltous chloride, two hypoxia mimetic compounds, also increased visfatin mRNA levels. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF1alpha), mimicked the hypoxia-mediated upregulation of visfatin, and YC1, an inhibitor of HIF1 cancelled the hypoxia-induced upregulation of visfatin mRNA. We identified two functional hypoxia responsive elements (HRE) in mouse visfatin promoter. Hypoxic treatment and overexpression of HIF1alpha increased the promoter activity, and mutation of the HRE blunted hypoxia-induced activation of visfatin promoter. Our results suggest that visfatin mRNA expression is upregulated in the fat tissue of obesity through the activation of HIF1alpha pathway due to hypoxia.

Isomura K, Kono S, Moore MA, Toyomura K, Nagano J, Mizoue T, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Imaizumi N. · Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. · Cancer Sci. · Pubmed #16918995 No free full text.

Abstract: The number of cases of colorectal cancer in Japan has increased over the past few decades, and incidence rates are now among the highest in the world. The present investigation within the Fukuoka Colorectal Cancer Study, including 778 cases and 767 controls aged 20-74 years, examined the association between physical activity and colorectal cancer risk by subsite. Employment-associated and leisure time physical activity was assessed by a questionnaire and interview. Division of sites into the proximal and distal colon, as well as the rectum, revealed clear site-dependent protective effects, with adjustment for smoking, alcohol consumption, BMI and age. In males, greater job-related physical activity was associated with significant reduction of risk in the distal colon and rectum (P = 0.047 and 0.02, respectively), whereas total and moderate or hard non-job physical activity exerted effects limited to the rectum (P = 0.01 and 0.004, respectively). In females, job-related physical activity and moderate or hard non-job physical activity was also protective, but only in the distal colon. Separate assessment of the influence of BMI 10 years previous to the study showed increase in risk with obesity in males but not in females, limited to distal colon and rectum. The results of the present study indicate that physical activity associated with work and leisure-time exerts beneficial effects in Japanese, but not on the proximal colon.

Hamano S, Nakatsu H, Suzuki N, Tomioka S, Tanaka M, Murakami S. · Department of Urology, Asahi General Hospital, Asahi-city, Chiba, Japan. · Int J Urol. · Pubmed #16323977 No free full text.

Abstract: BACKGROUND: We conducted a case-control study to examine the impact of coronal heart disease (CHD) risk factors on calcium oxalate (CaOX) stone formation. METHODS: Variables included body mass index (BMI), current alcohol use, smoking habit, hypertension, hypercholesterolemia, diabetes mellitus, and hyperuricemia. Data suf fi cient for analysis were obtained for 181 CaOX stone formers and 187 controls. RESULTS: Seven of 181 stone formers (3.9%) had a history of CHD compared with none of 187 control subjects (P = 0.007). In univariate logistic regression analysis, smoking habit (OR 4.41, 95% CI 2.85-6.84, P < 0.0001), hypertension (OR 4.24, 95% CI 2.61-6.91, P < 0.0001), hypercholesterolemia (OR 3.03, 95% CI 1.77-5.20, P < 0.0001) and BMI (OR 1.10, 95% CI 1.04-1.17, P = 0.007) reached statistical signi fi cance. In a multivariate logistic regression analysis, smoking habit (OR 4.29, 95% CI 2.68-6.86, P < 0.0001), hypertension (OR 3.57, 95% CI 2.11-6.07, P < 0.0001), and hypercholesterolemia (OR 2.74, 95% CI 1.51-5.00, P = 0.001) reached statistical signi fi cance, while BMI (OR 1.06, 95% CI 0.99-1.12, P = 0.09) did not. CONCLUSIONS: CaOX stone formers are signi fi cantly associated with several CHD risk factors, including smoking habit, hypertension, hypercholesterolemia, and obesity.

Tanaka M, Umezaki M, Natsuhara K, Yamauchi T, Inaoka T, Hongo T, Nagano M, Watanabe C, Ohtsuka R. · Department of Human Ecology, School of International Health, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. · Am J Hum Biol. · Pubmed #16254894 No free full text.

