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Toshihiko Hashinaga,
Nobuhiko Wada,
Shuichi Otabe,
Xiaohong Yuan,
Yayoi Kurita,
Satomi Kakino,
Kayo Tanaka,
Takahiro Sato,
Masayasu Kojima,
Tsuyoshi Ohki, Hitomi Nakayama,
Tomoka Egashira,
Yuji Tajiri,
Kentaro Yamada
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ABSTRACT: To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.
Endocrine Journal 12/2012; · 2.03 Impact Factor
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S Otabe,
N Wada,
T Hashinaga,
X Yuan,
I Shimokawa,
T Fukutani,
K Tanaka,
T Ohki,
S Kakino,
Y Kurita, H Nakayama,
Y Tajiri,
K Yamada
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ABSTRACT: We previously reported that transgenic (Tg) expression of adiponectin significantly prolonged the lifespan of normal mice. The aim of this study was to elucidate the mechanism involved in the longevity effects of adiponectin using KK/Ta mice, a murine model of metabolic syndrome. We established a Tg line of KK/Ta (Tg-KK/Ta) mice expressing human adiponectin in the liver, and assessed their lifespan. The cause of death was determined by macroscopic and microscopic examinations immediately after death. The expressions of SIRT1, C-reactive protein (CRP), inflammatory cytokines, AMPK, and AKT were measured by quantitative real-time PCR, ELISAs, and/or western blotting. KK/Ta mice had lower serum adiponectin levels and shorter lifespan (57.6±13.9 vs 106.5±18.3 weeks, P<0.0001) than C57BL/6N mice. Tg adiponectin expression significantly extended the lifespan of KK/Ta mice (73.6±16.6 weeks, P<0.001) without affecting body weight, daily food consumption, or plasma glucose levels. Neoplasms were observed in only three of 22 KK/Ta mice that died spontaneously because of tumors. Atherosclerotic lesions were not detected in any mice. SIRT1 levels were not significantly different between KK/Ta and Tg-KK/Ta mice. Gene expressions of Crp, Tnfα, Il6, and Nfκb were increased in KK/Ta mice, but they were significantly attenuated in Tg-KK/Ta mice. Phosphorylated AMPK levels were increased and phosphorylated AKT levels were decreased in Tg-KK/Ta mice. The anti-inflammatory effects of adiponectin, achieved by inhibiting the AKT signaling pathway, may explain how adiponectin slows the accelerated aging process associated with the metabolic syndrome.
Journal of Endocrinology 01/2012; 213(1):67-76. · 3.55 Impact Factor
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Takato Ueno,
Anna Nakamura, Hitomi Nakayama,
Shuichi Otabe,
Xiaohong Yuan,
Tomoka Fukutani,
Hideki Iwamoto,
Toru Nakamura,
Hironori Koga,
Takuji Torimura,
Michio Sata,
Kentaro Yamada
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ABSTRACT: In this study, we examined whether adiponectin suppresses endoplasmic reticulum (ER) stress in nonalcoholic steatohepatitis (NASH) using male transgenic mice expressing nSREBP-1c in adipose tissue, nSREBP-1c/adiponectin double-transgenic mice expressing human adiponectin in the liver, and wild-type male mice as the control. Histological findings similar to those observed in liver specimens from patients with NASH were observed in the livers from the nSREBP-1c transgenic mice at 30 weeks of age. By contrast, the NASH-like liver histology was markedly attenuated in age-matched nSREBP-1c/adiponectin double-transgenic mice. The nSREBP-1c/adiponectin double-transgenic mice showed human adiponectin production in the liver and a restored circulating human adiponectin level. Human adiponectin messenger ribonucleic acid (mRNA) expression in the liver was identified in the nSREBP-1c/adiponectin double-transgenic mice, but adiponectin receptor 1 and 2 mRNA expression in the liver was normal. TNFα mRNA was decreased in the liver of the nSREBP-1c/adiponectin double-transgenic mice compared with the nSREBP-1c transgenic mice. The protein expressions of X-box-binding protein-1, activating transcription factor 4, acetyl-CoA carboxylase, TNFα and NFκB were down-regulated in liver tissues from the nSREBP-1c/adiponectin double-transgenic mice. Mouse adiponectin and activating transcription factor 6 expressions were almost the same in the three groups. Post-load plasma glucose levels were significantly lower in the nSREBP-1c/adiponectin double-transgenic mice compared with the nSREBP-1c transgenic mice. These results indicate that adiponectin expressed in the liver suppresses ER stress and attenuates hepatic steatosis, inflammation and insulin resistance in NASH. Adiponectin may open the way to novel therapies for human NASH.
