Obesity: Nakano T

Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T, Beysen C, Hellerstein MK, Berglund L, Havel PJ. · Department of Molecular Biosciences, UCD, Davis, California 95616, USA. · J Clin Invest. · Pubmed #19381015 links to  free full text

Abstract: Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Satoh N, Wada H, Ono K, Yamakage H, Yamada K, Nakano T, Hattori M, Shimatsu A, Kuzuya H, Hasegawa K. · Division of Metabolic Research, Clinical Research Institute for Endocrine and Metabolic Diseases, National Hospital Organization, Kyoto Medical Center, 1-1 Fukakusa, Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan. · Circ J. · Pubmed #18503219 links to  free full text

Abstract: BACKGROUND: Small dense low-density lipoprotein (sd-LDL) is an atherogenic lipoprotein closely associated with an increased risk of cardiovascular diseases. However, a precise analysis of the actual amount of sd-LDL-cholesterol (sd-LDL-C) in patients with metabolic syndrome (MS) has not been performed. Methods and RESULTS: Among 214 patients enrolled in the present study, 101 patients (47%) met the Japanese MS criteria. The serum levels of sd-LDL-C determined with a dual detection HPLC system were higher in MS than non-MS patients, while total cholesterol and low-density lipoprotein-cholesterol (LDL-C) were similar between MS and non-MS patients. Compared with the sd-LDL-C and LDL-C level, the ratio sd-LDL-C/LDL-C was more closely correlated with various parameters associated with MS. A multivariate regression analysis revealed that the ratio sd-LDL-C/LDL-C is the strongest independent determinant of hypoadiponectinemia. Furthermore, weight reduction therapy through diet and exercise rapidly decreased LDL-C but slowly decreased sd-LDL-C. At 12 months after the therapy, weight reduction led to a significant decrease in the ratio sd-LDL-C/LDL-C in tandem with increasing adiponectin levels. CONCLUSIONS: These findings demonstrate that the ratio sd-LDL-C/LDL-C is tightly connected with hypoadiponectinemia and provides a useful clinical indicator for MS. The results also suggest that the elevation of this ratio can be modulated by long-term lifestyle changes.

Nakano T, Inoue I, Koyama I, Kanazawa K, Nakamura K, Narisawa S, Tanaka K, Akita M, Masuyama T, Seo M, Hokari S, Katayama S, Alpers DH, Millán JL, Komoda T. · Dept. of Biochemistry, Faculty of Medicine, Faculty of Health and Medical Care, Saitama Medical Univ., Saitama, Japan 350-0495. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #17332477 links to  free full text

Abstract: Intestinal alkaline phosphatase (IAP) is involved in the process of fat absorption, a conclusion confirmed by an altered lipid transport and a faster body weight gain from 10 to 30 wk in both male and female mice with a homozygous null mutation of the IAP coding gene (Akp3(-/-) mice). This study was aimed to delineate morphologically and quantitatively the accelerated lipid absorption in male Akp3(-/-) mice. Feeding a corn oil bolus produced an earlier peak of triacylglycerol in serum (2 vs. 4 h for Akp3(-/-) and wild-type mice, respectively) and an approximately twofold increase in serum triacylglycerol concentration in Akp3(-/-) mice injected with a lipolysis inhibitor, Triton WR-1339. A corn oil load induced the threefold enlargement of the Golgi vacuoles in male wild-type mice but not in Akp3(-/-) mice, indicating that absorbed lipids rarely reached the Golgi complex and that the transcytosis of lipid droplets does not follow the normal pathway in male Akp3(-/-) mice. Force feeding an exaggerated fat intake by a 30% fat chow for 10 wk induced obesity in both male Akp3(-/-) and wild-type mice, and therefore no phenotypic difference was observed between the two. On the other hand, the forced high-fat chow induced an 18% greater body weight gain, hepatic steatosis, and visceral fat accumulation in female Akp3(-/-) mice but not in female wild-type controls. These results provide further evidence that IAP is involved in the regulation of the lipid absorption process and that its absence leads to progressive metabolic abnormalities in certain fat-forced conditions.

Nakano T, Shinka T, Sei M, Sato Y, Umeno M, Sakamoto K, Nomura I, Nakahori Y. · Department of Human Genetics and Public Health, Institute of Health Biosciences, The University of Tokushima Graduate School. · J Med Invest. · Pubmed #16953057 links to  free full text

Abstract: UCP-1 is suggested to have important roles for thermogenesis and energy expenditure. To elucidate whether the A-3826G polymorphism that is located in the 5' flanking region of the UCP-1 gene has roles in healthy young people, the polymorphism was genotyped among 251 young Japanese men whose mean age is 22.7 years old. We analyzed relationship between the A-3826G polymorphism and body mass index (BMI) or six biochemical parameters, serum concentration of total cholesterol (TC), high density lipoprotein (HDL) cholesterol, triglyceride (TG), asparatate aminotransferase (AST), alanine aminotransferase (ALT), fasting plasma glucose. The genotype frequencies were observed at the frequencies of 24.3% for AA, 48.2% for AG and 27.5% for GG, respectively. When BMI and the biochemical parameters were compared by ANOVA among individuals with each genotype, the statistical difference was observed only for BMI (P=0.016). Bonferroni's test demonstrated that the men with the AG genotype have higher BMI than those with the AA genotype (22.4+/-2.8 vs. 21.4+/-2.2) (P=0.04). The individuals with the AG genotype also showed trend to have higher BMI than those with the GG, although the difference was not statistically apparent (22.4+/-2.8 vs. 21.5+/-2.3) (P=0.07). Our results indicated that the young healthy Japanese men with the AG heterozygote showed higher BMI than those with other genotypes.