Abstract: Pacific Islands populations can be broadly divided into Austronesians (AN) and Non-Austronesians (NAN); obesity and type 2 diabetes are prevalent in the former, although leptin levels in both groups have seldom been investigated. Thirty-seven (20 male and 17 female) adult pairs, matched by age and percent body fat, from AN-speaking Balopa and NAN-speaking Huli, all of whom migrated to settle in Port Moresby, the capital of Papua New Guinea, were selected for comparison of their serum leptin concentrations. The Balopa did not differ significantly from the Huli in age (30.5 +/- 9.7 and 30.0 +/- 8.7 years for males, 33.7 +/- 8.9 and 34.1 +/- 7.5 years for females, respectively) or percent body fat (19.4 +/- 5.6 and 18.8 +/- 4.6 for males, 34.1 +/- 6.2 and 33.3 +/- 5.0 for females), although the BMI of females was lower in the Balopa (26.4 +/- 4.9) than in the Huli (29.7 +/- 4.7) (P = 0.02). In both ethnic groups, females had markedly higher leptin concentrations than males, but there was no significant inter-group difference in males (3.5 +/- 2.6 and 3.1 +/- 4.7 ng/ml, P = 0.14) or females (22.7 +/- 12.9 and 19.7 +/- 11.9 ng/ml, P = 0.40), after controlling for lifestyle factors and serum lipids. Multiple regression analysis revealed that significant predictors of leptin concentration were % body fat (beta = 0.58), sex (male, 0; female, 1; beta = 0.27), and smoker status (non-smoker, 0; smoker, 1; beta = -0.15) (R(2) = 0.80), implying that the leptin concentration was primarily determined by lifestyle-derived body fatness. In conclusion, the NAN populations do not endogenously differ in leptin status from the AN populations, who have been recognized as a typical group with a "thrifty" genotype.

Akimoto T, Kobayashi S, Tamura N, Ohsawa T, Kawano T, Tanaka M, Hashimoto H. · Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan. · Angiology. · Pubmed #16193200 No free full text.

Abstract: Not only antiphospholipid antibodies (aPLs) but also other factors should be considered in assessing the risk of thrombosis development in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPLs). The kinds of risk factors, including past history of thrombotic event (PHTE), hypertension, hypercholesterolemia, diabetes mellitus (DM), obesity, and smoking, in conjunction with aPLs, that contribute to the development of new thrombotic events in patients with SLE and aPLs were studied prospectively over a 5-year observation period. One-hundred and sixty-six Japanese patients with SLE (55 patients with aPLs and 111 patients without aPLs) were examined and followed up for 5 years. Five major risk factors for ischemic coronary disease and stroke according to the Framingham heart cohort study were evaluated objectively in these patients. A significant difference was seen for 4 factors: past history of thrombotic event (PHTE; odds ratio: 101.93; 95% confidence interval: 12.29-845.22; p < 0.0001), hypertension (odds ratio: 8.87; 95% CI: 2.58-30.53; p < 0.001), DM (odds ratio: 5.42; 95% CI: 1.44-20.46; p < 0.05), and lupus anticoagulant (LAC; odds ratio: 47.41; 95% CI: 5.88-382.03, p < 0.0001) as aPLs, when the incidence of these risk factors was compared between patients with and without new thrombotic events. Furthermore, PHTE (odds ratio: 30.19, 95% CI: 1.33-683.13), hypertension (odds ratio: 15.44; 95% CI: 1.77-134.80), and LAC (odds ratio: 14.11; 95% CI: 0.48-412.42) showed higher odds ratios than DM (odds ratio: 11.53; 95% CI: 0.83-159.94) on multivariate logistic analysis as well as analysis of the combination of risk factors, suggesting that these are important risk factors for the development of new thrombotic events in patients with SLE and aPLs.

Igaki N, Tanaka M, Goto T. · Department of Internal Medicine, Takasago Municipal Hospital, Japan. · Intern Med. · Pubmed #16157982 links to  free full text

Abstract: A patient with type 2 diabetes and hypothalamic damage due to a suprasellar tumor developed impaired glycemic control and central obesity. The patient showed exaggerated adrenocorticotropic hormone responsiveness as determined by a corticotrophin releasing hormone test and elevated serum leptin concentrations associated with ravenous appetite and insulin resistance mediated in part through disturbances in leptin signaling. Combination treatment with metformin and pioglitazone was markedly effective in improving glycemic control. Additionally, metformin treatment showed marked anorectic effects on the hyperphagia. This case has important implications for the pathogenesis and management of diabetes in patients with hypothalamic-pituitary-adrenal axis deficiencies.