Experimental and therapeutic medicine 01/2011; 2(6):1035-1040.
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ABSTRACT: Introduction: The aim of the present study is to propose a novel index of insulin sensitivity instead of homeostasis model assessment of insulin resistance (HOMA-IR), which has a fundamental limitation of validity when applied to subjects with lower insulin secretions or high fasting plasma glucose (FPG) levels.Materials and Methods: A total of 25 apparently healthy subjects and 24 patients with type 2 diabetes participated in the study. We assessed relationships of glucose infusion rate (GIR), obtained by using the euglycemic hyperinsulinemic glucose clamp technique, with other measurements of metabolic and anthropometric parameters.Results: In multiple regression analysis, a model including log-transformed (log) triglyceride/log high-density lipoprotein cholesterol and waist circumference as predictive variables showed the strongest contribution rate to explain GIR as an outcome variable (R2 = 0.710). The validity of estimated GIR (EGIR) calculated from the regression equation composed of these factors was further tested in another group of patients including type 1, type 2 and pancreatic diabetes in whom HOMA-IR could not be used as a result of either high FPG or low fasting insulin level, or both. Even in those patients, EGIR showed a good positive relationship with measured GIR (r = 0.681, P < 0.0001).Conclusions: The proposed index without HOMA-IR can adequately show insulin sensitivity in Japanese diabetic patients, even in cases with the limitation of HOMA-IR application. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00076.x, 2010)
Journal of Diabetes Investigation. 10/2010; 2(2):140 - 147.
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ABSTRACT: The aim of the present study was to evaluate characteristics of body composition in Japanese patients with type 2 diabetes.
Measurement of regional body composition was performed using bioelectrical impedance analysis (INBODY720) in 198 patients with type 2 diabetes (group D) and 198 apparently healthy subjects matched for age, gender, and body mass index (BMI) (group C), together with measurements of metabolic parameters.
The percentage of skeletal muscle of whole body (M%) and in lower extremities (leg M%) was significantly lower in group D than that in group C. These sarcopenic features were manifest in patients with longer durations of diabetes or lack of exercise. M% and leg M% in diabetic patients were negatively correlated with the log-transformed triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio, a marker of insulin resistance and atherosclerosis risk. Furthermore, reduced leg M% was significantly correlated with increasing numbers of risk factors for cardiovascular disease (CVD).
Because this distinctive feature of body composition becomes more evident as duration of diabetes is longer and less marked in patients with habitual exercise, early intervention, such as the instruction of exercise including resistance training, seems to be worthwhile for the prevention of future burdens in these patients.
Metabolic syndrome and related disorders 11/2009; 8(2):137-42.