Yamada N, Nakamura M, Ishikura K, Ota M, Yazu T, Hiraoka N, Tanaka H, Ito M, Fujioka H, Isaka N, Nakano T. · The 1st Department of Internal Medicine, Mie University, Tsu, Japan. · Int Angiol. · Pubmed #12771856 No free full text.

Abstract: AIM: In Japan, acute pulmonary thromboembolism (APTE) is still rare, but the number of patients with APTE has been steadily increasing. It is important for early diagnosis and early management of APTE to recognize epidemiological characteristics of this condition. METHODS: We investigated the epidemiological characteristics of 252 patients with APTE who were admitted to our institutions between 1975 and 2001. APTE was more prevalent in women that in men. It was observed the most in the age group between 50s to 70s, especially in women. Many patients had prolonged immobilization, recent major operation, obesity, or cancer, as risk factors for venous thromboembolism. One hundred and thirty-eight patients developed APTE in hospital; 60 patients were in Department of Internal Medicine, 28 in General Surgery, 15 in Orthopedics, 15 in Obstetrics and Gynecology, and 20 in other services. RESULTS: Among 58 patients with malignancy, 43% had cancers in digestive organs, 21% in gynecological, and 17% in urological. Among 61 patients who were examined for the presence of thrombophilia, 13 patients had inherited thrombophilia (8 protein C deficiency, 4 protein S deficiency, and 1 antithrombin III deficiency) 11 had antiphospholipid antibodies which indicated thrombophilia. Five out of the above 61 patients (8%) had no obvious risk factors including thrombophilia. CONCLUSION: The findings in our patients were almost the same as those in Western patients, except for some points. These results might be useful to establish a preventive approach for APTE in Japan.

Tamada H, Nishikawa H, Mukai S, Setsuda M, Nakamura M, Suzuki H, Oonishi T, Kakuta Y, Yeung AC, Nakano T. · The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. · Circ J. · Pubmed #12736481 links to  free full text

Abstract: Constrictive remodeling occurs in significant atherosclerotic lesions of the diabetic patient, but the impact of diabetes mellitus (DM) on the angiographically normal coronary artery is still unclear. Morphometric analysis using intravascular ultrasound (IVUS) prior to intervention evaluated 54 sites in 33 DM patients and 106 in 62 non-diabetic patients. Vessel area (VA) and lumen area (LA) were measured at angiographically normal sites in the vessel. Plaque area (PA) was calculated as VA - LA. Percentage plaque area (%PA) was calculated as PA VA. Even in the angiographically normal site, mild coronary atherosclerosis was detected by IVUS in both groups. In the patients with DM, VA and LA were significantly smaller than in the non-diabetic patient (15.5 vs 17.8 mm(2), p<0.01; and 10.1 vs 12.2 mm(2), p<0.01 respectively), whereas % PA was similar (34.5 vs 31.6%). At angiographically normal sites where mild coronary atherosclerosis is detected by IVUS, the coronary artery of diabetic patients is smaller than that of the non-diabetic. These results suggest impaired compensatory enlargement or some other constrictive mechanism has already occurred in the early stages of coronary atherosclerosis in patients with DM.

Nakamura M, Fujioka H, Yamada N, Sakuma M, Okada O, Nakanishi N, Miyahara Y, Kuriyama T, Kunieda T, Sugimoto T, Nakano T. · The First Department of Internal Medicine, Mie University, Tsu, Japan. · Clin Cardiol. · Pubmed #11214743 No free full text.

Abstract: BACKGROUND: Although the incidence of acute pulmonary thromboembolism (APTE) has been increasing in Japan, patient characteristics, management strategies, and outcome have not yet been assessed in large series. HYPOTHESIS: The present study was designed to investigate the current status of APTE in Japan. METHODS: Of a total of 533 registry patients with pulmonary thromboembolism, 309 with APTE were analyzed with respect to clinical symptoms and signs, predisposing factors, diagnostic procedures, estimation of deep venous thrombosis, treatment, and clinical course. RESULTS: Main risk factors were recent major surgery, cancer, prolonged immobilization, and obesity; only a few patients had coagulopathy and 36% were in cardiogenic shock at presentation. The majority of registry patients underwent lung scans or pulmonary angiography; 30% were diagnosed only by lung scanning. Venous ultrasonography was used in only 34 patients, while 188 patients underwent at least one diagnostic procedure for deep venous thrombosis. Thrombolysis was more frequently performed in patients with cardiogenic shock, and only a few patients received thromboembolectomy. In-hospital mortality rate was 14%. In patients with cardiogenic shock, the mortality rate was reduced by thrombolysis. The predictors of in-hospital mortality were male gender, cardiogenic shock, cancer, and prolonged immobilization. CONCLUSIONS: The patients in this registry had almost the same findings as those in Western patients, except for some points that had the possibility of demonstrating a difference between Westerners and Japanese in the development of APTE. These results can prove especially helpful in planning prospective, randomized trials that will clarify the impact of widely used treatment modalities on the outcome of patients with APTE.

Komazawa N, Matsuda M, Kondoh G, Mizunoya W, Iwaki M, Takagi T, Sumikawa Y, Inoue K, Suzuki A, Mak TW, Nakano T, Fushiki T, Takeda J, Shimomura I. · Department of Social and Environmental Medicine, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, Osaka, Japan. · Nat Med. · Pubmed #15489860 No free full text.

Abstract: Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.