Guo LJ, Oshida Y, Fuku N, Takeyasu T, Fujita Y, Kurata M, Sato Y, Ito M, Tanaka M. · Department of Sports Medicine, Graduate School of Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. · Mitochondrion. · Pubmed #16060290 No free full text.

Abstract: Although a strong correlation between type-2 diabetes and obesity has been found, no comparative analysis between diabetes and obesity has been performed with respect to mitochondrial DNA (mtDNA) polymorphisms. To test the hypothesis that certain mitochondrial single nucleotide polymorphisms (mtSNPs) might be associated with obesity or type-2 diabetes, we determined the entire sequences of the mitochondrial genomes from 96 patients with type-2 diabetes and those from 96 young obese adults by direct sequencing and compared the frequencies of mtSNPs between these two groups. A mtSNP, 8684C > T (T53I) in the mitochondrial ATP synthase subunit 6 gene (ATP6), was detected in 5 of the 96 patients with type-2 diabetes, whereas this substitution was not detected in any of the 96 young obese adults. Two mtSNPs, 3497C > T (A64V) in NADH dehydrogenase subunit 1 gene (ND1) and 1119T > C (472U > C) in the 12S rRNA gene, were detected in 5 of the 96 young obese adults, whereas these substitutions were not detected in any of the 96 diabetic patients. The 8684C > T transition associated with type-2 diabetes represents haplogroup M8a, and the 3497C > T and 1119T > C transitions predisposing to obesity represent haplogroup B4c. These results suggest that distinct mtSNPs contribute to susceptibility to type-2 diabetes or obesity, pointing out the necessity of large-scale case control studies.

Nishida N, Tanaka M, Hayashi N, Nagata H, Takeshita T, Nakayama K, Morimoto K, Shizukuishi S. · Japan Foundation for Aging and Health, Aichi, Japan. · J Periodontol. · Pubmed #15948686 No free full text.

Abstract: BACKGROUND: A model that focuses on personal risk factors associated with poor lifestyle has been proposed for the etiology of generalized periodontitis. Numerous investigations have linked individual lifestyle-related factors to periodontitis risk; however, a definite relationship among lifestyle-related factors remains unclear. The objective of this study was to determine which lifestyle-related factors demonstrated the greater impact on periodontitis risk. METHODS: The association of lifestyle-related factors, such as smoking status and obesity, with periodontitis was assessed in 372 Japanese workers via a self-administered questionnaire. Smoking status and obesity were evaluated in terms of pack-years and body mass index (BMI), respectively. Clinical periodontal examination included probing depth (PD). The effective impact on periodontitis risk was analyzed by the classification and regression tree (CART) method and multiple logistic regression analysis. RESULTS: Simple logistic regression analyses revealed that factors such as age, gender, alcohol consumption, smoking status, BMI, and frequency of toothbrushing were associated with periodontitis. CART results demonstrated a significant correlation between periodontitis and pack-years, BMI, and age; in contrast, alcohol consumption, gender, and toothbrushing frequency were not correlated with periodontitis. The strongest factor for periodontitis risk was pack-years of smoking. Additionally, both pack-years and BMI exhibited clear dose-response relationships with periodontitis. These relationships were maintained despite adjustment for known confounding factors. CONCLUSIONS: Smoking displays the greatest impact on periodontitis among lifestyle-related factors. Both smoking and obesity are independent risk indicators for periodontitis; moreover, these parameters exhibit a dose-response relationship with respect to periodontitis risk.