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Shuichi Otabe, Hitomi Nakayama,
Tomoka Fukutani,
Xiaohong Yuan,
Nobuhiko Wada,
Toshihiko Hashinaga,
Akiko Mitsui,
Tomoko Kato,
Chizuko Inada,
Yuji Tajiri,
Kentaro Yamada
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ABSTRACT: The aim of the study is to identify the clinical characteristics of Japanese patients with young-onset type 2 diabetes (YT2D). Family history of diabetes and clinical data were collected for 30 unrelated males (from 11 to 20 years old at age of onset) and 20 females (from 10 to 20 years old at age of onset) with YT2D diagnosed at ≤ 20 years of age. Fasting C-peptide levels were measured in all, and glucagon stimulation tests were performed twice in six of them over several years. Moreover, 858 people with type 2 diabetes (T2D) diagnosed at >20 years of age were randomly recruited in order to compare the transmission pattern of them. Among the study subjects, 68% reported at least one parent with diabetes. Diabetes was more frequent among mothers than fathers of probands (P = 0.020), although this tendency was not observed in T2D diagnosed at >20 years of age. Fasting C-peptide levels of patients with diabetes duration of ≥ 10 years were significantly lower than for patients with diabetes duration of <10 years (0.61 ± 0.26 vs. 0.84 ± 0.43 nmol/l, P = 0.036). The fasting C-peptide levels among male patients with a family history of diabetes were also significantly lower than those without a family history (0.56 ± 0.25 vs. 0.83 ± 0.37 nmol/l, P = 0.034), while all female subjects had a family history of diabetes. Glucagon stimulation tests showed the following data; 0 min: 0.56 ± 0.31 vs. 0.39 ± 0.22 nmol/l, 3 min: 1.41 ± 0.77 vs. 0.87 ± 0.47 nmol/l, 6 min: 1.37 ± 0.80 vs. 0.79 ± 0.35 nmol/l, 10 min: 1.06 ± 0.60 vs. 0.81 ± 0.49 nmol/l, and 30 min: 0.58 ± 0.30 vs. 0.50 ± 0.19 nmol/l, respectively. These results demonstrated that YT2D among Japanese people occurring in excess with maternal transmission is associated with β-cell dysfunction at the onset of diabetes and as the disease advances.
Acta Diabetologica 09/2009; 47(Suppl 1):133-8. · 2.78 Impact Factor
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Takato Ueno,
Takuji Torimura,
Toru Nakamura,
Ramadoss Sivakumar, Hitomi Nakayama,
Syuichi Otabe,
Xiaohong Yuan,
Kentaro Yamada,
Osamu Hashimoto,
Kinya Inoue,
Hironori Koga,
Michio Sata
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ABSTRACT: We examined whether or not epigallocatechin-3-gallate (EGCG) improves liver injury of nonalcoholic steatohepatitis (NASH) model mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue. nSREBP-1c transgenic C57BL6 mice aged 30 weeks were divided into group 1 (no treatment), group 2 (ascorbic acid alone), group 3 (ascorbic acid and 0.05% EGCG), and group 4 (ascorbic acid and 0.1% EGCG). At 42 weeks, we performed measurement of liver weight to body weight, biochemical assays, morphometry of liver specimens, immunohistochemistry for 8-hydro-2'-deoxyguanosine (8-OhdG), and Western blotting for insulin and TNF-alpha signalings. Ratio of liver weight to body weight in the high dose EGCG-treated group (group 4) was significantly lower than those of groups 1 and 2 (p<0.05 and <0.01, respectively). Blood ALT, glucose, total cholesterol, and triglyceride levels of group 4 were significantly low compared with those of the EGCG-non-treated group (groups 1 and 2) (p<0.05, respectively). The degrees of steatosis, inflammation, ballooning hepatocytes and Mallory-Denk bodies in group 4 significantly improved compared with those in other groups (p<0.05, respectively). The 8-OhdG immunolocalization in liver tissues of the group 4 obviously decreased compared with those of groups 2 and 3. For Western blotting, the expressions of insulin receptor substrate-1 (IRS-1) and phosphorylated IRS-1 (pIRS-1) in liver tissues of group 4 increased compared with those of groups 2 and 3. On the other hand, the expressions of pAkt, pIKKbeta and pNF-kappaB decreased compared with those of groups 2 and 3. From these results, EGCG reduces inflammation, insulin resistance and oxidative stress, and suppresses liver injury in nSREBP-1c transgenic mice.
International Journal of Molecular Medicine 07/2009; 24(1):17-22. · 1.98 Impact Factor
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ABSTRACT: We have previously reported that transgenic mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue under the control of aP2 promoter, an inherited lipodystrophic model with insulin resistance and fatty liver, developed with age liver lesions similar to those of human nonalcoholic steatohepatitis (NASH). Because the spontaneous NASH model mice had marked hypoadiponectinemia, here we assessed the effect of adiponectin transgenically expressed in the liver of nSREBP-1c transgenic mice. The nSREBP-1c/adiponectin double-transgenic mice showed hepatic adiponectin production and restored circulating adiponectin levels. Both subtypes of adiponectin receptors proved to be expressed normally in the liver. Peroxisome proliferator-activated receptor-alpha was up-regulated in the double-transgenic mice. Histologic findings similar to those observed in the liver specimens of patients with NASH were observed in the livers from nSREBP-1c transgenic mice at the age of 30 weeks. In contrast, the NASH-like hepatic lesions were obviously attenuated in age-matched double-transgenic mice. Immunoreactivity of 8-hydroxy-2'-deoxyguanosine and proliferating cell nuclear antigen-positive cells were increased in nSREBP-1c transgenic mice, but not in the double-transgenic mice. Postload plasma glucose levels were significantly lower in the double-transgenic mice compared with nSREBP-1c transgenic mice, whereas serum leptin levels did not differ significantly in the 2 groups. These observations suggest that hypoadiponectinemia plays a key role in the pathogenesis of NASH associated with insulin resistance and may provide a clue to the novel therapy for human NASH.
Metabolism: clinical and experimental 05/2009; 58(7):901-8. · 2.59 Impact Factor
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ABSTRACT: We aimed to define the detailed clinical features of Japanese childhood-onset Type 2 diabetes mellitus (T2DM) patients who were followed-up, and to determine whether discernable characteristics were dissimilar or not from those of adult- and childhood-onset T2DM in other countries. Subjects were 22 patients (10 males and 12 females) under treatment without HNF-1alpha or mitochondrial gene mutations, and who were apparently diagnosed as diabetic when less than 15 years of age. Body mass indexes at onset in boys and girls were 25.8 +/- 6.3 and 24.7 +/- 3.6, respectively, with mean ages 13.3 +/- 1.7 and 12.8 +/- 2.0 years, respectively. Most patients had a short diabetic duration that required insulin treatment. One or both parents of 18 of the 22 T2DM subjects were diabetic and 7 subjects had a history of diabetes in their family across three generations. We demonstrated that a relatively large number of Japanese childhood-onset T2DM cases have a strong genetic factor, and are not necessarily related to excessive obesity. Furthermore, most required insulin therapy in the initial stages because of insufficient pancreatic beta-cell reserves. This suggests that malfunction of pancreatic beta-cells triggers hyperglycemia resulting in the requirement for insulin in Japanese some childhood-onset T2DM patients.
Acta Diabetologica 01/2008; 44(4):181-5. · 2.78 Impact Factor
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ABSTRACT: Adiponectin, a physiologically active polypeptide secreted by adipocytes, shows insulin-sensitizing, anti-inflammatory, and antiatherogenic properties in rodents and humans. To assess the effects of chronic hyperadiponectinemia on metabolic phenotypes, we established three lines of transgenic mice expressing human adiponectin in the liver. When maintained on a high-fat/high-sucrose diet, mice of two lines that had persistent hyperadiponectinemia exhibited significantly decreased weight gain associated with less fat accumulation and smaller adipocytes in both visceral and subcutaneous adipose tissues. Macrophage infiltration in adipose tissue was markedly suppressed in the transgenic mice. Expression levels of adiponectin receptors were not altered in skeletal muscle or liver. Circulating levels of endogenous adiponectin were elevated, whereas fasting glucose, insulin, and leptin levels were reduced compared with control mice. In the hyperadiponectinemic mice daily food intake was not altered, but oxygen consumption was significantly greater, suggesting increased energy expenditure. Moreover, high-calorie diet-induced premature death was almost completely prevented in the hyperadiponectinemic mice in association with attenuated oxidative DNA damage. The transgenic mice also showed longer life span on a conventional low-fat chow. In conclusion, transgenic expression of human adiponectin blocked the excessive fat accumulation and reduced the morbidity and mortality in mice fed a high-calorie diet. These observations may provide new insights into the prevention and therapy of metabolic syndrome in humans.