Kouyama R, Suganami T, Nishida J, Tanaka M, Toyoda T, Kiso M, Chiwata T, Miyamoto Y, Yoshimasa Y, Fukamizu A, Horiuchi M, Hirata Y, Ogawa Y. · Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. · Endocrinology. · Pubmed #15878965 links to  free full text

Abstract: Given that angiotensin II (AII) type 1 and 2 receptors (Agtr1 and Agtr2) are expressed in adipose tissue, AII may act directly on adipose tissue. However, regardless of whether AII directly modulates adipose tissue growth and metabolism in vivo and, if so, whether it is mediated via Agtr1 are still matters of debate. To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtr1a (Agtr1a-/- mice) during a high-fat diet. The Agtr1a-/- mice exhibited the attenuation of diet-induced body weight gain and adiposity, and insulin resistance relative to wild-type littermates (Agtr1a+/+ mice). They also showed increased energy expenditure accompanied by sympathetic activation, as revealed by increased rectal temperature and oxygen consumption, increased expression of uncoupling protein-1 mRNA in brown adipose tissue, and increased urinary catecholamine excretion. The heterozygous Agtr1a-deficient mice (Agtr1a+/- mice) also exhibited metabolic phenotypes similar to those of Agtr1a-/- mice. Using mouse embryonic fibroblasts derived from Agtr1a+/+ and Agtr1a-/- mice, we found no significant difference between genotypes in the ability to differentiate into lipid-laden mature adipocytes. In primary cultures of mouse mature adipocytes, AII increased the expression of mRNAs for some adipocytokines, which was abolished by pharmacological blockade of Agtr1. This study demonstrates that Agtr1a-/- mice exhibit attenuation of diet-induced weight gain and adiposity through increased energy expenditure. The data also suggest that AII does not affect directly adipocyte differentiation, but can modulate adipocytokine production via Agtr1.

Tanaka M, Takeyasu T, Fuku N, Fujita Y. · No affiliation provided · Nippon Ronen Igakkai Zasshi. · Pubmed #15387279 No free full text.

This publication has no abstract.

Tanaka M, Takeyasu T, Fuku N, Li-Jun G, Kurata M. · Department of Gene Therapy, Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. · Ann N Y Acad Sci. · Pubmed #15126279 No free full text.

Abstract: Polymorphisms in the human mitochondrial genome have been used for the elucidation of phylogenetic relationships among various ethnic groups. Because analysis by mitochondrial genetics has detected pathogenic mutations causing mitochondrial encephalomyopathy or cardiomyopathy, most of the mitochondrial single nucleotide polymorphisms (mtSNPs) found in control subjects have been regarded as merely normal variants. However, we cannot exclude the possibility that the mitochondrial functional differences among individuals are ascribable at least in part to the mtSNPs of each individual. Human lifespan in ancient history was much shorter than that at the present time. Therefore, it is reasonable to speculate that certain mtSNPs that predispose one toward susceptibility to adult- or elderly-onset diseases, such as Parkinson's disease and Alzheimer's disease, have never been a target for natural selection in the past. Similarly, thrifty mtSNPs that had been advantageous for survival under severe famine or cold climate conditions might turn out to be related to satiation-related diseases, such as diabetes mellitus and obesity. To examine these hypotheses, we have constructed a mtSNP database by sequencing the entire mitochondrial genomes of 672 subjects: 96 in each of seven groups (i.e., centenarians, young obese or non-obese subjects, diabetic patients with or without major vascular involvement, patients with Parkinson's disease, and those with Alzheimer's disease).

Miyakoshi K, Tanaka M, Matsumoto T, Hattori Y, Ueno K, Teranishi T, Minegishi K, Ishimoto H, Shimada A, Yoshimura Y. · Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. · Diabetes Res Clin Pract. · Pubmed #15126008 No free full text.

Abstract: We investigated the relationship between gestational glucose intolerance and the development of pregnancy-induced hypertension including gestational hypertension (GH) and preeclampsia. Consecutive Japanese women with singleton pregnancies underwent a standard 1h, 50g oral glucose challenge test (GCT) at 24-27 weeks of gestation, followed by a 75g, 2h oral glucose tolerance test (OGTT) if the GCT result exceeded 130mg/dl. Using criteria of the Japan Society of Obstetrics and Gynecology, gestational diabetes mellitus (GDM) was defined by two or more abnormal OGTT values and mild glucose intolerance by one abnormal value. The normal glucose tolerance group included women with GCT results below 130mg/dl or normal OGTT values. GH was defined as blood pressure of at least 140/90mmHg occurring for the first time after mid-pregnancy, without proteinuria. Preeclampsia was determined as GH with proteinuria. Of 2651 consecutive patients, 49 women were found to have GDM, and 139 showed mild glucose intolerance. Sixty patients showed GH, and 58 developed preeclampsia. The frequency of GH in mild glucose intolerance or GDM was 5.8% or 8.2%, respectively, significantly greater than in normal glucose tolerance (P<0.01). Incidence of preeclampsia was not significantly increased in women with mild glucose intolerance or GDM (2.2% or 4.1%, respectively, compared to those with normal glucose tolerance). Japanese women with gestational glucose intolerance therefore have an increased risk of developing GH.