AJP Endocrinology and Metabolism 07/2007; 293(1):E210-8. · 4.75 Impact Factor
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ABSTRACT: Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases associated with insulin resistance. Here we report that nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) transgenic mice, an inherited lipodystrophic model with severe insulin resistance, spontaneously develop steatohepatitis. The animal had marked fatty liver accompanied by hyperglycemia, hypoleptinemia, and hypoadiponectinemia. Liver histology similar to NASH, that is, mononuclear cell infiltration, pericellular fibrosis, ballooning degeneration, and Mallory hyaline body formation were seen in the livers from transgenic mice 20 weeks or older. In contrast, no liver histologic abnormalities were noted in wild-type mice aged 30 weeks. Immunoreactive 8-hydroxy-2'-deoxyguanosine was observed in the nuclei of livers from transgenic mice, suggesting that in addition to insulin resistance, oxidative stress may be involved in the development of the NASH-like lesion. Thus, the nSREBP-1c transgenic mouse may serve as a unique model of spontaneously occurring NASH.
Metabolism 05/2007; 56(4):470-5. · 2.66 Impact Factor
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ABSTRACT: To assess the mechanism of beta-cell lipotoxicity in comparison with Fas-mediated cell death, we used a mouse beta-cell clone stably transfected with human Fas. Palmitate induced beta-cell death in correlation with medium glucose levels between 5 and 20 mmol/l, while Fas-mediated cytotoxicity was observed irrespective of glucose concentration. At the glucose level of 10 mmol/l, palmitate induced caspase-6 activity within 3 h, and caspase-3 activity after a lag period of 6 h. The activities of caspases were correlated with glucose concentration. A caspase-6 inhibitor attenuated caspase-3 activation and cell death induced by palmitate. Oxfenicine, an inhibitor of carnitine palmitoyltransferase-1, attenuated both palmitate-induced cytotoxicity and activation of caspases. Finally, beta-cell cytotoxicity caused by the combination of anti-Fas and palmitate at 25 mmol/l of glucose was greater than the sum of those induced by each. These observations suggest that palmitate induces sequential activation of caspase-6 and caspase-3 through a mitochondrial signal(s), and caspase-6 plays a primary role in the mechanism. Fas-mediated beta-cell death and lipotoxicity may share common mechanisms involving caspase activation, and thereby synergistically inducing beta-cell death, although upstream signaling pathways are distinct.
Life Sciences 09/2006; 79(13):1312-6. · 2.53 Impact Factor
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ABSTRACT: A 46-year-old man presented with frontal headache, a visual field defect and general fatigue. Magnetic resonance imaging (MRI) of the brain showed symmetrical enlargement of the pituitary gland and stalk due to the presence of a mass lesion extending toward the optic chiasm. Gadolinium injection further revealed homogeneous strong enhancement with involvement of the adjacent dura (dural tail). Basal plasma levels of ACTH, free thyroxine and gonadotropins were decreased, and 24-h urinary 17-OHCS excretion was reduced. An elevated anti-thyroglobulin antibody titer indicated the presence of autoimmune thyroiditis. Under the suspicion of autoimmune hypophysitis, 60 mg/day prednisolone sodium succinate was intravenously administered for two weeks followed by a decreasing dose of oral prednisolone. Clinical symptoms and pituitary dysfunction recovered during steroid treatment and MRI showed marked shrinkage of the pituitary mass. Early initiation of an intravenous dose of glucocorticoid followed by oral steroid administration therefore seems to be an efficient treatment for autoimmune hypophysitis even in patients with visual dysfunction.
Internal Medicine 02/2006; 45(21):1249-52. · 0.94 Impact Factor
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ABSTRACT: Graves' disease (GD) is an autoimmune disorder with genetic predisposition. IL-13 is an important mediator of antiinflammatory immune responses and is expressed in the thyroid and orbit. The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD. IL-13 gene polymorphisms were studied in Japanese GD patients (n = 310) and healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders (n = 244). A C/T polymorphism at position -1112 of the promoter region was measured using the direct sequencing method, and an Arg(130)Gln (G2044A) polymorphism in exon 4 was examined using the PCR-restriction fragment length polymorphism method. There was a significant decrease in -1112T allele frequency in GD patients compared with controls (16% vs. 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the -1112T/2044A haplotype in GD patients. There was no association between IL-13 gene polymorphisms and ophthalmopathy, severity, or serum IgE levels. In conclusion, IL-13 gene polymorphisms are associated with GD susceptibility in Japan.
Journal of Clinical Endocrinology & Metabolism 02/2005; 90(1):296-301. · 6.50 Impact Factor