Noshiro H, Shimizu S, Nagai E, Ohuchida K, Tanaka M. · Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. · Ann Surg. · Pubmed #14578729 links to  free full text

Abstract: OBJECTIVE: In this retrospective review, we evaluated the advantages and disadvantages of LADG for patients of heavier weight with early gastric cancer. SUMMARY BACKGROUND DATA: LADG has been used to treat early gastric cancer. We and others have reported less operative blood loss, less pain, early recovery of bowel activity, early restart of oral intake, and a shorter hospital stay with LADG compared with a conventional open method. There is, however, little information on the advantages of LADG for obese patients with early gastric cancer. METHODS: Between January 1996 and March 2002, 76 patients with preoperatively diagnosed early gastric carcinoma underwent LADG in our department. We classified these patients into 2 groups on the basis of body mass index (BMI). Nineteen patients had a high-BMI (>/= 24.2 kg/m2), and 57 patients had a normal-BMI (<24.2 kg/m2). We collected data by retrospectively reviewing the medical charts. RESULTS: Extension of the minilaparotomic incision or conversion to laparotomy was needed in 6 (32%) of the 19 patients in the high-BMI group, whereas only 3 (5%) of 57 patients in the normal-BMI group required either. In the high-BMI group, Roux-en-Y anastomosis rather than Billroth I anastomosis was adopted more often than in the normal-BMI group, due to the difficulty of the reconstruction (58% versus 4%, P = 0.001). Significantly longer operative time (370 +/- 61 minutes versus 317 +/- 58 minutes, P = 0.015) and prolonged recovery of bowel activity (3.5 +/- 1.0 days versus 2.6 +/- 1.0 days, P = 0.007) were observed in the patients in the high-BMI group. CONCLUSIONS: In the current study, LADG in patients of heavier weight was accompanied by more technical difficulties, and the disadvantages of longer operative time and delayed recovery of bowel activity was observed in patients of heavier weight. Heavier weight appears to be an ominous factor in the successful completion of LADG and should be considered in the decision to use LADG. There are still benefits of a decreased incidence of serious wound and hernia complications in successful cases.

Okura T, Koda M, Ando F, Niino N, Tanaka M, Shimokata H. · Department of Epidemiology, National Institute for Longevity Sciences, 36-3 Gengo Morioka-cho, Obu-shi, 474-8522, Aichi, Japan. · Hum Genet. · Pubmed #12905068 No free full text.

Abstract: Although polymorphism of the mitochondrial DNA 15497guanine/adenine (Mt15497G-->A) leads to the Gly251Ser amino acid replacement on human cytochrome b, it is unknown whether functional alteration of the mitochondrion is induced by the Gly251Ser replacement. To see if an association exists between the Mt15497G-->A polymorphism and obesity, we examined differences in body size, body composition, and regional body fat distribution between the two genotypes in middle-aged and elderly Japanese individuals (825 women and 906 men). The Mt15497 genotype was determined with an automated colorimetric allele-specific DNA probe assay system using the polymerase chain reaction (PCR) method. The Mt15497G-->A polymorphism was detected in 3.5% ( n=60) of all subjects: 2.8% ( n=23) among women and 4.1% ( n=37) among men. After adjusting for age and smoking, we found that body weight, body mass index, waist and hip circumferences, fat mass, fat-free mass, intra-abdominal fat and triglycerides were significantly greater in women with the A allele compared with the G allele ( p=0.001-0.025). For men, waist to hip ratio was significantly greater ( p=0.032), and waist circumference, intra-abdominal fat and triglycerides had a trend to be significantly greater ( p=0.062-0.087) in subjects with the A allele compared with the G allele. These data suggest that the Mt15497 polymorphism may be associated with obesity-related variables and lipid metabolism.